FDA Briefing Document Nonprescription Drugs Advisory Committee Meeting

Transcription

1 FDA Briefing Document Nonprescription Drugs Advisory Committee Meeting Montelukast (Singulair Allergy) NDA Proposed Indication: Temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: nasal congestion runny nose itchy, watery eyes sneezing itching of the nose Topic: Risk/Benefit Considerations for Use of Montelukast as an OTC Allergy Symptom Reliever Meeting Date: May 2, of 207

2 Disclaimer Statement The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought the application for montelukast to this Advisory Committee in order to gain the Committee s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 of 207

3 Table of Contents 1 Draft Topics for Advisory Committee Discussion Division Director Memorandum. 5 Page 3 Review Findings 3.1 Overview of Regulatory Background and Clinical Trials Statistical Assessment of Efficacy Overview of Post-marketing Experience Pharmacovigilance Update Literature Update on Risk of Suicide Association Drug Use Update Consumer Studies Appendix 1 Prescription Label 174 Appendix 2 Proposed Carton Label 199 Appendix 3 Proposed Drug Facts Label and Consumer Information Leaflet of 207

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5 Date: April 3, 2014 DIVISION DIRECTOR MEMORANDUM From: To: Subject: Theresa M. Michele, MD Director Division of Nonprescription Clinical Evaluation CDER, FDA Members, Nonprescription Drugs Advisory Committee Overview of the FDA background materials for New Drug Application (NDA) 204,804, montelukast 10 mg tablets for the over the counter (OTC) use to temporarily relieve symptoms due to hay fever or other respiratory allergies in adults 1 INTRODUCTION Thank you for your participation in the joint Nonprescription Drugs Advisory Committee (NDAC) meeting to be held on May 2, As members of the Advisory Committee (AC) you provide important expert scientific advice and recommendations to the US Food and Drug Administration (the Agency) on the regulatory decision making process related to the approval of a drug for over-the-counter (OTC) marketing in the United States. The upcoming meeting is to discuss the New Drug Application (NDA) from MSD Consumer Care (Merck), seeking approval for montelukast (proposed trade name Singulair Allergy), at a once daily dose of 10 mg for OTC use for the temporary relief of symptoms due to hay fever or other respiratory allergies in adults, including nasal congestion, runny nose, itchy, watery eyes, sneezing, and itching of the nose. Montelukast (trade name Singulair) is approved as a prescription product in adults and children for the treatment of asthma (12 months of age and older), prevention of exerciseinduced bronchospasm (EIB; 6 years of age and older), relief of symptoms of allergic rhinitis including seasonal allergic rhinitis (SAR; 2 years of age and older) and perennial allergic rhinitis (PAR; 6 months of age and older). The prescription dosage is 10 mg (film coated tablet) for adults and adolescents aged 15 years and older, 5 mg (chewable tablet) for children aged 6-14 years, 4 mg (chewable tablet) for children aged 2-5 years, and 4 mg (oral granules sprinkle ) for infants aged 6 months to 2 years. Under this partial prescription to OTC switch, the sponsor proposes that use in children under 18 years of age and the indications for treatment of asthma and EIB would remain prescription. If approved, this would be a first-in-class prescription to OTC switch for a leukotriene receptor antagonist. The indication that the sponsor is proposing relief of symptoms due to hay fever or other respiratory allergies in adults is consistent with other OTC products available for treatment of allergic rhinitis. However, the sponsor is also proposing to include itchy, watery eyes, the indication for the treatment of ocular allergy symptoms, which would represent a new 5 of 207 1

6 indication for montelukast. The current prescription labeling does not include a claim for ocular symptoms. Merck s OTC development program for montelukast relies on the safety and efficacy established for the prescription product, since the allergic rhinitis indication is considered to be similar for both prescription and OTC use. To support the new indication for ocular allergy symptoms, Merck submitted the results of three SAR trials, which were previously reviewed as part of the prescription AR program. In addition, the OTC indication is supported by three consumer studies one self-selection and label comprehension study in adults, one self-selection and label comprehension study in adolescents aged years, and one targeted label comprehension study in adults focusing on neuropsychiatric events. A review of safety data was submitted including clinical trial data and post-marketing data from the time of first worldwide marketing approval in July of 1997 through March This memorandum provides an overview of the original NDA submission. The content of this document and the materials prepared by the Agency contain findings and opinions based on reviews of information submitted by Merck. These represent preliminary findings and do not represent the final position of the Agency. An important piece in our decision on this application will be the opinions and input that we receive at this AC meeting. The materials to be discussed at this AC meeting and the opinions we are seeking are primarily related to the efficacy and safety of montelukast for the relief of symptoms of allergic rhinitis in the OTC setting, including information regarding the proposed ocular symptom indication, and the proposed Drug Facts Label. Factors to consider for these discussions include potential off-label use in patients with asthma, implications for the pediatric population, and neuropsychiatric adverse events. In the regulatory decision making process to determine approvability of a product, the Agency takes into consideration various other factors in addition to clinical and statistical issues, including manufacturing and controls of a product and preclinical considerations. These will not be the focus of this AC meeting. Attached are the background materials for this meeting. In addition to this memorandum, the FDA background materials include reviews of clinical trial results, statistical assessment of efficacy, post-marketing safety (clinical, pharmacovigilance epidemiology, and drug use data), and consumer studies. The approved prescription label, proposed Drug Facts Label, and the proposed Package Insert are also included. 2 BACKGROUND 2.1 Allergic rhinitis Allergic rhinitis is a common IgE-mediated inflammatory condition characterized by one or more of the following symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching. Symptoms may significantly affect quality of life, and may be associated with sleep disturbance, fatigue, headache, cognitive impairment. Traditionally, allergic rhinitis is divided into two subsets, SAR and PAR, depending on the aeroallergens involved and persistence of symptoms. Although estimates vary, allergic rhinitis may affect as many as 6 of 207 2

7 30-60 million people in the US, including 10-30% of adults and up to 40% of children. 1 Because the conditions share a common pathophysiology, there is considerable overlap between allergic rhinitis and asthma, with 10-40% of patients with allergic rhinitis having coexisting asthma. 1 Conversely, up to 90% of asthmatics have concomitant allergic rhinitis. This overlap and the fact that montelukast is indicated for and predominantly prescribed for asthma raises the question as to whether consumers will use this product to treat asthma symptoms, and if such use would lead to adverse asthma outcomes due to stopping other asthma medications or failing to follow up with health care providers for asthma. Allergic rhinitis is a well-established OTC indication, with both monograph and NDA OTC products, available in a variety of intranasal and oral formulations. These include first and second generation oral antihistamines, oral antihistamine/decongestant combination products, intranasal decongestants, and intranasal cromolyn. In addition, in October 2013, FDA approved the first intranasal corticosteroid as a prescription to OTC switch. Professional guidelines for the treatment of adults with allergic rhinitis recommend nasal steroids as first line therapy for moderate-severe disease with or without a second generation antihistamine. Montelukast is frequently used as add on therapy or in select patients with both allergic rhinitis and asthma. 1 The chewable tablet dosage form also makes it an attractive therapy for children. Whether inappropriate use of the 10 mg OTC tablet may occur in adolescents and children given the pediatric indications and frequent prescription use in children is a topic for your consideration. The standard OTC indication language for allergic rhinitis, covering the prescription indications for both SAR and PAR, is derived from the OTC monograph indication for first generation antihistamines temporarily relieves runny nose and sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever or other upper respiratory allergies. 2 For products that are approved via the NDA pathway, ocular symptoms are considered to be a separate indication from allergic rhinitis, as the primary endpoint for allergic rhinitis trials focuses on total nasal symptom scores. Montelukast was approved for SAR and PAR based on nasal symptoms and does not carry a claim for ocular symptoms in the prescription label. 2.2 Asthma Asthma is a chronic inflammatory disease of the airways characterized by varying and recurring symptoms of shortness of breath, chest tightness, wheezing and cough, airflow obstruction, bronchial hyper-responsiveness, and underlying inflammation. In the United States, asthma affects more than 22 million persons. It is one of the most common chronic diseases of childhood, affecting more than 6 million children. Worldwide, about 300 million people are affected. 3,4 Currently, there are no approved OTC therapies for asthma, 1 The diagnosis and management of rhinitis: An updated practice parameter, Joint Task Force on Practice Parameters for Allergy and Immunology CFR Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the- Counter Human Use; Labeling of antihistamine drug products (1992, as amended Dec 6, 2002). 3 National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Health, Lung, and Blood Institute, (NIH publication nu ). Full text available online: htm 7 of 207 3

8 although OTC monograph indications exist for the temporary relief of occasional symptoms of mild asthma: wheezing, tightness of the chest, and shortness of breath. 5 Asthma is classified into four categories based on the level of symptoms, nighttime awakening from symptoms, short-acting beta-agonist bronchodilator use for symptom control, interference with normal activity, and lung function as well as the risk of exacerbations. To establish a diagnosis of asthma, the NHLBI National Asthma Education and Prevention Program (NAEPP) Guidelines 3 state that the clinician should determine that: Episodic symptoms of airflow obstruction are present Airflow obstruction is at least partially reversible, and Alternative diagnoses are excluded Whether potential off-label use in patients with asthma is a concern for the OTC marketing of montelukast, and if so, whether it has been adequately addressed is a topic for your consideration. 2.3 Relevant Regulatory History for Montelukast Two major milestone meetings were held between Merck and FDA [Division of Nonprescription Clinical Evaluation (DNCE) and Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)] regarding the development program for the OTC switch of montelukast. These included a pre-ind meeting in October 2007 and a pre-nda meeting in February Key discussion topics included FDA concern regarding potential off label use in asthma, neuropsychiatric adverse events, and the need for data to support a potential ocular symptoms indication. FDA noted that self-selection/label comprehension studies testing asthma versus allergic rhinitis, pediatric use, and warnings regarding neuropsychiatric events would be needed. For a more detailed discussion of regulatory interactions, refer to the Clinical Review by Dr. Erika Torjusen (DPARP). PRODUCT AND PHARMACOLOGY INFORMATION Montelukast is an oral leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor found in airway smooth muscle cells, macrophages, eosinophils and other inflammatory cells. The proposed product is the same 10 mg film coated tablet that is approved for prescription use in adults and adolescents aged 15 years and older. No new clinical pharmacology data were submitted as part of this application. According to the prescription label, the 10 mg tablet of montelukast is rapidly absorbed following oral administration with a mean peak plasma concentration in 3 to 4 hours (Cmax). Following absorption montelukast is more than 99% plasma bound, with minimal distribution across the blood-brain barrier. Elimination is via liver metabolism, including CYP3A4, 2C8, and 4 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, Updated Full text available online: CFR (b) Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Labeling of OTC Bronchodilator Drug Products (1992, as amended 2005). 8 of 207 4

9 2C9, with a plasma half-life of 2.7 to 5.5 hours. No dosage adjustment is required in mildmoderate hepatic impairment or renal insufficiency. 4 CLINICAL AND STATISTICAL EFFICACY A large number of clinical trials have been conducted with montelukast, including a number of trials supporting the asthma and EIB indications as well as pediatric dosing. This summary will focus on the adult allergic rhinitis trials, since that is the proposed indication for OTC use. The efficacy of montelukast for SAR and PAR has been previously established for the prescription product, so efficacy will be reviewed only briefly here, as the OTC indication is similar. Efficacy for an ocular symptom indication has not been previously established. Overall, there were 8 Phase 2 and 3 trials in SAR and 2 in PAR. Three of the Phase 3 SAR trials previously reviewed for the prescription indication were resubmitted for analysis in support of the proposed OTC ocular symptom indication. All of the trials enrolled adults and adolescents aged 15 years and older with active allergic rhinitis symptoms at the time of entry and a positive skin test to at least one relevant allergen. The Phase 3 SAR trials were large, randomized, double-blind, parallel group, placebo- and active treatment (loratadine 10 mg) controlled studies of 2 weeks duration, with the exception of Study 240, which was of 4 weeks duration. The primary efficacy endpoint for the Phase 3 SAR trials was mean change from baseline in the patient-rated daytime nasal symptom score (the mean of individual symptom scores of nasal congestion, rhinorrhea, nasal itching, and sneezing) as assessed by patients on a 0-3 categorical scale. The PAR trials were also large, randomized, double-blind, parallel group, placebo controlled trials, although of 4 and 6 weeks duration. One trial included a cetirizine active control arm. The primary endpoint was daytime nasal symptom score, with nasal itching removed for the second (positive) study. 4.1 Seasonal allergic rhinitis Of the five Phase 3 efficacy trials in SAR, four demonstrated a statistically significant reduction in daytime nasal symptom scores with montelukast compared to placebo. Overall, efficacy is generally modest. See Table 1. 9 of 207 5

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14 with low literacy, 75.6% correctly self-selected. Of those who incorrectly self-selected to use, the most frequent reason given (40%) was that it would help relieve my allergy symptoms. Similar to adults in Study 13007, the study met endpoints regarding comprehension of the warnings for neuropsychiatric events. 5.3 Post marketing data As part of this application, post-marketing safety data for montelukast were submitted and reviewed from the following sources: the sponsor s pharmacovigilance database, FDA s Adverse Event Reporting System (FAERS), the World Health Organization (WHO Vigibase), the American Association of Poison Control Centers National Poison Data System (NPDS), the Drug Abuse Warning Network (DAWN) and the published literature. All of these sources are subject to a number of limitations, primarily due to issues inherent in spontaneous reporting. In addition to data submitted by the sponsor, FDA conducted separate reviews of the FAERS data, post-marketing drug use, and epidemiology data available in the literature, with a focus on neuropsychiatric events. Key issues are reviewed here; additional primary discipline reviews are provided in the background package. Merck pharmacovigilance database The sponsor s pharmacovigilance database includes data from first worldwide market introduction in July 2007 (Mexico) through March During this time period, there were 46,527 individual case reports including 95,517 adverse events. Of these, 13,346 cases included serious adverse events (SAEs), and there were 367 deaths reported by the sponsor. Removing duplicates, FDA review included 348 deaths. Over this same time period, Merck reports sales of over 24 billion doses of montelukast or over 66 million patient years of exposure. The most common adverse events were in the psychiatric disorders, general disorders, and injury/poisoning/procedural complications System Organ Classes (SOC). The most common individually reported adverse events in order of frequency were accidental exposure, headache, overdose, no adverse event, insomnia, aggression, nightmare, abnormal behavior, and depression. The term no adverse event was coded in reports of overdose or maternal exposure with no clinical effect. Merck reports that the majority of overdose cases came from a retrospective study of pediatric overdoses in 0-5 year olds reported to Texas Poison Control during the 6-year period from In general, adverse events found in the database are described in the US prescription product label. Overall, serious adverse events largely mirrored those reported as adverse events, except that over 50% were in the injury/poisoning/procedural complications SOC, largely due to pediatric overdose. In addition, 24% of serious reports were in the psychiatric SOC. Notably, a breakdown of SAEs by age (where known) shows that approximately 62% of cases occurred in patients under 18 years, with 40% of all SAE reports in the 2-5 year old age group. In contrast to serious reports, which largely occurred in pediatrics, the majority of the 348 fatal reports occurred in adults. The most frequent cause of death was suicide; other frequent causes included unspecified, abortion/miscarriage (spontaneous and intentional) in which the mother took montelukast during pregnancy, and asthma. FDA Adverse Event Database (FAERS) 14 of

15 FDA review of the FAERS database from February 1998 through October 2013 included a total of 11,649 case reports, more than half of which (57%) occurred in adults. Consistent with drug use data, 53% occurred in the asthma indication. Unlike the data reported by the sponsor in the Merck database, 76% (8,846/11,649) of FAERS cases reported SAEs, including 567 deaths. Skewing towards cases with serious outcomes may reflect FDA sponsor reporting requirements for serious, unexpected (i.e. not in the product label) events. A specific review of neuropsychiatric adverse events from March 2008 to October 2013 revealed 2,430 cases, 54% of which occurred in pediatric patients, and 22% of which occurred in the allergy indication. The most frequently reported Preferred Terms were suicidal ideation, depression, and aggression. During this same time period, there were 43 completed suicides, excluding duplicate reports and reports from poison control centers. Some evidence of enhanced reporting has been evident since 2008, when FDA issued an Early Communication regarding neuropsychiatric events, with over half of the suicides reported since Drug use data FDA analysis of United States drug use data demonstrated that the overall number of prescriptions has been relatively stable at approximately 6.5 to 7 million patients since Of these, pediatric patients less than 18 years of age accounted for 38% of total patients, particularly in the 6-14 year old age group. In both adults and children, asthma accounted for the primary indication for use, including 52% of all patients, while allergic rhinitis was about a fifth of all use (22% age 0-17 years, and 17% age 18 years and above). Neuropsychiatric events In 2008, the FDA initiated a safety review of drugs that act via the leukotriene pathway (including montelukast) and the potential association of neuropsychiatric events, including suicidality. This safety review was initiated because of updates to the montelukast package insert to include neuropsychiatric events, such as tremor and depression as well as the report of suicide in a 15 year old male taking montelukast in the fall of The Agency issued an Early Communication in March 2008, regarding its ongoing safety review. 6 The Agency evaluated controlled clinical trial data and AERS data regarding neuropsychiatric events. The Agency requested that the manufacturers of the leukotriene modifiers submit controlled trial data for suicidality, using the Columbia Classification strategy. 7 This classification strategy was used for the FDA s evaluation of suicidality in clinical trials for anti-depressant drugs. In addition, based upon post-marketing reports of other neuropsychiatric events, the Agency also requested the manufacturers submit controlled trial data for these types of events. In its review of spontaneous post-marketing reports, the Agency noted a broad set of neuropsychiatric adverse events; some of these reports appeared consistent with a druginduced effect (e.g. positive dechallenge or rechallenge). However, the agency also concluded that the events were typically non-serious and reversed with the cessation of therapy. The sponsor of montelukast submitted results from 41 placebo-controlled trials in 6 fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafet yinformationforheathcareprofessionals/ucm htm [accessed March 18, 2014] 7 Posner K et al. Am J Psychiatry 2007; July 164(7): of

16 patients 6 years of age and older of which 9,929 were treated with montelukast and 7,780 were treated with placebo. When the Agency reviewed the clinical trial data, a similar broad set of neuropsychiatric events was noted with low frequency. Although a possible association between the drug and post-marketing neuropsychiatric adverse events could not be absolutely ruled out, a strong signal for neuropsychiatric events was not identified in the clinical database. However, the Agency acknowledged the limitations of the clinical trial data because the clinical trials were not designed specifically to examine neuropsychiatric event. Overall, the clinical data did not show a causal association between Singulair and suicide or suicidal behavior, and there was no quantitative signal for an association of suicide with Singulair treatment in the spontaneous reports. In April 2009, based upon its review, the Agency requested that the manufacturers update the product labels to include a Precaution regarding neuropsychiatric events. The labeling was approved on August 19, 2009, and is shown below. The Agency issued follow up communications in January and June ,9 Eosinophilic conditions (Churg Strauss Syndrome) Churg Strauss Syndrome (CSS) is a vasculitis of the small to medium sized arteries. The American College of Rheumatology has 6 criteria for the diagnosis: asthma, eosinophilia (>10%), paranasal sinusitis, pulmonary infiltrates, histological proof of vasculitis with extravascular eosinophils, and mononeuritis multiplex. 10 The presence of 4 or more criteria has a reasonable sensitivity and specificity for the diagnosis of CSS. The potential association of leukotriene receptor antagonists and vasculitis, including CSS, is wellrecognized. When montelukast was first approved on February 20, 1998, information was included in the product label regarding the potential for Churg-Strauss syndrome (CSS). This information was updated in October of 1998, based upon post-marketing reports. Because CSS occurs primarily in asthmatics, often in the setting of tapering corticosteroids, its relevance to OTC use for allergic rhinitis may be limited. 6 BENEFIT RISK ASSESSMENT The efficacy of montelukast for the treatment of the nasal symptoms of allergic rhinitis has been established for prescription use. It is expected that the product would have similar nasal efficacy in the OTC setting, as the allergic rhinitis indication is the same and allergic 8 fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafet yinformationforheathcareprofessionals/ucm htm [accessed March 18, 2014] 9 fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafet yinformationforheathcareprofessionals/ucm htm [accessed March 18, 2014] 10 Masi AT, Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: of

17 rhinitis is a well-established OTC indication. In addition, Merck has proposed an additional OTC indication for the treatment of ocular allergy symptoms. Whether or not there is sufficient data to support such an indication is a topic for discussion; however, FDA considers these two indications to be separate, and voting questions regarding efficacy will focus on the primary nasal indication. A substantial safety database for montelukast exists, including nearly 10,000 patients treated with montelukast in placebo-controlled clinical trials and over 66 million patient years of post-marketing exposure worldwide. The safety profile of montelukast in clinical trials is generally reassuring. However, post-marketing neuropsychiatric events have been observed, including agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. These adverse events have occurred in all age groups, including adult, adolescent, and pediatric patients. Merck proposes to address these events through labeling, and has conducted two label comprehension studies to evaluate the issue. Another potential safety issue for OTC use of montelukast is the possibility of OTC use in patients with asthma, since montelukast is approved as a prescription product for asthma and EIB in addition to allergic rhinitis. Currently, there are no approved OTC controller medications for the treatment of asthma, and it is unclear if consumers would attempt to treat their asthma symptoms using montelukast rather than seeking care from a health care professional. The considerable overlap between the two conditions increases the complexity of the issue. Merck proposes to address this issue through labeling, and has conducted a self-selection study targeting OTC use in asthma. Finally, Merck is proposing an indication in adults (18 years and older) for the 10 mg tablet, with no pediatric indications. The 10 mg tablet is currently approved as a prescription product for adolescents aged 15 years and above, with age appropriate formulations and dosing supporting the allergic rhinitis indication down to age 6 months. Drug use data suggests that a substantial portion of the prescription market is in children. A label comprehension study in adolescents aged years demonstrated that many teens selected to use the product, despite instructions not to use under age 18. This raises concern for inappropriate OTC use in children, particularly since the dose is reduced below age 15 years. Input from the AC panel is needed to help determine the appropriate benefit-risk equation to apply to montelukast in the OTC setting, taking into account potential safety issues of use for the treatment of asthma, neuropsychiatric adverse events, and pediatric use. 7 SUMMARY The purpose of the NDAC meeting is to discuss the adequacy of the efficacy and safety data submitted by Merck to support approval for montelukast at a once daily dose of 10 mg for OTC use for the temporary relief of symptoms due to hay fever or other respiratory allergies in adults, including nasal congestion, runny nose, itchy, watery eyes, sneezing, and itching of the nose. The major issues for discussion at the AC meeting are related to the efficacy and safety of montelukast for the relief of symptoms of allergic rhinitis in the OTC setting, including information regarding the proposed ocular symptom indication, and the 17 of

18 proposed Drug Facts label. Factors to consider for these discussions include potential offlabel use in patients with asthma, implications for the pediatric population, and neuropsychiatric adverse events. Points for discussion, which we ask you to keep in mind during the AC presentations, are provided in this briefing document. 18 of

19 3. Overview of Regulatory Background and Clinical Trials Division of Pulmonary, Allergy, Rheumatology Products Briefing Document Date: March 31, 2014 From: Through: Through: To: Subject: Erika Torjusen, MD, MHS, Medical Officer, Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) Banu Karimi-Shah, MD, Medical Team Leader, DPARP Sally Seymour, Deputy Director for Safety, DPARP Members, Nonprescription Drugs Advisory Committee (NDAC) Partial prescription to OTC switch for montelukast10 mg tablets in patients 18 years of age with allergic rhinitis [seasonal (SAR) and perennial (PAR)] 1 Executive Summary Merck submitted a New Drug Application (NDA ) for a prescription (Rx) to nonprescription (over-the-counter; OTC) switch for Singulair (montelukast), a leukotriene receptor antagonist, for the indication of allergic rhinitis in patients 18 years of age and older. There are two other prescription products which act via the leukotriene pathway approved for use in the United States. Montelukast would be a first-in-class to the OTC market, and would provide a treatment for allergic rhinitis with a mechanism of action that is different from other OTC allergy medications. In addition to allergic rhinitis, montelukast is also approved for the prescription use of asthma and exercise-induced bronchoconstriction (EIB). Prescription montelukast is marketed in multiple dosage forms and strengths: 10 mg film-coated tablets, 4 and 5 mg chewable tablets, and 4 mg oral granules. In this NDA, the Applicant proposes a partial Rx to OTC switch for the allergic rhinitis indications (SAR and PAR) for the montelukast 10 mg tablet, in patients 18 years of age and older. The use of montelukast for allergic rhinitis by children under 18 years of age, the other formulations, and for the indications related to asthma and EIB would remain prescription. The proposed OTC indication for montelukast is as follows: temporarily relieves these symptoms of hay fever or other respiratory allergies: nasal congestion, runny nose, itchy, watery eyes, sneezing, and itching of the nose. The proposed indication corresponds to the current OTC monograph for antihistamines. However, because montelukast is not an antihistamine, and the basis for its Rx approval was based on nasal symptom scores only, 19 of 207 1

20 the prescription product label does not include any ocular claims. To support the additional claim that montelukast temporarily relieves itchy, watery eyes, the Applicant has submitted for review the data from three studies in patients with SAR. The attached statistical review by Dr. Kiya Hamilton provides the regulatory history and review of the data with respect to the relief of eye symptoms with montelukast. Issues include the posthoc analysis and multiplicity adjustment as well as treatment effect size. Inclusion of the ocular claim in the OTC label is an issue for the committee s consideration. Dose selection and efficacy for the treatment of the nasal symptoms of allergic rhinitis were established in the pivotal studies conducted in support of the original montelukast prescription product. These results, previously reviewed by the Agency, are summarized in the current prescription product label and in this review. The safety information for montelukast is derived from the clinical development program for the prescription montelukast product in conjunction with post-marketing experience obtained over the past 15 years, during which montelukast has been approved in more than 100 countries for the treatment of asthma and in more than 50 countries for the treatment of allergic rhinitis. Clinical trial data in support of safety include information from the clinical studies used to support the approval in patients with asthma, SAR, PAR, and EIB. Neuropsychiatric events, including agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor, have been reported with montelukast. In 2008, the FDA conducted a safety review of controlled clinical trial data and post-marketing data with respect to neuropsychiatric events. This safety review was initiated because of requested updates to the montelukast package insert to include neuropsychiatric events, such as tremor and depression seen in the post-marketing setting, as well as the report of suicide in a 15 year-old male taking montelukast in the fall of The post-marketing data will be discussed in the review by the FDA s Office of Surveillance and Epidemiology (OSE). Per request of the FDA, the Applicant submitted results from 41 placebo-controlled trials in patients 6 years of age and older of which 9,929 were treated with montelukast and 7,780 were treated with placebo. A broad set of neuropsychiatric events was noted with low frequency. Although a possible association between the drug and post-marketing neuropsychiatric adverse events could not be absolutely ruled out, a strong signal for neuropsychiatric events was not identified in the clinical database. Overall, the clinical data did not show a causal association between montelukast and suicide or suicidal behavior, and there was no quantitative signal for an association of suicide with montelukast treatment in the spontaneous reports. Of note, due to the potential for neuropsychiatric events, the Applicant has chosen to limit the OTC switch to patients 18 years of age or older. As this is a partial OTC switch, the Applicant is not seeking an OTC indication for asthma. This partial switch raises potential challenges associated with targeting the allergic rhinitis population while excluding the off-label OTC use among asthmatics. 20 of 207 2

21 This is of particular importance, given the significant overlap between these two populations. It is estimated that 10-40% of patients with allergic rhinitis also have asthma and these numbers are even higher when looking at the number of asthmatics with allergic rhinitis (up to 90%). 1,2 Therefore, it may be difficult to address these as distinct populations for the purposes of OTC labeling, and the potential for off-label use in patients with asthma presents an issue that will warrant the committee s consideration. Allergic rhinitis is an established OTC indication, and there are many products available OTC for this indication. Over-the-counter products to treat symptoms associated with allergic rhinitis have been available for many years and include both intranasal and oral products: first and second generation oral antihistamines, oral antihistamine/decongestant combination products, intranasal decongestants, and intranasal cromolyn. Most recently, an intranasal corticosteroid was approved for OTC use as well. Each of these products has a different role in the clinical landscape of treating allergic rhinitis, based on their relative efficacy and safety profiles, and their recommended use is described in a number of practice parameters and guidelines. For example, intranasal corticosteroids are considered to be the most effective for controlling symptoms, and are considered to be first-line therapy for moderate-to-severe rhinitis, with second-generation antihistamines generally preferred for the treatment of mild rhinitis. Whether the complexities of managing allergic rhinitis in the face of multiple treatment options can be communicated to and understood by the OTC consumer is an important issue that we ask the committee to consider. 2 Introduction and Regulatory Background 2.1 Product Information Montelukast was first approved for prescription use in the United States in 1998 for the treatment of asthma in patients 15 years of age. The approved indications were expanded in 2002 to include seasonal allergic rhinitis (SAR), and in 2005, perennial allergic rhinitis (PAR). In 2007, montelukast was approved for the prevention of exercise-induced bronchoconstriction (EIB). Prescription montelukast is marketed in multiple dosage forms and strengths. The currently approved indications and prescription dosing by indication and patient age are summarized in Table 1. 1 Bousquet et al. Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. J Allergy Clin Immunol. November Navarro et al. Coexistence of asthma and allergic rhinitis in adult patients attending allergy clinics: ONEAIR study. J Investig Allergy Clin Immunol. 2008;18(4): of 207 3

22 Table 1: Approved Montelukast Prescription Dosing by Indication and Age Indication/Age Dose Asthma 15 years 10 mg 6-14 years 5 mg 2-5 years 4 mg months 4 mg Seasonal Allergic Rhinitis (SAR) 15 years 10 mg 6-14 years 5 mg 2-5 years 4 mg Perennial Allergic Rhinitis (PAR) 15 years 10 mg 6-14 years 5 mg 2-5 years 4 mg 6-23 months 4 mg Exercise-Induced Bronchoconstriction (EIB) 15 years 10 mg 6-14 years of age 5 mg Source: Singulair Prescription Package Insert 2.2 Currently Available Nonprescription Treatments for Proposed Indications Leukotriene pathway inhibitors have been available by prescription for the treatment of allergic rhinitis for 12 years. There are no approved OTC leukotriene pathway inhibitor products in the United States. However, the symptomatic relief of allergic rhinitis is a well-established OTC indication with numerous treatment options. OTC products to treat symptoms associated with allergic rhinitis have been available for many years and include both intranasal and oral products: first and second generation oral antihistamines, oral antihistamine/decongestant combination products, intranasal decongestants, and intranasal cromolyn. Most recently, an intranasal corticosteroid was approved for OTC use as well. Randomized trials in patients with allergic rhinitis have shown the effectiveness of the numerous therapies listed above. With a number of treatment options available for allergic rhinitis, it is important to review how each of these therapies fits into the clinical landscape of treating allergic rhinitis, when evaluating a newly proposed OTC product for the same indication. A number of practice parameters and guidelines, which are largely in agreement with each other, have been set forth to aid in the treatment of patients. Intranasal corticosteroids are recommended as first-line therapy for moderate- 22 of 207 4

23 to-severe allergic rhinitis, with second-generation oral antihistamines generally preferred for the treatment of mild allergic rhinitis owing to their safety and ease of use. Intranasal corticosteroids can be combined with second-generation oral antihistamines for persistent symptoms. 3 For resistant nasal symptoms, a leukotriene inhibitor (e.g. montelukast) may be added. Practice guidelines note that montelukast, while shown to relieve nasal symptoms when compared with placebo, is a relatively weak monotherapy. A meta-analysis demonstrated that, as compared with placebo, montelukast induced a moderate but significant reduction in scores for daily symptoms of rhinitis; in comparison, nasal corticosteroids induced a significant and substantial reduction in symptom scores. 4 Thus, per clinical guidelines, montelukast s role is generally as an adjunct in the treatment of a patient who does not have an adequate response to an antihistamine, a nasal corticosteroid, or both. However, there are no clear data demonstrating that leukotriene-receptor antagonists combined with either antihistamines or nasal corticosteroids reduce symptom scores more than antihistamines or corticosteroids alone. Additionally, montelukast can also be used in patients with concomitant asthma Availability of Proposed Active Ingredient in the United States Montelukast is available in multiple formulations in the United States (film coated tablet, chewable tablets, and oral granules). Three NDA applications for Singulair have been approved and are currently marketed. Singulair (NDA ; approved February 20, 1998): Tablets 10mg (the subject of this Rx to partial to partial OTC switch.) Singulair (NDA ; approved February 20, 1998): Chewable Tablets 4mg, 5 mg Singulair (NDA ; approved July 26, 2002): Oral Granules 4mg Generic montelukast has also been marketed under numerous Abbreviated New Drug Applications (ANDAs) for all formulations (4 mg, 5mg, and 10 mg, and oral granules) beginning on August 3, Summary of Presubmission Regulatory Activity Related to Submission Discussions regarding the proposed OTC switch were held on October 22, 2007 and February 7, 2013, between participants from Merck, the Division of Nonprescription 3 Marshall Plau, Martin Valtine. Clinical Practice. Allergic Rhinitis. NEJM 2005; 353: Wilson AM, O'Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 2004;116: The diagnosis and management of rhinitis: An updated practice parameter, Joint Task Force on Practice Parameters for Allergy and Immunology of 207 5

24 Clinical Evaluation (DNCE), and the Division of Pulmonary, Allergy, and Rheumatology Products (DPARP). Major discussion points are outlined below. October 22, 2007: The Agency expressed concerns that because prescription montelukast has both asthma [including EIB] and allergic rhinitis indications, OTC use in asthma may result in inappropriate treatment of bronchospasm by consumers who are not under the care of a physician, with potentially serious adverse consequences. The Sponsor was informed that consumer studies would need to be conducted to demonstrate an understanding of the proposed non-prescription indication for allergic rhinitis versus the prescription asthma/eib indication and appropriate self-selection. In addition, appropriate self-selection based on the age of the child would also need to be demonstrated. The Agency expressed concern that the trade name Singulair is most closely associated with the asthma indication and this might pose a problem regarding trade name recognition by consumers in the OTC setting. The Agency stated that additional consumer testing on the use of this product to treat allergic rhinitis would not be necessary. However, upon review of the label comprehension and self-selection study protocols, a determination will be made whether an actual use study is needed. February 7, 2013: The Agency instructed the Sponsor to propose language for the non-prescription label to warn consumers about neuropsychiatric events that can occur with montelukast use and how to respond if they experience such an event. The Agency noted that the Sponsor included eye (b) (4) symptoms in the proposed nonprescription labeling. Montelukast was approved for allergic rhinitis on the basis of the Daytime Nasal Symptom Score (DNSS). The DNSS is based on the sum of four nasal symptoms including runny nose, itchy nose, sneezing, and nasal congestion. Eye (b) (4) symptoms are not included in this score. While the Sponsor clarified that they had modeled their proposed OTC indication based on that of antihistamines, the Agency noted that montelukast is not an antihistamine, and the proposed labeling should not be modeled directly after the antihistamine monograph. The Agency informed the Sponsor that submission of comprehensive data providing substantial evidence to support the relief of eye symptoms would be required in order to support the addition of relief of eye (b) (4) symptoms to the OTC labeling and this would be a review issue. The Agency noted that the Sponsor was planning to conduct a label comprehension/self-selection study and not an actual use study. This was in agreement with the advice letter of March 25, 2009, which stated that an actual use study would not be needed if a well-designed self-selection study were to be conducted. The Agency informed the Sponsor that should a warning regarding neuropsychiatric adverse events be included in labeling, comprehension of this warning would require assessment (including the comprehension of what consumers should do if they experience a neuropsychiatric adverse event). In addition, the Agency conveyed to the Sponsor that their secondary medical risk 24 of 207 (b) (4) 6

25 objective of understanding that consumers should not take another montelukast product along with Singulair Allergy should be elevated to one of their primary communication objectives. 3 Overview of Clinical Database and Post Marketing Safety Database The proposed partial Rx to OTC switch is proposed for patients 18 years old with allergic rhinitis. Therefore, the discussion of the clinical database will focus on those trials conducted in this age group. Note that the pivotal clinical trials included patients down to 15 years of age. Clinical trial data to support dose selection, efficacy, and safety of montelukast for the treatment of allergic rhinitis have already been reviewed in detail by the Agency and are summarized in the currently approved Rx product label. This review provides a brief summary of data from premarketing clinical trials which formed the basis of approval of montelukast for SAR and PAR. A total of 10 studies were conducted to support the efficacy and safety of montelukast for SAR and PAR in patients 15 years and older: 8 studies for SAR and 2 studies for PAR (Table 2). 25 of 207 7

26 Table 2: Efficacy and Safety Studies Trial Age Range (yrs) SAR - Supportive Efficacy Studies P2, R, DB, PC, AC, PG P2, R, DB, PC, AC, PG P2, R, DB, PC, AC, PG, MC SAR Pivotal Efficacy Studies P3, R, DB, PC, AC, PG, MC P3, R, DB, PC, AC, PG, MC P3, R, DB, PC, AC, PG, MC P3, R, DB, PC, AC, PG, MC P3, R, DB, PC, AC, PG, MC PAR Pivotal Efficacy Studies P3, R, DB, PC, AC, PG, MC Design Treatment Arms (N) Treatment Period Montelukast + Loratadine 10mg (90) Montelukast 20mg (90) Montelukast 10mg (95) Loratadine 10mg (92) Placebo (91) Montelukast + Loratadine 10mg (174) Montelukast 10mg (112) Loratadine 10mg (116) Beclomethasone (173) Placebo (57) Montelukast + Loratadine 10mg (209) Montelukast 10mg (103) Loratadine 10mg (164) Placebo (54) Montelukast + Loratidine 10mg (302) Montelukast 10mg (155) Loratadine 10mg (301) Placebo (149) Montelukast 10mg (348) Loratadine 10mg (602) Placebo (352) Montelukast 10mg (326) Loratadine 10mg (170) Placebo (333) Montelukast 10mg (522) Loratadine 10mg (171) Placebo (521) Montelukast 10mg (448) Loratadine 10mg (180) Placebo (451) Montelukast 10mg (630) Cetirizine 10mg (122) Placebo (613) Montelukast 10mg (1002) Primary Outcome 2 weeks DNSS 2 weeks Composite Score 2 weeks Composite Score 2 weeks DNSS 2 weeks DNSS 2 weeks DNSS 2 weeks DNSS 4 weeks DNSS* 6 weeks DNSS P3, R, DB, 6 weeks DNSS PC, PG, MC Placebo (990) SAR: seasonal allergic rhinitis, (N): number of patients, P: phase, R: randomized, DB: double blind, PC: placebo controlled, AC: active control, PG: parallel group, Composite score (average of daytime nasal and nighttime symptoms scores), DNSS: daytime nasal symptom score (mean of the individual symptoms of congestion, rhinorrhea, pruritus, and sneezing), * measured at 2 weeks, PAR: perennial allergic rhinitis, C: cetirizine, : measured at 4 weeks, : did not include nasal itching Source: Study 068 Clinical Study Report p14, Study 077 Clinical Study Report p14, Study 102 Clinical Study Report p16, Study 117 Clinical Study Report p15, Study 162 Clinical Study Report p16, Study 192 Clinical Study Report p16, Study 235 Clinical Study Report p15, Study 240 Clinical Study Report p18, Study 246 Clinical Study Report p19, Study 265 Clinical Study Report p of 207 8

27 In addition to the clinical trial database, the safety information is also derived from postmarketing data. The Applicant performed an analysis of its internal pharmacovigilance database, Merck Adverse Event Reporting and Review System (MARRS), from market introduction in Mexico on July 31, 1977 through March 31, The Applicant also conducted an analysis of reports in external safety databases (AERS, WHO VigiBase), which covers a period from the date of US market approval (February 20, 1998) through August 27, 2012 for the AERS database and through March 31, 2013 for WHO VigiBase. During the period evaluated, 33,832 total events from 8,815 cases were submitted to AERS and 10,810 total events from 5,342 ex-us cases to VigiBase. The post-marketing data will be discussed in more detail in the reviews by OSE and DNCE. 4 Review of Efficacy While the Applicant has conducted numerous clinical trials in asthma and EIB, this review focuses on the efficacy of SAR and PAR in adult patients as this is the subject of the proposed Rx to OTC switch. The proposed OTC dosing and indication for montelukast are consistent with the dosing and indications approved for the prescription product, with the exception that the Applicant seeks an additional ocular claim for the OTC product. The proposed OTC indication is as follows: temporarily relieves symptoms of hay fever or other respiratory allergies: nasal congestion, runny nose, itchy, watery eyes, sneezing, and itching of the nose. The efficacy data reviewed as a part of the Rx clinical development program support the nasal components of the OTC indication (i.e. temporary relief of symptoms of hay fever or other respiratory allergies: nasal congestion, runny nose, sneezing, and nasal congestion). This partial Rx to OTC switch application seeks the addition of a new ocular indication in the OTC market. Therefore, the Applicant has submitted for review the data from three previously conducted studies in patients with SAR, to support the additional claim that montelukast temporarily relieves itchy, watery eyes. A discussion of the detailed statistical analysis of the three studies with respect to the new ocular claim is included in a separate document in this briefing package (see the statistical review by Dr. Kiya Hamilton), and is briefly reviewed below. Seasonal Allergic Rhinitis (SAR) The supplemental NDA to support the addition of the SAR indication contained results from 8 SAR studies in subjects 15 years of age: 3 phase 2 studies (Studies 68, 77, and 102), and 5 phase 3 studies (Studies 117, 162, 192, 235, and 240). The initial focus of the montelukast development program for SAR was to investigate the benefit of montelukast and loratadine (an antihistamine), in combination, for the relief of SAR symptoms. The first phase 3 study (Study 117) that investigated the effect of the montelukast and loratadine combination showed promising efficacy of montelukast alone 27 of 207 9

28 over placebo. Subsequently, the Applicant shifted the focus of the program to evaluate the efficacy and safety of montelukast alone in the treatment of SAR symptoms. A total of 5,029 patients (1,799 treated with montelukast 10 mg tablets) were included in the five phase 3 clinical studies in SAR. Patients were 15 to 82 years of age, with a history of SAR, a positive skin test to at least one relevant seasonal allergen, who had active symptoms at study entry. The phase 3 studies were large, randomized, doubleblind, parallel group, placebo- and active treatment (loratadine 10 mg) controlled studies of 2 weeks duration, with the exception of Study 240, which was of 4 weeks duration. The primary efficacy endpoint for all the trials was mean change from baseline in the patient-rated daytime nasal symptom score (the mean of individual symptom scores of nasal congestion, rhinorrhea, nasal itching, and sneezing) as assessed by patients on a 0-3 categorical scale. Secondary efficacy endpoints included nighttime symptoms score (mean of scores of difficulty going to sleep, nighttime awakening, and nasal congestion upon awakening), eye symptoms, global evaluation of allergic rhinitis, and rhinoconjunctivitis quality- of-life assessment. The primary efficacy data are summarized in Table 3. Table 3: Premarketing Efficacy Results in SAR Clinical Studies Daytime Nasal Symptom Score Study (Mean Change from Baseline) Montelukast 10mg Loratadine 10mg Placebo Montelukast vs. Placebo Effect Size p value Phase 3 Studies (N=151) (N=300) (N=148) (N=344) (N=599) (N=351) (N=326) (N=168) (N=331) (N=519) (N=170) (N=521) (N=445) (N=180) (N=448) Phase 2 Studies (N=94) (N=91) (N=89) (N=111) (N=115) (N=57) (N=103) (N=162) (N=53) Source: Study 117 Clinical Study Report p17, Study 162 Clinical Study Report p18, Study 192 Clinical Study Report p17, Study 235 Clinical Study Report p17, Study 240 Clinical Study Report p20, Study 68 Clinical Study Report p15, Study 77 Clinical Study Report p15, Study 102 Clinical Study Report p17. As shown in Table 3, a statistically significant difference between montelukast and placebo was demonstrated in Studies 117, 162, 235, and 240. Loratadine was included in all studies as a positive control, serving to validate the study results. Although a formal comparison between montelukast and loratadine was not pre-specified, inclusion of 28 of

29 loratadine demonstrated that the mean effect sizes of montelukast in these studies, while statistically significant versus placebo, were numerically small and consistently less than the effect sizes noted with loratadine. Overall, the clinical development program in SAR demonstrated a statistically significant separation between montelukast and placebo for the primary efficacy variable. The secondary efficacy variables, specifically the nighttime symptoms score, also favored montelukast over placebo. The results supported approval of montelukast for the treatment of SAR symptoms. Perennial Allergic Rhinitis (PAR) The supplemental NDA to support the addition of the PAR indication contained results from 2 PAR studies in adults (Studies 246 and 265). The Applicant conducted two studies, because Study 246, which was conducted first, failed to show efficacy. Guided by the results of the first study, the Applicant conducted a second study, Study 265, which demonstrated the efficacy of montelukast in PAR. A total of 3,357 patients (1,632 treated with montelukast 10 mg tablets) were included in the two phase 3 clinical studies in PAR. Patients were 15 to 82 years of age, with PAR as confirmed by history, and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry. Study 246 was double-blind, double-dummy, multi-center, placebo- and activecontrolled, parallel group in design conducted in the United States in patients 15 to 85 years of age with PAR. The study had a 5-7 day placebo run-in period, followed by 6 week double-blind treatment period. The treatment arms were montelukast 10 mg, cetirizine 10 mg (an antihistamine), and placebo, all dosed in the evening. Efficacy was assessed by morning and evening reflective patient scoring of four nasal symptoms (nasal congestion, rhinorrhea, sneezing, and nasal itching) on a four point scale (0=none, 1=mild, 2=moderate, and 3=severe), and several other secondary variables. The primary efficacy endpoint was the change from baseline in the Daytime Nasal Symptom Score (DNSS) averaged over the first 4 weeks of treatment. DNSS was the pre-dose evening reflective patient scoring of the four nasal symptoms mentioned above. The study was not designed to compare montelukast and cetirizine. Results of the primary endpoint are shown in Table 4. Montelukast failed to show statistically significant difference from placebo in the primary efficacy endpoint, whereas cetirizine was statistically significantly better than placebo. 29 of

30 Table 4: Premarketing Efficacy Results in PAR Clinical Studies: Study 246 Treatment Groups N Mean Baseline DNSS Score Mean Change from Baseline in DNSS LS mean Treatment vs. Placebo (p value) Primary Efficacy Endpoint DNSS Montelukast 10mg (0.150) Cetirizine 10mg (0.038) Placebo DNSS: Daytime Nasal Symptom Score Source: Study 246 Clinical Study Report p21, p95. Study 265 was conducted in follow-up to Study 246, which failed to show efficacy of montelukast in PAR. The design and conduct of this study was similar to Study 246 with four notable differences. First, nasal itching was removed from the DNSS (but still evaluated) because in Study 246 there was no numerical effect on nasal itching score for montelukast. Second, the primary efficacy endpoint was assessed over 6 weeks of treatment as opposed to 4 weeks in Study 246. Third, no active comparator was included in this study. Fourth, the study had centers in the United States, as well as in Canada, and Europe, as opposed to Study 246 only having centers in the United States. The sample size of this study was calculated based on the difference between the montelukast and placebo treatment arms of Study 246, and was notably larger. A total of 1,922 patients were randomized to the two treatment arms, of which 1,819 (91%) completed the study. Results of the primary efficacy endpoint are shown in Table 5. Montelukast was statistically significantly superior to placebo for the primary efficacy endpoint. Results of the secondary efficacy endpoints (data not shown) generally tracked with the results of the primary efficacy endpoint. Table 5: Premarketing Efficacy Results in PAR Clinical Studies: Study 265 Treatment Groups N Mean Baseline DNSS Score Mean Change from Baseline in DNSS LS mean Treatment vs. Placebo (p value) Primary Efficacy Endpoint DNSS * Montelukast 10mg ( 0.001) Placebo Source: Study 265 Clinical Study Report p15, p67. DNSS: Daytime Nasal Symptom Score; *Nasal itching not included in score. The treatment effect size of montelukast in this program was small, as was seen for montelukast in the SAR program. In Study 265, montelukast was statistically significantly superior to placebo for the primary efficacy endpoint. In Study 246, 30 of

31 montelukast failed to separate from placebo statistically, but the numerical trend was in favor of montelukast compared to placebo. The secondary efficacy variables also generally favored montelukast over placebo (data not shown). Overall, the clinical development program supported the efficacy of montelukast in the treatment of PAR. Relief of Ocular Symptoms Associated With Allergic Rhinitis With this Rx to OTC switch NDA, the Applicant submitted three previously conducted studies, which had been reviewed at the time of the supplemental NDA submission for SAR in Of note, the Applicant did not specifically request an ocular claim at the time of Rx approval, and review of the application did not result in inclusion of ocular symptom relief in the Rx product label. A detailed statistical analysis of the three studies in SAR patients with respect to the newly proposed ocular claim is included in a separate document in this briefing package (see the statistical review by Dr. Kiya Hamilton). A high level overview of the data is provided here. Studies 162, 192 and 235 were previously submitted and reviewed in the original application for montelukast. All three studies were again submitted, but now in support of the indication of itchy and watery eyes being added to the over-the-counter label for montelukast. In each study, the daytime eye symptoms score was a secondary endpoint that was defined as the average of tearing, itchy, red and puffy eyes (each score on a 0 to 3 point scale). The results of the DESS in these 3 studies are shown in Table 6. Table 6: Daytime Eye Symptom Score (DESS) in patients with SAR Daytime Eye Symptom Score Study (Mean Change from Baseline) Montelukast Placebo Montelukast vs. Placebo 10mg Effect Size p value (N=344) (N=351) * (N=326) (N=331) (N=519) (N=521) Source: Integrated Summary of Efficacy Table 9, page 17 *In accordance with the post-hoc Bonferroni adjustment for multiple comparisons, p-values smaller that a significance level of 0.05/5=0.01 are statistically significant. As can be seen in Table 6 above, all three studies showed a numerical trend in the DESS in favor of montelukast over placebo. The ocular endpoint was not part of a pre-specified multiplicity analysis plan. Without adjustment for multiple comparisons, differences between montelukast and placebo for this endpoint resulted in statistically significant results in two out of the three studies (Studies 162 and 235). When the adjustment (Bonferroni correction) was applied post-hoc to adjust for multiplicity, only one of the three studies demonstrated a statistical significance difference between treatment groups for the DESS endpoint (Study 162). Aside from the issues regarding statistical analysis, the treatment effect sizes are small and of questionable clinical significance. Whether 31 of

32 there is substantial evidence to support inclusion of an ocular claim in the OTC label is an issue for the committee s consideration. 5 Review of Safety 5.1 Safety Summary The safety of montelukast is derived from the clinical development program for the prescription montelukast product in conjunction with post-marketing experience obtained over the past 15 years. Prescription labeling for montelukast contains Warnings and Precautions statements pertaining to the use of montelukast. These statements include: Cautioning against use for the treatment of acute asthma Advising against abrupt cessation of concomitant inhaled or oral corticosteroids Advising for continued avoidance of aspirin and NSAIDs in those with known broncho-reactivity to these agents Alerting to the potential for neuropsychiatric events Alerting to the potential for development of eosinophilic conditions, such as Churg- Strauss Syndrome Informing phenylketonuric patients that the 4 and 5 mg chewable tables contain phenylalanine Serious adverse events were relatively few across all indications, and similar in frequency between montelukast and placebo arms. Adverse events leading to withdrawal were also infrequent across indications. In the overall safety database, including all approved Rx indications for montelukast, the most common adverse reactions from controlled clinical trials as described in the current prescription label include (incidence 5% and greater than placebo; listed in descending order of frequency): upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis and otitis. Of those warnings, precautions, and adverse reactions outlined in the package insert, neuropsychiatric events were recently identified as a safety issue and have been of particular interest, and thus warrant further discussion. Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast. Post-marketing reports with montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. In 2008, the FDA conducted a safety review of the controlled clinical trial data of montelukast, and other leukotriene inhibitors. This safety review was initiated because of updates to the montelukast package insert to include neuropsychiatric events, such as tremor and depression as well as the report of suicide in a 15 year-old male taking 32 of

33 montelukast in the fall of Based upon FDA review, a broad set of neuropsychiatric events was noted in the clinical trials and in the post-market setting, and while there are limitations with the data (described below), the Agency requested that the sponsor add information to the montelukast product label to describe the reports of neuropsychiatric events. 5.2 Adequacy of Safety Assessments Safety information in adults was reviewed for all indications (asthma, allergic rhinitis, and EIB) as follows 6 : 1) Asthma (NDA ) Safety database consisted of 10 phase 2b/3 clinical studies (in addition to phase 1/2a and extension studies) N= 2,606 subjects 15 years of age treated with montelukast (most treated for 3 months or longer) Of these, N=253 adults were treated for at least 1 year, and N=21 for 2 years 2) Seasonal Allergic Rhinitis (NDA , Supplement 17) Safety database consisted of 8 phase 2/3 clinical studies N = 2, years of age treated with montelukast Studies were 2 to 4 weeks in duration 3) Perennial Allergic Rhinitis (NDA , Supplement 33) Safety database consisted of 2 phase 3 clinical studies N = 1, years of age patients treated with montelukast Studies were 6 weeks in duration 4) Exercise Induced Bronchoconstriction (NDA , Supplement 36) Safety database consisted of 3 phase 3 clinical studies and 2 supplemental studies N= 569 patients treated with montelukast Studies were 3 to 8 weeks in duration In addition to the clinical trial database, the safety information for the application is supplemented by post-marketing data for montelukast, which is discussed in the reviews by OSE and DNCE. Montelukast has been approved in more than 100 countries for the treatment of asthma and in more than 50 countries for the treatment of allergic rhinitis. For these post-marketing data, the Applicant performed an analysis of its internal pharmacovigilance database, Merck Adverse Event Reporting and Review System (MARRS) and an analysis of reports in external safety databases (AERS, VigiBase). During the time period evaluated 34,199 total events from 8,950 cases were submitted to AERS and 11,291 total events from 5,531 ex-us cases to VigiBase. 6 Applicant s pooled database differs slightly from the current product label. For consistency, this review will use the database outlined in the Applicant s integrated summary of safety (ISS). 33 of

34 5.3 Submission Specific Safety Concerns Neuropsychiatric Events In 2008, the FDA initiated a safety review of drugs that act via the leukotriene pathway (including montelukast) and their potential association with neuropsychiatric events, including suicidality. This safety review was initiated because of requested updates to the montelukast package insert to include neuropsychiatric events, such as tremor and depression, as well as the report of a suicide in a 15-year old male taking montelukast in the fall of The Agency issued an Early Communication in March 2008, regarding its ongoing safety review. 7 The Agency evaluated controlled clinical study data and AERS data regarding neuropsychiatric events. This document will focus on the safety review of the clinical database, with a brief overview of the post-marketing findings. The post-marketing experience is reviewed in more detail in the review by OSE. In its review of spontaneous post-marketing reports, the Agency noted a broad set of neuropsychiatric adverse events; some of these reports appeared consistent with a drug-induced effect (e.g. positive dechallenge or re-challenge). However, the Agency also concluded that the events were typically non-serious and reversed with the cessation of therapy. The Agency requested that the manufacturers of the leukotriene modifiers submit controlled trial data for suicidality, using the Columbia Classification strategy. 8 This classification strategy was used for the FDA s evaluation of suicidality in clinical trials for anti-depressant drugs. In addition, based upon post-marketing reports of other neuropsychiatric events, the Agency also requested the manufacturers submit controlled trial data for these types of events. Merck identified 41 trials in which 9,929 subjects were treated with montelukast, 7,780 were treated with placebo, and 4,724 were treated with an active control for a total population of 22,433 subjects. Of the 41 studies, 27 were conducted in patients with asthma, 11 in subjects with SAR, 2 in patients with PAR, and 1 in patients with migraine headaches. The duration of randomized treatment ranged from was 2 weeks to 56 weeks. In the Agency s review of the 41 submitted controlled clinical trials in 2008, one case of suicidal ideation was identified in montelukast-treated patients. This resulted in a final incidence of suicidal ideation of 1 in 9,929 subjects or 0.01%. Behavior-related adverse events (BRAE) were also evaluated in this safety database. The final population for the behavioral analysis consisted of 11,673 subjects treated with montelukast, 8,827 treated with placebo and 4,724 treated with active control. 7 fetyinformationforheathcareprofessionals/ucm htm [accessed March 18, 2014] 8 Posner K et al. Am J Psychiatry 2007; July 164(7): ) 34 of

35 The frequency for all events was 2.73% and 2.27% for montelukast and placebo treatment, respectively. The frequency of behavior-psychiatric events was 2.56% and 2.12% in the montelukast and placebo-treated subjects, respectively. In the adult population, sleep disorders were the most common, and they were more common with montelukast treatment. In the 18 to 30 year-old subjects the incidence was 0.91% and 0.38% for montelukast and placebo-treated subjects, respectively. A strong signal for neuropsychiatric events was not identified in the clinical database. However, the Agency acknowledged the limitations of the clinical trial data because the clinical trials were not designed specifically to examine neuropsychiatric events. Overall, the clinical data did not show a causal association between montelukast and suicide or suicidal behavior, and there was no quantitative signal for an association of suicide with montelukast treatment in the spontaneous reports. The overall rate of behavior and mood-related events was low, with sleep disorders being the most common in adult patients. Despite the limitations, the Agency requested that the Sponsor add information to the montelukast product label to describe the reports of neuropsychiatric events. Eosinophilic Conditions Eosinophilic conditions have been reported with montelukast; however, because these conditions are primarily noted in patients with asthma, only a brief summary is included here. Churg-Strauss Syndrome (CSS) is a vasculitis of the small to medium sized arteries. The American College of Rheumatology has 6 criteria for the diagnosis: asthma, eosinophilia (>10%), paranasal sinusitis, pulmonary infiltrates, histological proof of vasculitis with extravascular eosinophils, and mononeuritis multiplex. 9 The presence of 4 or more criteria has a reasonable sensitivity and specificity for the diagnosis of CSS. The potential association of leukotriene receptor antagonists and vasculitis, including CSS, is well-recognized. When montelukast was first approved on February 20, 1998, information was included in the product label, regarding the potential for CSS. In October of 1998, Merck submitted a labeling supplement to update the language in the product label based upon post-marketing reports with montelukast. According to the reviews, 6 of the post-marketing reports were consistent with CSS. 5.4 Common Adverse Events In the overall safety database, including all approved Rx indications for montelukast, the most common adverse reactions from controlled clinical trials as described in the current prescription label include (incidence 5% and greater than placebo; listed in descending order of frequency): upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis and otitis. 9 Masi AT, Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: of

36 Montelukast was evaluated in 5,029 adult and adolescent patients 15 years of age and older in clinical trials for SAR. Upper respiratory infection was the only adverse reaction reported with a frequency of 1% and at an incidence greater than placebo (1.9% montelukast vs. 1.5% placebo). In PAR clinical trials, 3,357 adult and adolescent patients 15 years of age and older reported the following adverse reactions with a frequency of 1% and at an incidence greater than placebo: sinusitis, upper respiratory tract infection, sinus headache, cough, epistaxis, and increased ALT. 6 Risk-Benefit Analysis While the efficacy and safety of montelukast for the proposed indication and age range have been established as a part of the Rx approval, the committee will need to consider whether these safety and efficacy findings are appropriate in the OTC setting. Overall, no new safety signals have been identified during this review. The safety of montelukast is derived from the clinical development program for the prescription montelukast product. Fifteen years of post-marketing experience have raised some safety concerns associated with neuropsychiatric events. We ask the committee to consider whether concerns related to neuropsychiatric events can be addressed with appropriate labeling in the OTC setting. Given that this is a partial OTC switch for allergic rhinitis in adults, there is a potential challenge associated with targeting the allergic rhinitis population while excluding offlabel OTC use among the asthmatic population. This is of particular importance, given the significant overlap between these two populations and the role of montelukast in treating allergic rhinitis in those patients with asthma, per practice guidelines. Therefore, the potential for off-label use in asthma is another important issue for discussion. Finally, OTC products to treat symptoms associated with allergic rhinitis have been available for many years and include both intranasal and oral products. Each of these products has a different role in the clinical landscape of treating allergic rhinitis, based on their relative efficacy and safety profiles, and their recommended use is described in a number of practice parameters and guidelines. Whether the complexities of managing allergic rhinitis in the face of multiple variable treatment options can be communicated to and understood by the OTC consumer will be an important issue for discussion. 36 of

37 Statistical Review for the Pulmonary-Allergy Drug Advisory Committee Meeting May 2, 2014 Singulair Allergy (Montelukast Sodium 10mg Tablets) NDA Dose: Montelukast Sodium 10mg Proposed indication: The relief of symptoms of allergic rhinitis, temporarily relieves itchy, watery eyes due to hay fever or other upper respiratory allergies Statistical Reviewer: Kiya Hamilton, PhD Concurring Statistical Reviewer: Ruthanna Davi, PhD Division of Biometrics 2 Director: Thomas Permutt, PhD Department of Health & Human Services Food & Drug Administration Center for Drug Evaluation & Research Division of Pulmonary, Allergy and Rheumatology Products Silver Spring, MD of 207

38 Table of Contents LIST OF TABLES EXECUTIVE SUMMARY INTRODUCTION OVERVIEW DATA SOURCES STATISTICAL EVALUATION DATA AND ANALYSIS QUALITY EVALUATION OF EFFICACY EVALUATION OF SAFETY FINDINGS IN SPECIAL/SUBGROUP POPULATIONS SUMMARY AND CONCLUSIONS STATISTICAL ISSUES COLLECTIVE EVIDENCE CONCLUSIONS AND RECOMMENDATIONS of 207

39 LIST OF TABLES Table 1 Summary of Study Design... 7 Table 2 Study 162 Subject Disposition (ITT)... 9 Table 3 Study 192 Subject Disposition (ITT)... 9 Table 4 Study 235 Subject Disposition (ITT) Table 5 Study 162 Subject Demographic and Baseline Characteristics (ITT) Table 6 Study 192 Subject Demographic and Baseline Characterisitcs (ITT) Table 7 Study 235 Subject Demographic and Baseline Charactersitics (ITT) Table 8 Effects of Montelukast (10mg once daily) in Patients with Seasonal Allergic Rhinitis: Overall Daytime Eye Symptoms Score (dess) (ITT) of 207

40 1. EXECUTIVE SUMMARY Singulair (montelukast sodium) tablets, chewable tablets and oral granules are currently FDA approved for prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction (EIB) and relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). With this submission, the sponsor proposes to change the marketing status of the indication for the relief of symptoms of allergic rhinitis in adults for Singulair Tablets (montelukast sodium) from prescription (Rx) to over-the-counter (OTC). The applicant is also requesting approval for the indication temporarily relieves itchy, watery eyes due to hay fever or other upper respiratory allergies is included in the labeling. The applicant submitted three pivotal studies, Protocol 162, Protocol 192 and Protocol 235 to support adding the ocular indication to the non-prescription label; however, this indication is not included in the current prescription label. All three studies were conducted in patients with SAR. Singulair will be referred to herein as montelukast. The focus of this review is on the addition of the ocular endpoint to the label. The relevant secondary endpoint, daytime eye symptoms score, was not included in the pre-specified endpoints to be adjusted for multiple comparisons in protocols 162, 192, and 235. At the time of proposed promotional materials for montelukast, there were several discussions between the applicant and FDA about this endpoint; FDA was not in agreement with the use of this endpoint to claim efficacy for the ocular indication. FDA stated that the secondary endpoints may constitute an overstatement of efficacy because the secondary endpoints were not corrected for multiple comparisons using a pre-specified analysis and the effect sizes were so small that they were not considered substantial evidence to support claims of clinical significance. In addition, the applicant did not pre-specify any missing data imputations for this endpoint stating that the amount of missing data was expected to be low. The conclusion of this statistical review is that there is insufficient evidence to support adding the secondary endpoint, daytime eye symptoms score, and an ocular indication to the over-thecounter label for Singulair. 2. INTRODUCTION 2.1 Overview Class and Indication Montelukast sodium tablets, chewable tablets and oral granules are currently FDA approved for prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction (EIB) and relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). In the current submission, the sponsor proposes to change the marketing status of the indication for the relief of symptoms of allergic rhinitis in adults for montelukast sodium tablets from prescription (Rx) to over-the-counter (OTC). The sponsor is also requesting approval that the indication temporarily relieves itchy, watery eyes due to hay fever or other upper respiratory allergies be included in the labeling of 207

41 2.1.2 History of Drug Development The sponsor had several interactions with the Division of Drug, Marketing, Advertising and Communications (DDMAC) and the Division of Pulmonary and Allergy Products (DPAP) regarding their proposed promotional materials (under NDAs , and ). The applicant also met with the Division of Nonprescription Drug Clinical Evaluation/ONP regarding the proposed nonprescription label for the Rx-to-OTC switch (under IND 74,291). Pertinent parts of the statistical portion of the communications and interactions for the montelukast program are summarized herein. In the written response from FDA to the sponsor in 2005 regarding the proposed health care professional launch promotional materials based on the secondary endpoints DDMAC stated that claims for SAR based on secondary endpoints constitutes an overstatement of efficacy because they are based on secondary endpoints which were not corrected for multiple comparisons using a pre-specified analysis. In studies P162, P192 and P235 (the studies included in the current submission) the sponsor then proposed a post-hoc multiplicity adjustment using the Bonferroni correction. In February 2006, DDMAC consulted the Division of Biometrics (DB) II statistics team at FDA to evaluate the data submitted by the sponsor to support the efficacy claims in the proposed promotional materials for SAR and PAR for montelukast. The response from the statistical consult stated that from a statistical point of view, the sponsor s proposal to use a Bonferroni correction for the pre-specified secondary endpoints was acceptable. There were numerical trends in daytime eye symptoms score, the secondary endpoint of interest, in favor of montelukast 10mg over placebo in all three of the pivotal studies that were submitted. However, results for the daytime eye symptoms score reached statistical significance (using the Bonferroni correction for multiple endpoints) in only 1 of the 3 pivotal studies. DDMAC and DPAP conveyed these results as well as addressed other issues to the sponsor in a teleconference on March 30, In this meeting DPAP also stated that even though the post-hoc Bonferroni correction for multiple secondary endpoints was statistically acceptable, the effect sizes for these endpoints were not clinically meaningful. The effect sizes from the secondary endpoint were so small that they were not considered substantial evidence to support claims of clinical significance. The sponsor agreed that the secondary endpoints were not appropriate for labeling but with DDMAC s concurrence could be used in the promotion if presented properly. DDMAC and DPAP agreed to further communication on this issue when the sponsor submits the alternative way to present the secondary endpoints. On May 22, 2006 FDA sent a written response to the sponsor regarding their alternative proposed promotional spread. The sponsor proposed: "Significantly reduced daytime eye symptom scores - measured as the average of the following individual scores: tearing, itchy eyes, redness, puffiness. SINGULAIR 10 mg vs. placebo: vs (P 0.001) Active control (loratadine 10 mg) vs. placebo: vs (P 0.001) "Efficacy further supported by secondary endpoints, although the minimum differences of clinical relevance for secondary end points have not been established" 5 41 of 207

42 "Secondary end-point data for the seasonal allergic rhinitis pivotal studies were collected in patient diaries. Although the results for SINGULAIR were statistically significant vs placebo, the end points and the diary were not separately validated for these studies." DDMAC maintained their objection that the claims were misleading because they overstate the efficacy of montelukast by implying clinical significance for the secondary endpoints of daytime eye symptoms score, nighttime symptoms score and full 24-hour nasal symptom relief, when such has not been demonstrated by substantial evidence. A pre-nda meeting was held on February 7, 2013 with the sponsor and the Division of Nonprescription Drug Clinical Evaluation/ONP to discuss development requirements for an Rxto-OTC switch. FDA noted that the sponsor included eye symptoms in their (b) (4) nonprescription labeling. The sponsor stated that they modeled the proposed labeling after the current OTC monograph for antihistamines. FDA clarified that montelukast does not currently have these claims in the product label of the prescription product and because montelukast is not an antihistamine, the proposed labeling should not be modeled after the antihistamine monograph. In addition, FDA noted that the proposed labeling claims included nasal congestion, which is not part of the monograph for antihistamines, but was one of the components of the TNSS that formed the basis of the initial approval and is included in the prescription label. FDA (b) (4) stated that any approval of a claim of relief of eye symptoms would be a review issue Specific Studies Reviewed Efficacy studies Protocol 162, Protocol 192 and Protocol 235 are the focus of this review. All three studies were a multicenter, double-blind, randomized, placebo-controlled, parallel-group studies of 2 weeks duration in subjects with seasonal allergic rhinitis (SAR). 2.2 Data Sources All data was supplied by the applicant to the CDER electronic data room in SAS transport format. The data and final study report for the electronic submission were archived under the network path location \\CDSESUB1\evsprod\NDA204804\ enx. The information needed for this review was contained in modules 1, 2.5, 2.7, and STATISTICAL EVALUATION 3.1 Data and Analysis Quality In general, the submitted efficacy data are acceptable in terms of quality and integrity. Primary and secondary efficacy analyses for studies Protocol 162, Protocol 192 and Protocol 235 were reproducible from the data sets provided. 3.2 Evaluation of Efficacy Study Design and Endpoints 6 42 of 207

43 Montelukast is an approved drug for allergic rhinitis (AR). The applicant is seeking to switch this drug from prescription (Rx) to over-the-counter (OTC). The focus of this review is on the eye efficacy endpoints in the three efficacy studies submitted by the applicant, studies Protocol 162, Protocol 192 and Protocol 235, referred to as 162, 192 and 235 respectively. Note that these three studies have been reviewed previously for the approval of montelukast; however, the eye efficacy endpoint was not the focus of that review. A summary of the study design and efficacy endpoints for each study are given in Table 1. Table 1 Summary of Study Design Study ID Indication Length of the Study Treatment Arms 162 SAR 2 weeks Montelukast 10mg Loratadine 10mg Placebo 192 SAR 2 weeks Montelukast 10mg Loratadine 10mg Placebo 235 SAR 2 weeks Montelukast 10mg Loratadine 10mg Placebo Number of Patients Secondary Eye and Other Eye Efficacy Endpoints of Interest Daytime Eye Symptoms Score Daytime Eye Symptoms Score End of Day symptoms score (exploratory endpoint) Daytime Eye Symptoms Score End of Day symptoms score (exploratory endpoint) Each of the three studies was multicenter, double-blind, randomized, placebo-controlled, and parallel-group with 2 weeks double-blind treatment duration in subjects with seasonal allergic rhinitis (SAR). Subjects were randomized to receive either 10mg of montelukast, 10mg of loratadine or placebo once daily at bedtime, irrespective of food intake. Loratadine was included in these studies as an active control and was only compared to placebo. To maintain the treatment blind, subjects were given three bottles, two placebo and one active of each of 10 mg montelukast, 10 mg loratadine, and placebo and were instructed to take one tablet from each bottle. No rescue mediations were allowed during these studies. Study 162 had a fourth treatment group, montelukast/loratadine, but this arm was removed due to the results from study Protocol 117 (not discussed here). In each study the primary efficacy endpoint was the change from baseline in daytime nasal symptoms score, which is the average score of nasal congestion, rhinorrhea, nasal itching and sneezing. The secondary efficacy endpoints were change from baseline in nighttime symptoms score, change from baseline in daytime eye symptoms score (average score for tearing, 7 43 of 207

44 itchy, red and puffy eyes), change from baseline in global evaluations of allergic rhinitis by the patient and by the physician and change from baseline in rhinoconjunctivitis quality-of-life questionnaire (RQLQ) score. The statistical data analysis plan (SDAP) pre-specified that there were no adjustments for multiplicity with respect to between treatment comparisons in these studies since the prespecified primary comparison was between the montelukast and placebo treatment arms. The comparison of loratadine and placebo was secondary. The SDAP also pre-specified that there were no multiplicity adjustments with respect to the efficacy variables. The primary variable was change from baseline in daytime nasal symptom score and all the other variables named above were considered secondary Statistical Methodologies The SDAP pre-specified that the efficacy analyses were to be performed using the intent-to-treat (ITT) population, defined as all subjects who have a baseline value and at least one post treatment measurement. For each study, the primary and secondary endpoints were analyzed using an analysis of covariance (ANCOVA) model with baseline value of the dependent variable as covariate and treatment and study center as factors in the model. The SDAPs specified that there were no imputations for missing data since the primary and key secondary endpoints were analyzed as averages over the 2-week treatment period. While not specified as an explicit missing data procedure this is effectively a missing data imputation based on an assumption that a subject s missing scores would, on average, be the same as that subject s observed scores. The applicant conducted subgroup analyses for the primary and key secondary efficacy endpoints in the ITT population based on age, gender, race, country, reported history of allergic conjunctivitis patient reported, reported history of asthma patient reported, active asthma at the start of study patient reported, average pollen count exposure during treatment period, baseline congestion score (<2, 2) and baseline congestions score (by tertile). Treatment-by-factor interactions were examined for each of the subgroups to determine whether the treatment effects were consistent across different study centers and the subgroups. ANCOVA models were used to analyze the subgroups with treatment, study center subgroup and treatment-by-subgroup interaction and baseline as covariate. The subgroup analyses were performed using the ITT population only. These analyses were reviewed in the original submission of these studies, montelukast 10mg showed a consistent effect except among the black population where placebo was numerically better than montelukast 10mg. This numeric imbalance was not believed to represent a true effect in this subgroup and was likely a random imbalance. Thus, the subgroups analyses are not described in this review and the reader is referred to the Statistical Review and Evaluation of montelukast dated January 1, Patient Disposition, Demographic and Baseline Characteristics The summary of the patient disposition in studies 162, 192 and 235 are given in Table 2, Table 3 and Table 4 respectively. In study 162 there were 1302 subjects who met the inclusion criteria and were randomized in a 1:2:1 ratio. There were 348 subjects assigned to receive montelukast 10mg, 602 were assigned to receive loratadine 10mg and 352 were assigned to placebo. In study 8 44 of 207

45 192 there were 829 subjects who met the inclusion criteria and were randomized in a 2:1:2 ratio. There were 326 subjects assigned to receive montelukast 10mg, 170 assigned to receive loratadine 10mg and 333 assigned to receive placebo. There were 1214 subjects who met the inclusion criteria and randomized in a 3:1:3 ratio in study 235. There were 522 subjects assigned to receive montelukast 10mg, 171 assigned to receive loratadine 10mg and 521 assigned to receive placebo. Study 162 had 59 (5%) subjects withdraw from the study early, study 192 had 34 (4%) withdraw from the study early and study 235 had 56 (5%) withdraw from the study early. The primary reasons for discontinuation were lack of efficacy (2% in study 162, 1% in study 192 and 1% in study 235) and clinical adverse experience (1% in study 162, 2% in study 192 and 1% in study 235). The reasons for discontinuations were infrequent and balanced across the treatment groups in each study and therefore not expected to have overly influenced the primary and secondary efficacy analyses. Table 2 Study 162 Subject Disposition (ITT) Placebo Montelukast 10mg Loratadine 10mg Subjects Randomized Discontinued 18 (5%) 12 (3%) 29 (5%) Reasons for early discontinuation Clinical adverse Experience 1 (<1%) 3 (1%) 9 (2%) Lack of efficacy 8 (2%) 4 (1%) 8 (1%) Lost to follow-up 1 (<1%) 1 (<1%) 2 (<1%) Patient withdrew 2 (<1%) 1 (<1%) 1 (<1%) Consent Protocol deviation 2 (<1%) 2 (<1%) 7 (1%) Other 4 (1%) 1 (<1%) 2 (<1%) Source: MRL (Merck Research Laboratories) Clinical Study Report for Study (Protocol 162) Table 10, page 63 Table 3 Study 192 Subject Disposition (ITT) Placebo Montelukast 10mg Loratadine 10mg Subjects Randomized Discontinued 10 (3%) 17 (5%) 7 (4%) Reasons for early discontinuation Clinical adverse experience 4 (1%) 8 (2%) 2 (1%) Lack of efficacy 3 (1%) 4 (1%) 2 (1%) Lost to follow-up 1 (<1%) 0 0 Patient withdrew 1 (<1%) 2 (<1%) 1 (<1%) consent Protocol deviation 1 (<1%) 3 (1%) 2 (1%) Source: MRL Clinical Study Report for Study (Protocol 192) Table 10, page of 207

46 Table 4 Study 235 Subject Disposition (ITT) Placebo Montelukast 10mg Loratadine 10mg Subjects Randomized Discontinued 29 (6%) 21 (4%) 6 (4%) Reasons for early discontinuation Clinical adverse experience 8 (2%) 7 (1%) 1 (<1%) Lack of efficacy 11 (2%) 5 (1%) 1 (<1%) Lost to follow-up 1 (<1%) 1 (<1%) 0 Patient moved 1 (<1%) 0 0 Patient withdrew 4 (1%) 5 (1%) 1 (<1%) consent Protocol deviation 3 (<1%) 2 (<1%) 1 (<1%) Other 1 (<1%) 1 (<1%) 2 (<1%) Source: MRL Clinical Study Report for Study (Protocol 235) Table 10, page 64 The demographics and baseline characteristics in studies 162, 192 and 235 are summarized in Table 5, Table 6 and Table 7 respectively for the ITT population. These factors were generally well-balanced across the treatment groups in each study. Table 5 Study 162 Subject Demographic and Baseline Characteristics (ITT) Placebo N=352 Montelukast 10mg N=348 Loratadine 10mg N=602 Age (years) Mean ± SD 35.9 ± ± ± 13 Range 15 to to to 74 Gender [n (%)] Male 123 (35%) 115 (33%) 212 (35%) Female 229 (65%) 233 (67%) 390 (65%) Race [n (%)] Black 26 (8%) 34 (10%) 8 (5%) Hispanic American 9 (3%) 15 (5%) 9 (5%) White 289 (87%) 269 (83%) 149 (88%) Other 9 (3%) 8 (2%) 4 (2%) Weight (kg) Mean ± SD 74 ± ± ± 16.8 Range 42 to to to 138 Height (cm) Mean ± SD ± ± ± 10.2 Range 145 to to to 203 Duration of Allergic Rhinitis (Years) Mean ± SD 17.9 ± ± ± 12.3 Range 0 to 55 2 to 60 1 to 64 Source: MRL Clinical Study Report for Study (Protocol 162) Table 12 and Table 13, pages of 207

47 Table 6 Study 192 Subject Demographic and Baseline Characteristics (ITT) Placebo N=333 Montelukast 10mg N=326 Loratadine 10mg N=170 Age (years) Mean ± SD 36.4 ± ± ± 12.3 Range 15 to to to 66 Gender [n (%)] Male 111 (33%) 99 (30%) 51 (30%) Female 222 (67%) 227 (70%) 119 (70%) Race [n (%)] Black 26 (8%) 34 (10%) 8 (5%) Hispanic American 9 (3%) 15 (5%) 9 (5%) White 289 (87%) 269 (83%) 149 (88%) Other 9 (3%) 8 (3%) 4 (2%) Weight (kg) Mean ± SD 76.2 ± ± ± 18.5 Range 44 to to to 138 Height (cm) Mean ± SD ± ± ± 10 Range 135 to to to 198 Duration of Allergic Rhinitis (Years) Mean ± SD 18.6 ± ± ± 13.0 Range 0 to 70 2 to 65 2 to 52 Source: MRL Clinical Study Report for Study (Protocol 192) Table 12 and Table 13, pages Table 7 Study 235 Subject Demographic and Baseline Characteristics (ITT) Placebo N=521 Montelukast 10mg N=522 Loratadine 10mg N=171 Age (years) Mean ± SD 35.8 ± ± ± 12.7 Range 15 to to to 72 Gender [n (%)] Male 183 (35%) 196 (37%) 71 (41%) Female 338 (65%) 326 (63%) 100 (59%) Race [n (%)] Black 47 (9%) 39 (8%) 8 (5%) Hispanic American 27 (5%) 14 (3%) 9 (5%) White 406 (78%) 427 (82%) 149 (88%) Other 41 (8%) 42 (8%) 4 (2%) Weight (kg) Mean ± SD 75.7 ± ± ± 16.9 Range 29 to to to 137 Height (cm) Mean ± SD ± ± ± 10.6 Range 142 to to to 198 Duration of Allergic Rhinitis (Years) Mean ± SD 18 ± ± ± 11.8 Range 2 to 57 2 to 72 2 to 53 Source: MRL Clinical Study Report for Study (Protocol 235) Table 12 and Table 13, pages of 207

48 3.2.4 Results and Conclusions Secondary Efficacy Endpoint, Daytime Eye Symptoms Score The focus of this review is on the ocular secondary endpoint, daytime eye symptoms score. The primary endpoint for all three studies, daytime nasal symptoms score, has previously been reviewed and will not be discussed here. The applicant s results for each of the three pivotal studies are shown in Table 8 for daytime eye symptoms score. The daytime eye symptoms score was the average of tearing, itchy, red and puffy eyes (with each symptom scored on a 0 (none) to 3 (symptom bothersome most of the time and/or very bothersome some of the time) point ordinal scale) over the two week period. There were no pre-specified multiplicity corrections in place for the secondary endpoints, including the ocular endpoints, for any of the three studies. The applicant proposed a post-hoc Bonferroni correction to adjust for multiple endpoints. From a statistical point of view the applicant s posthoc proposal to adjust for multiplicity in the pre-specified secondary endpoints using a Bonferroni procedure is acceptable. No missing data imputations were explicitly made for the daytime eye symptoms score. Missing values were, in essence, assumed to be the same as the average response for each subject. The dropout rates were small overall, 3% to 6% in the three studies so these factors surrounding the handling of missing data are not expected to have overly influenced the efficacy comparisons. All three studies showed a numerical trend in daytime eye symptoms score in favor of montelukast 10mg over placebo. However, in accordance with the post-hoc Bonferroni adjustment for multiple comparisons, p-values smaller than a significance level of 0.05/5=0.01 are statistically significant. Using the Bonferroni approach, only one of the three studies achieved statistical significance for the daytime eye symptoms score endpoint. Table 8 Effects of Montelukast (10 mg once daily) in Patients with Seasonal Allergic Rhinitis: Overall Daytime Eye Symptoms Score (dess) (ITT) Study N Mean Baseline (Score) Change from Baseline (Score) Mean±SE Difference in Means (95%CI) P-Value Montelukaslukast Placebo Monte- Placebo Montelukast Placebo Montelukast-Placebo ± ± (-0.22, -0.06) 0.001* ± ± (-0.14, 0.01) ± ± ( -0.13, -0.01) Source: Integrated Summary of Efficacy Table 9, page 17 *In accordance with the post-hoc Bonferoni adjustment for multiple comparisons, p-values smaller that a significance level of 0.05/5=0.01 are statistically significant of 207

49 3.3 Evaluation of Safety As part of this review, no special types of safety events were identified for thorough statistical evaluation. Please refer to the Medical Review of this submission for more information regarding the safety findings. 4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS The subgroup analyses were conducted during the original submission. In that review, montelukast 10mg showed a consistent effect except among the black population where placebo was numerically better than montelukast 10mg. This numeric imbalance was not believed to represent a true effect in this subgroup and was likely a random imbalance. Thus, this review does not include the subgroup analysis and the reader is referred to the Statistical Review and Evaluation of Singulair dated January 1, SUMMARY AND CONCLUSIONS 5.1. Statistical Issues During the course of this review, the following statistical issues were identified and resolved. Each issue is further described in the context of the referenced sections. Secondary endpoints were not corrected for multiple comparisons using a pre-specified analysis. (Refer to section ) Applicant had already been informed by DDMAC and DPAP that the secondary endpoints were an overstatement of efficacy because they are based on secondary endpoints which were not corrected for multiple comparisons using a pre-specified analysis (Refer to section 2.1.2) Applicant submitted a post-hoc Bonferroni correction that showed that only 1 out of the 3 studies were statistically significantly different in favor of montelukast over placebo for daytime eye symptoms score. (Refer to section ) No explicit imputation methods for missing data were performed but since the primary and key secondary endpoints were analyzed as averages, missing scores were assumed to be the same, on average, as the observed scores within a subject. (Refer to section 3.2.2) 5.2. Collective Evidence Three pivotal studies were reviewed in support of this application, study 162, 192 and 235. No assessment of collective evidence across studies is provided in this review and the reader is referred to section 5.3 for the conclusions and recommendations resulting from the review of studies 162, 192 and Conclusions and Recommendations of 207

50 Studies 162, 192 and 235 were previously submitted and reviewed in the original application for montelukast. All three studies were again submitted, but now in support of the indication of itchy and watery eyes being added to the over-the-counter label for montelukast. In each study, the daytime eye symptoms score was a secondary endpoint that was defined as the average of tearing, itchy, red and puffy eyes (each score on a 0 to 3 point scale). This endpoint was not part of a pre-specified multiplicity plan. Not taking any post-hoc multiplicity adjustments into account, the differences between motelukast and placebo for this endpoint resulted in p-values smaller than a nominal 0.05 in two out of the three studies, studies 162 and 235. When the Bonferroni correction was applied post-hoc to adjust for multiplicity, only one of the three studies demonstrated a statistical significance difference between treatment groups for the daytime eye symptoms score endpoint, study 162. FDA and the applicant have had many discussions about the secondary endpoints. FDA noted on many occasions that claims for SAR based on secondary endpoints constitutes an overstatement of efficacy because they are based on secondary endpoints which were not corrected for multiple comparisons using a pre-specified analysis. Even separate from the issue of determining statistical significance, DPAP has indicated that the estimated differences between the treatment groups were not clinically meaningful and that the effect sizes from the secondary endpoint were so small that they were not considered substantial evidence to support claims of clinical significance. Based on the above evaluations and discussions on the analysis of the secondary endpoint, daytime eye symptoms score, the conclusion of this statistical review of studies 162, 192 and 235 is that there is insufficient evidence to support adding the claim of temporarily relieves itchy and water eyes to the non-prescription label for montelukast of 207

51 FDA Clinical Review: Overview of Post-marketing Experience for Singulair Division of Nonprescription Clinical Evaluation (DNCE) Review Date: March 31, 2014 From: Linda Hu, MD, Medical Officer, DNCE Through: Lucie Yang, MD, PhD, Team Leader, DNCE To: Subject: Members, Nonprescription Drugs Advisory Committee (NDAC) Post-marketing data for the Singulair partial over-the-counter (OTC) switch for individuals >18 years of age with allergic rhinitis This section summarizes the safety data for prescription montelukast submitted by the applicant from Post-marketing databases, including the applicant s pharmacovigilance database (MARRS), FDA s Adverse Event Reporting System (FAERS), the World Health Organization (WHO Vigibase), the American Association of Poison Control Centers (AAPCC), the Drug Abuse Warning Network (DAWN) Published literature, which focused on neuropsychiatric events and Churg- Strauss Syndrome (CSS) Review of post-marketing adverse events for montelukast consistently, across databases, revealed high reporting frequencies for neuropsychiatric events and CSS, among other events. We reviewed the submitted post-marketing data, including case descriptions, and determined that the reported events are generally reflected in the current prescription labeling. The FDA reviews of post-marketing data assessed the association of montelukast use with neuropsychiatric events and concluded that the clinical details of some postmarketing reports involving montelukast appear consistent with a drug-induced effect. There also appear to be cases in patients on montelukast for a short time in which a delay in effective treatment of an acute asthma attack resulted in death. An important consideration for the partial switch is whether montelukast can be safely used in the OTC setting. Montelukast is a widely used prescription medication for asthma, where a substantial portion of the prescription use is also in children. Currently 1 51 of 207

52 there is no approved OTC controller medication for the treatment of asthma. The present application is a partial switch of montelukast only for allergic rhinitis symptoms and only in adults. If montelukast is approved OTC, consumers may recognize it as a prescription asthma medication and use it to treat asthma -- including childhood asthma. The proposed label states, DO NOT USE TO TREAT ASTHMA ; whether such labeling is effective is an important issue (see FDA Social Science Review by Barbara Cohen). Due to the potential for increased inappropriate OTC use of Singulair if marketed OTC for some, but not all, prescription indications and age groups, extrapolation of postmarketing safety from the prescription product to the proposed OTC product must be interpreted with caution. Background The first prescription approval for montelukast was in Mexico in In 1998, montelukast was approved in the U.S. as prescription medication for prophylaxis and chronic treatment of asthma. Additional indications were approved in the U.S. in 2002 (seasonal allergic rhinitis), 2005 (perennial allergic rhinitis), and 2012 (exercise induced bronchoconstriction). Montelukast has been approved in over 100 countries worldwide for prescription treatment of asthma and in over 50 countries for prescription treatment of allergic rhinitis. Montelukast has not been approved for nonprescription use in any country. The prescription label warns against use in acute asthma. There are additional warnings regarding the need to taper concomitant corticosteroids gradually, aspirin sensitivity, neuropsychiatric events, systemic eosinophilia (including Churg-Stauss Syndrome), and phenylketonuria (chewable tablet only). Post-marketing Databases The applicant reports 24.2 billion units distributed worldwide for all indications since market introduction to May 30, Montelukast has not been withdrawn from marketing in any country for reasons related to safety or efficacy. Interpretation of spontaneously reported adverse events (AEs) has limitations such as voluntary submission of reports, unknown magnitude of underreporting, inability to calculate incidences, limited clinical information in reports, inability to determine causality for most cases, duplicate cases, and reporter bias. Additionally, information from publications, lawsuits, or public health agencies may stimulate reporting of 207

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55 16 year old male with asthma visited his physician to "get ready for football." Never hospitalized or seen in ER for asthma. The patient was previously managed with inhalers (regimen not changed) and was given montelukast sodium. The patient took one dose of montelukast sodium and on the next day, visited his primary care physician with complaints of breathlessness and bronchospasm. At nighttime one day after the first montelukast dosing, the patient's asthma symptoms worsened; in the morning 36 hours after first dosing, while in the car on the way to the physician's office, the patient suddenly stopped breathing. Autopsy was consistent with acute bronchial asthma. 7 year old female diagnosed with asthma and seen in ER three times in two weeks. Sixteen days after asthma was diagnosed, given montelukast sodium tablet, 5 mg daily for the treatment of asthma with concomitant Albuterol prn. Five days after given montelukast, the patient complained of a stomach ache, had trouble breathing, went to bed, woke up and collapsed in ventricular fibrillation. The autopsy showed signs consistent with reactive airway disease, no suggestion of eosinophilia, no history of sinusitis or cardiac dysrhythmias. No suggestion of medication overdose. 59 year old female with arthralgia and hypercholesterolemia and history of smoking until five years before montelukast therapy, but no history of cardiac disease, was placed on therapy with montelukast sodium for asthma. Concomitant therapy included diclofenac and misoprostol. One month after given montelukast, the patient experienced status asthmaticus and died. The patient s husband commented that the patient s asthma attack was quite different from her previous attacks. Serious Adverse Events In general, the percent of serious AEs in each system organ class (SOC) largely mirrored the percents in SOCs among all reported AEs (serious and non-serious). The top five SOCs with the highest percent serious AEs were injury, poisoning and procedural complications (51%); psychiatric disorders (24%); general disorders and administration site conditions (24%); nervous system disorders (14%); and respiratory, thoracic and mediastinal disorders (14%). By age, 62% of serious AEs were in children, with 40% in 2-5 year olds of 207

56 Most Common SOC Categories and Adverse Events According to the sponsor, the top five most frequent events in each of the top five most common SOCs from MARRS are as follows. Numbers of events are in ( ). Psychiatric SOC insomnia (1816), aggression (1756), nightmare (1729), abnormal behaviour (1617), depression (1567) General disorders no adverse event (2082), drug ineffective (1341), irritability (1072), crying (677), fatigue (659) Injury, poisoning and procedural complications accidental exposure (3756), headache (2703), overdose (2111), maternal exposure during pregnancy (808), accidental overdose (558), maternal exposure timing unspecified (521) Nervous system disorders headache (2703), dizziness (860), psychomotor hyperactivity (749), paraesthesia (616), somnolence (616) Gastrointestinal disorders abdominal pain (1169), nausea (1031), diarrhea (1012), vomiting (819), abdominal pain upper (605) In general, the adverse events listed above are listed in the prescription label. The sponsor explains that no adverse event refers to events of overdose or maternal exposure where no clinical effect is reported. The majority of overdoses were cases in 0-5 year old subjects reported to the Texas Poison Center Network in a retrospective study from 2000 to In that report, the majority of ingestions produced no effects, and no outcomes greater than minor effects were reported. Overdose information in the current prescription label describes trials administering doses up to 200 mg/day for 22 weeks and up to 900 mg/day for ~ 1 week without clinically important adverse experiences. There are no adverse experiences in the majority of overdose reports. The prescription label describes the most frequently occurring adverse experiences in overdose as abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. FDA s Adverse Event Reporting System and WHO s Vigibase (ex-us) Please see FDA s Pharmacovigilance Review for a detailed review of FAERS data through October Below we review the FAERS information submitted by the applicant. The applicant s search of FAERS from February 1998 to October 2012 identified 8815 case reports with adverse events. Cases were not analyzed by age or indication for which montelukast was prescribed of 207

57 Table 4 shows the 25 most frequently reported adverse events (Preferred Terms) in FAERS over the time period from U.S. montelukast approval through June Most of the AEs came from the Psychiatric Disorders SOC (13 of the top 25 events). The most common event was depression (866 events, 2.56% of all AEs), followed closely by suicidal ideation (852 events, 2.52% of AEs). Abnormal behavior, aggression, anxiety, insomnia and anger are all among the top 10 most common terms, and all occurred at rates between 1 and 2% of all AEs. Crying, nightmare, mood swings, mood alteration, irritability, and agitation appear among the top 20 most common AEs, and these occurred at rates between 0.75% and 1% of all AEs. Other frequently reported events in FAERS relate to suicidality, such as suicidal ideation (2.52% of all events) and suicide attempt (0.58% of all events) as well as other behavior-related events such as depression and anxiety. Allergic granulomatous angiitis (Churg-Strauss Syndrome) was third in terms of frequency (829 events, 2.45% of AEs). Headache, pyrexia, cough, vomiting, abdominal pain and nausea are also among the most frequently reported AEs of 207

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59 The applicant s search of WHO s Vigibase from February 1998 to October 2012 identified 5342 ex-us case reports (cases reported from outside the US to avoid overlap with FAERS) with 10,810 adverse events. Table 5 shows the 25 most frequently reported adverse events (Preferred Terms) in Vigibase (ex-us cases) over this time period. While behavior-related AEs such as depression, anxiety, aggression, irritability, nightmare, and hallucinations are found in this dataset, suicidality related terms are not in the 25 most frequently reported events in the ex-us WHO VigiBase. Headaches, abdominal pain, rash, nausea, allergic granulomatous angiitis, dyspnea, palpitations and asthma are among the 25 most frequently reported events of 207

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63 concomitant medications. Twelve of the cases were suspected intentional suicides. For all AAPCC reports, the contribution of montelukast is unclear. Updated AAPCC data through March 2013 are generally consistent with the earlier reports. DAWN The applicant searched the Drug Abuse Warning Network (DAWN) database, a surveillance system monitoring drug-related emergency department visits. Based on the available data for 2004 through 2010, the applicant identified 1339 reports listing montelukast as a drug. The majority (~60%) of reports were in adults; among children, ~60% were from individuals <5 years old. A total of 126 (9%) suicide attempts were reported, of which none resulted in death and 14 identified montelukast as the sole drug of record. Safety Topics of Interest Neuropsychiatric Events Please see the Division Director s memo and FDA s Pharmacovigilance Review for additional details and history regarding neuropsychiatric events in the post-marketing setting. We note that the reported neuropsychiatric events are not limited to suicide or related behaviors, but include abnormal behavior, depression, aggression, insomnia, and nightmares. From an updated FDA review of FAERS and datamining results (see FDA Pharmacovigilance Review), association of neuropsychiatric events with montelukast continue to be found consistent with previous FDA reviews. Table 8 provides summaries of ten sample suicide case reports for which the behavior change appears to be correlated with use of the drug or the suicide occurs within a short time after starting or restarting montelukast. No new neuropsychiatric signals have been detected with this review of 207

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65 Churg-Strauss Syndrome (CSS) Please see the Division Director s memo and FDA s Pharmacovigilance Review for additional details regarding CSS. From an updated FDA review of FAERS and datamining results (see FDA Pharmacovigilance Review), potential association of CSS with montelukast continues to be found. According to Bibby et al (Thorax 65(2): ), corticosteroid withdrawal or pre-existing CSS may not explain the majority CSS cases reported in FAERS. As seen above, allergic granulomatous angiitis, also referred to as CSS, was one of the top 25 most frequently reported adverse events in FAERS and WHO s Vigibase. The sponsor s search of FAERS revealed 829 events of CSS, 2.5% of all events retrieved. The sponsor s search of MARRS identified 339 confirmed reports of CSS, of which 293 cases reported steroid use, both oral and systemic. Of the 293 cases with reported steroid use, 124 (42%) reported a reduction or withdrawal of steroids. We note that CSS occurs primarily in asthmatics. Thus, its relevance to the OTC setting may be limited. Literature Please see the FDA s Epidemiology Review for a recent survey of the literature regarding the risk of suicide and leukotriene-modifying agents. The applicant s literature search identified over 500 articles on montelukast safety, 83 of which were reviewed and summarized in the submission. The articles included information from databases in countries such as Sweden, Spain, and the United Kingdom. Many of the reports described neuropsychiatric events among children and adults who were exposed to montelukast. None definitively conclude a causal role for montelukast in neuropsychiatric events even though some articles did report positive challenge and de-challenge. Regarding CSS, it remains controversial whether the association between LTRA therapy and development of CSS is a causal relation or is a confounding by indication (since CSS is associated with asthma) of 207

66 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Pharmacovigilance Review Date: February 21, 2014 Reviewer(s): Team Leader(s): Division Director(s): Carolyn Volpe, PharmD, Safety Evaluator Division of Pharmacovigilance II Dipti Kalra, RPh, Safety Evaluator Division of Pharmacovigilance I Ali Niak, MD, Medical Officer Division of Pharmacovigilance I Peter Diak, PharmD, M.P.H., Team Leader Division of Pharmacovigilance II Eileen Wu, PharmD, Team Leader Division of Pharmacovigilance I Allen Brinker, MD, Team Leader Division of Pharmacovigilance I Min Chen, RPh, MS (Acting) Division of Pharmacovigilance I Product Name(s): Subject: Scott Proestel, MD Division of Pharmacovigilance II Singulair (montelukast) Neuropsychiatric events and Churg-Strauss Syndrome Application Type/Number: NDA NDA NDA NDA Submission Number: Applicant/Sponsor: Original Submission OSE RCM #: Merck Consumer Care, Inc. Merck & Co, Inc of 207

67 TABLE OF CONTENTS Executive Summary Introduction Background Previous Postmarketing Reviews Regulatory History Product Labeling Overview of Post-Marketing Data with Montelukast Methods and Materials Results Discussion Of Overview of Post-Marketing Data with Montelukast Neuropsychiatric Events Methods and Materials Results Discussion Churg-Strauss Syndrome Methods and Materials Results Discussion Conclusion Recommendations References Appendices Appendix A. FDA Adverse Event Reporting System (FAERS) Appendix B. Selected Sections of the Singulair Patient Information Appendix C. Line Listing of Unique Completed Suicide FAERS Reports from June 13, 2008 to October 31, 2013 (N=43) Appendix D. Audit Trails for Asthma and Allergy Indication PTs Appendix E. Empirica Signal Datamining Results of 207 2

68 EXECUTIVE SUMMARY This review evaluates the FDA Adverse Event Reporting System (FAERS) database and published literature for serious events reported with montelukast including death, neuropsychiatric events, and Churg-Strauss Syndrome (CSS). Safety concerns have been raised and addressed by the FDA in the past regarding the increased risk of neuropsychiatric adverse events, including suicide and suicide attempts, and CSS associated with the use of montelukast. The Division of Nonprescription Clinical Evaluation (DNCE) requested this review to update the previous Division of Pharmacovigilance (DPV) reviews of these events and inform a New Drug Application (NDA) submitted by Merck Consumer Care, Inc. (Merck), which requests a partial switch of montelukast to nonprescription status for the temporary relief of allergy symptoms in adults 18 years and older. The FDA (the Division of Pulmonary, Allergy, and Rheumatology Products and Office of Surveillance and Epidemiology) previously conducted several scientific reviews for all ages using data from the pre-market clinical trials and data from FAERS and literature to assess the association of neuropsychiatric events and CSS with montelukast use. These FDA reviews concluded that the clinical details of some post-marketing reports involving montelukast appeared consistent with a drug-induced effect. Labeling for both neuropsychiatric events (including suicide) and CSS appear in the Warnings and Precautions section of the current montelukast prescribing information. To update previous reviews, a search of the entire FAERS database identified a total of 11,649 reports with montelukast from approval (1998) to October 31, Seventy-six percent of all reports indicated a serious outcome, and death was reported as an outcome in approximately 5% of the total FAERS reports for montelukast. Completed suicide was reported in 1.6% of the total montelukast FAERS reports. Asthma was the most frequently reported indication, followed by allergy-related indications. Additionally, the most frequently reported preferred terms (PTs) included depression, suicidal ideation, allergic granulomatous angiitis, and abnormal behaviour. The median age was 31 years for the total FAERS report series. The median age was 45 years old for the completed suicide report series; however, in the neuropsychiatric reports (excluding completed suicide), it was 11 years old. In patients less than 18 years of age, death was reported as an outcome in 19% of the report series, and CSS was reported with montelukast in 5% of the report series. These ages are consistent with previous FDA reviews of neuropsychiatric events with montelukast use. Both age and indication were consistent with recent drug utilization data for montelukast. Based on the drug utilization data, adults accounted for the majority (58%) of montelukast patients, followed by pediatric patients aged 0 17 years old at approximately 43% of total patients. Moreover, from year 2002 to 2012, asthma was the top diagnosis associated with the use of montelukast among all patient age groups, followed by allergic rhinitis. 1 The FAERS reports of neuropsychiatric events were mostly from the US. The most frequently reported neuropsychiatric PT when montelukast was used for allergy-related indication was abnormal behaviour and for asthma-related indication was suicidal ideation. Most of the neuropsychiatric PTs reported are labeled events with the exception of crying. However, crying may be a manifestation of reported PT terms Irritability and Mood swings. Although a 68 of 207 3

69 mechanism of action for montelukast causing these neuropsychiatric events is unknown at the present time, patients and healthcare providers are advised to monitor for symptoms and to consider discontinuation of the drug in the event of these symptoms occurring. The neuropsychiatric events identified in this review are labeled in the prescribing information and the proposed over-the-counter (OTC) Drug Facts label with similar terms to those preferred terms reported in this review. In addition to FAERS, we reviewed the literature and dataming results. The majority of potential signals through data mining for montelukast were related to either CSS or neuropsychiatric events, which have all been labeled with no additional or new safety signals. A literature search was conducted from January 1, 2012, until December 18, 2013, to update previous literature reviews. This literature review did not reveal any new evidence regarding serious events or safety concerns associated with the use of montelukast. However, a lack of well-designed epidemiologic studies that can lead to the quantification of the suicide/suicide attempt risk level was noted. This runs parallel to the joint statement made by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI), and previous conclusions from prior Office of Surveillance and Epidemiology reviews. Of note, the numbers in this review represent crude counts and were not further evaluated for an association with montelukast since the association of these events with montelukast use is welldocumented. In addition, this review does not indicate any increased trend in severity or frequency of reporting of neuropsychiatric events or CSS since previous reviews. However, a spike in reports was noted in 2008, which may have been a result of stimulated reporting after the release by the FDA of an Early Drug Safety Communication notifying the public of the potential association of neuropsychiatric events with montelukast use. Reports of CSS with montelukast continue to be submitted to FAERS with a total of 884 reports since approval. A majority of the reports were in adults and indicated for asthma, which is consistent with CSS etiology. These reports were not further evaluated for an association with montelukast since the potential association of CSS with montelukast is well-documented even though a mechanism of action for this association has not been identified. The current montelukast prescribing information adequately informs healthcare professionals of the potential association with CSS. The montelukast patient information sheet provided with the prescription also adequately informs patients, in consumer-friendly language, of CSS. In contrast, the proposed OTC Drug Facts label for montelukast does not offer any information for consumers about the potential association with CSS, symptoms of CSS, or what to do if symptoms develop. Although the majority of FAERS reports of CSS with montelukast use reported asthma as the indication for montelukast and the proposed indication for OTC montelukast is relief of allergy symptoms, the potential exists that patients with asthma may use OTC montelukast. CSS is a life-threatening condition. In general, early diagnosis of CSS improves survival, which increases the importance of including labeling for CSS. 69 of 207 4

70 In summary, a review of post-marketing data for montelukast did not identify any new safety issues that have not been previously recognized and reviewed by the FDA. The crude count analyses of up-to-date FAERS data on CSS and neuropsychiatric events are consistent with the current labeling. Although approvability of an OTC montelukast product is beyond the scope of this review, DPV agrees with the proposed labeling for neuropsychiatric events on the OTC montelukast Drug Facts label submitted with NDA , but the Drug Facts label lacks information about CSS. DPV recommends the following for consideration: If approved, add a statement to the OTC montelukast Drug Facts label Warnings Section for Churg-Strauss Syndrome using language that is similar to language found in the prescription montelukast Patient Information of 207

71 1 INTRODUCTION This review evaluates the FDA Adverse Event Reporting System (FAERS) database and published literature for serious events reported with montelukast including death, neuropsychiatric events, and Churg-Strauss Syndrome. The Division of Nonprescription Clinical Evaluation (DNCE) requested this review to inform a New Drug Application (NDA) submitted by Merck Consumer Care, Inc. (Merck), which requests a partial switch of montelukast to nonprescription status for the for the temporary relief of allergy symptoms in adults 18 years and older. 1.1 BACKGROUND On September 6, 2013, Merck submitted an NDA requesting a partial switch of montelukast 10 mg tablets (proposed tradename Singulair Allergy) from prescription to over-the-counter (OTC). The proposed OTC indication is for the temporary relief of allergy symptoms (sneezing, runny nose, itchy nose, watery eyes, itchy eyes, and nasal congestion) related to hay fever or other upper respiratory allergies in adults 18 years of age and older. This is not a full nonprescription switch since the prescription montelukast is also indicated for: the prophylaxis and chronic treatment of asthma in patients 12 months of age; acute prevention of exercise-induced bronchoconstriction in patients 6 years of age; and relief of symptoms of allergic rhinitis (seasonal in patients 2 years of age and perennial in patients 6 months of age). DNCE requested this review of post-marketing montelukast safety data to aid in the decision to approve the switch to nonprescription status. Montelukast is a leukotriene receptor antagonist which has been associated with neuropsychiatric adverse events in all age groups. The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) and the Office of Surveillance and Epidemiology (OSE) have reviewed this association previously (tracked safety issue number 415) after supplements were submitted by Merck in 2007 to add several different neuropsychiatric events to the post-marketing adverse event section of the montelukast prescribing information. (OSE s reviews are summarized below in section 1.2) Additionally, on (b) (6) October 22, 2007, correspondence was received by the FDA from Senator (b) (6), which requested the FDA review the safety of montelukast after a 15 year old living in her district committed suicide 17 days after starting montelukast. The OSE and DPARP reviews resulted in the addition of neuropsychiatric events to the Precautions section (currently Warnings and Precautions section, see section 1.4 of this review) of the montelukast prescribing information and patient information sheet. Several Drug Safety Communications were also posted on the FDA internet to inform healthcare professionals and patients of the new safety information. 2,3 The safety of montelukast was further reviewed after a Citizen Petition was submitted by the Parents United for Pharmaceutical Safety and Accountability on September 28, 2008 (FDA P-0039). The Petition requested the FDA remove the indication for montelukast use in children and requested labeling changes for the following adverse events: seizures, neurological damage, neuropsychiatric events, and Churg-Strauss Syndrome (CSS). DPARP and OSE opened a track safety issue for the Petition (number 837), and reviewed these safety issues (the OSE 71 of 207 6

72 review is summarized below in section 1.2). The reviewers concluded the montelukast labeling to be adequate for the concerns raised by the Petition. 4 FDA denied the Petition s request to remove the indication for use in children, but added Henoch-Schönlein purpura, a form of systemic vasculitis, to the Adverse Reactions, Post-marketing Experience section of the label. 1.2 PREVIOUS POSTMARKETING REVIEWS Previous reviews by OSE: 12/22/05 OSE Postmarketing Safety Review Congenital Anomaly-limb Reduction Defect 5 Epidemiological analyses did not support an association between montelukast and limb reduction defects. 12/19/08 (RCM # ) OSE AERS Postmarketing Safety Review: Mood, Cognitive, Perception, Sleep and Movement Adverse Events 6 Mood (including suicide and suicidal ideation), cognitive, perception, and sleep adverse events were reviewed for an association (b) (6) with montelukast use. This review was initiated by an inquiry to FDA from (b) (6) Senator on behalf of a constituent. The 15-year-old son of this constituent (b) (6) committed suicide, in, while taking montelukast to treat allergic rhinitis. The Recommendation listed: Neuropsychiatric events should be added to the Precautions section (currently Warnings and Precautions section) of the label. 06/30/10 (RCM# ) Labeling Submission for disorientation OSE 7 Disorientation reviewed for an association with montelukast use. Recommended disorientation be labeled based on Changes Being Effected (CBE). 11/17/10 (RCM# ) OSE Review of fatal anaphylaxis, serious skin reactions, immune thrombocytopenia 8 These events were reviewed and it was recommended to label thrombocytopenia only. 05/14/11 (RCM # ) Citizens Petition OSE 9 Consult received from the Office of Regulatory Policy. The Petitioner requested: remove the montelukast indication for use in children, changes to the product labeling, implement requirements that adverse events are reported by physicians, and that all labeling changes are communicated to consumers. This OSE review evaluated neuropsychiatric events (vocal and motor tics, seizures and brain damage, status epilepticus, death) and vasculitis (vasculitides, deaths, Churg-Strauss syndrome) with montelukast use. The reviewer recommended no labeling changes to the product labeling were necessary at that time. 05/12/12 (RCM# ) OSE Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) (TSI 1310) 10 Review was based upon the Japanese Pharmaceuticals and Medical Devices Agency update of the montelukast label to include TEN and SJS. The reviewer recommended adding SJS/TEN to the montelukast label. 02/27/13 (RCM# ) OSE Association between leukotriene-modifying agents (LTMA) and suicide 11 This review evaluated a newly published nested case-control study. The reviewer concluded that well-designed epidemiologic studies are lacking to quantify the suicide risk related to use of LTMAs. No need for further regulatory action by FDA. 1.3 REGULATORY HISTORY The FDA first approved montelukast on February 20, 1998, for the prophylaxis and chronic treatment of asthma in patients 15 years and older (10 mg tablets/nda ) and ages 6 to 14 years (4 and 5 mg chewable tablets/nda 20830). Subsequent indications include: prophylaxis 72 of 207 7

73 of asthma in 2 to 5 years of age (3/3/2000), treatment of asthma in 12 months and older (7/26/2002), relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older (12/31/2002), relief of symptoms of perennial allergic rhinitis (PAR) in adults and pediatric patients 6 month of age and older (7/27/2005), prevention of exerciseinduced bronchoconstriction in patients 15 years of age and older (4/13/2007), and prevention of exercise-induced bronchoconstriction in patients 6 to 14 years of age (3/26/2012). Montelukast is available as 5-mg and 10-mg film-coated tablets, 4-mg and 5-mg chewable tablets, and 4-mg oral granules. 1.4 PRODUCT LABELING The Prescribing Information 12 for montelukast contains the following information regarding neuropsychiatric events and Churg-Strauss in the Warnings and Precautions, Adverse Reactions, and Patient Counseling Information sections of the label: Neuropsychiatric Events Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast sodium. Post-marketing reports with montelukast sodium use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving montelukast sodium appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur, Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast sodium. Eosinophilic Conditions Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast sodium and these underlying conditions has not been established. These events are also described in the FDA approved Patient Information sheet for Singulair below. Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking SINGULAIR: agitation including aggressive irritability behavior or hostility memory problems attention problems restlessness bad or vivid dreams sleep walking depression suicidal thoughts and disorientation (confusion) actions (including suicide) feeling anxious tremor hallucinations (seeing or hearing things that are not really there) trouble sleeping 73 of 207 8

74 Increase in certain white blood cells (eosinophils) and possible inflamed blood vessels throughout the body (systemic vasculitis). Rarely, this can happen in people with asthma who take SINGULAIR. This sometimes happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered. Tell your healthcare provider right away if you get one or more of these symptoms: a feeling of pins and needles or numbness of arms or legs a flu-like illness rash severe inflammation (pain and swelling) of the sinuses (sinusitis) Selected sections of the Patient Information sheet are included in Appendix B. The proposed OTC Drug Facts label submitted September 6, 2013, as part of the NDA for Singulair Allergy includes: Uses: temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: nasal congestion; runny nose; itchy, watery eyes; sneezing; itching of the nose Warnings: Do not use to treat asthma. Asthma can be a life-threatening condition, and you should follow your doctor s directions. Do not use: With any other drug containing montelukast sodium. If you are not sure whether a drug contains montelukast sodium, ask a doctor or pharmacist. if you are allergic to montelukast sodium or any of the interactive ingredients of this product When using this product if you have asthma and allergies, you can use this product for your allergies if you are not taking another drug containing montelukast sodium if you are currently taking asthma medicines, do not stop taking them Stop use and ask a doctor if you experience unexpected changes in thoughts, behaviors and moods you experience unexpected changes or problems when you sleep an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breastfeeding, ask a health professional before use. Directions: use every day, only during the time you are suffering from allergies, for best results adults 18 years of age and older: take 1 tablet daily; not more than 1 tablet in 24 hours children under 18 years of age: do not use In addition, Merck has proposed to include a Consumer Information Leaflet with OTC Singulair Allergy, which Merck submitted on October 29, 2013, as part of the NDA. This Consumer Information Leaflet further addresses the neuropsychiatric events that are found in the prescription montelukast prescribing information and instructs consumers to stop use and talk to their doctor if they experience any of these events. The Consumer Information Leaflet submission lists the neuropsychiatric events identified in the prescription Singulair Patient Information Sheet; however, Merck states they would like to further discuss with DNCE what would be the most appropriate events for the OTC Consumer Information Leaflet. 74 of 207 9

75 2 OVERVIEW OF POST-MARKETING DATA WITH MONTELUKAST 2.1 METHODS AND MATERIALS FAERS Search Strategy The FDA Adverse Event Reporting System (FAERS) was searched with the strategy described in Table 1. Table 1. FAERS Search Strategy* Date of search December 12, 2013 Time period of search February 20, 1998^ - October 31, 2013 Product Terms Active ingredient: Montelukast, Montelukast sodium * See Appendix A for description of the FAERS database. ^ FAERS searched from US Approval to data lock date for this review Data Mining Search Strategy The Empirica Signal database was searched with the strategy described in Table 2. Table 2. Data Mining Search Strategy* Data Refresh Date December 5, 2013 Product Terms Montelukast Empirica Signal Run Name Generic By Suspect Drugs only MedDRA Search Strategy PT terms * See Appendix A and C for description of Data Mining of FAERS using Empirica Signal Literature Search The medical literature was searched with the strategy described in Table 3. Table 3. Literature Search Strategy Date of search December 18, 2013 Database PubMed@FDA, Google, Google Scholar Search Terms Singulair, Montelukast, Leukotriene-Modifying Agents, Neuropsychiatric Events, Suicide, Suicidal Ideation, Depression, Agitation, Anxiety, Aggressive Behavior, Hallucinations, Disorientation, and Churg- Strauss Syndrome Years included in search January 1, 2012-December 18, 2013 Languages English, French 75 of

76 2.2 RESULTS Overview of FAERS Montelukast Reports The search identified 11,649 postmarketing reports associated with montelukast in the FAERS database (crude counts). Table 4 summarizes the crude counts of all FAERS reports with montelukast from approval, February 20, 1998, to October 31, This table uses a crude count of reports. These reports have not been assessed for an association with montelukast and may contain duplicate reports. Table 4. Crude Counts * of FAERS Reports with Montelukast use, received by FDA from Approval to October 31, 2013 (N=11649) Age (N=9146) Mean 33 years Median 31 years Range 2 days-102 years <18 years 3892 (43%) Sex (N=10846) Male 4640 Female 6206 Initial FDA Received Date Event Date (N=7811) 76 of

77 Country of reporter United States 8355 Foreign 3294 Report type (N=11648) Serious Outcomes (N=8846) Frequently reported PTs, Most frequently reported PTs in reports with serious outcomes (N=8846) Primary suspect medication Most frequent indication for montelukast use (N=8209) Expedited 6894 Direct 2401 Periodic 2353 Death 567 Life-threatening 982 Hospitalized 3127 Disability 856 Congenital anomaly 105 Other serious 5128 Depression (1054), suicidal ideation (981), allergic granulomatous angiitis (884), abnormal behaviour (821), aggression (811), anxiety (751), asthma (715), headache (584), insomnia (647), dyspnoea (503), fatigue (439), anger (421), crying (421), nightmare (410) Suicidal ideation (893), allergic granulomatous angiitis (875), depression (862), aggression (659), abnormal behaviour (625), anxiety (592), asthma (588), insomnia (417) Montelukast (10538), other medications (1111) Asthma (6186), hypersensitivity (779), multiple allergies (629), rhinitis allergic (387), seasonal allergy (228) * May include duplicates Serious adverse drug experiences per regulatory definition (CFR ) include outcomes of death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events. Reports may include multiple outcomes. Each report may have multiple PTs PTs with 400 occurrences Indications with 200 occurrences The FAERS search identified 11,649 reports with montelukast from approval to October 31, Seventy-six percent (8846/11649) of all reports indicated a serious outcome. Spikes in reporting were noted in the years 2008 and 2013; however, review of event dates associated of 207

78 with these reports show a spike in 1998 (year of approval) and The 2008 spike could be due to stimulated reporting as a result of the Early Communication released by the FDA that discusses the neuropsychiatric events with montelukast. 2 A review of event dates does not reveal a spike of events in The majority of reports submitted in 2013 reported events prior to Preferred Terms related to neuropsychiatric events were most frequently reported, with depression and suicidal ideation topping the list. The preferred term allergic granulomatous angiitis (also known as Churg-Strauss Syndrome) was also frequently reported. Seventy-five percent (6186/8209) of the reports that provided information on indication for montelukast documented asthma Deaths Table 5 summarizes the 567 FAERS reports which reported death as an outcome. This table uses a crude count of reports. These reports have not been assessed for an association with montelukast and may contain duplicate reports. Table 5. Crude Counts * of FAERS Reports with Montelukast use and reporting an outcome of Death, received by FDA from February 20, 1998 to October 31, 2013 * (N=567) Age (N=470) Mean 47 years Median 53 years Range 0 94 years <18 years 90 (19%) Sex Male 214 Female 294 Unknown 59 Initial FDA received date Event date (n=315) of

79 Country of reporter United States 387 Foreign 180 Report type Expedited 514 Direct 49 Periodic 4 Frequently reported PTs^ (N=381) Primary suspect medication Most frequent indication for montelukast use (N=547) Completed Suicide 196 Death 62 Asthma 49 Toxicity to various agents 45 Abortion Spontaneous 37 Pregnancy 28 Maternal drug affecting foetus 26 Cardio-respiratory arrest 24 Depression 22 Cardiac arrest 21 Montelukast 428 Other medications 139 Unknown 260 Asthma 226 Abuse 26 COPD 20 Allergy 15 * These reports have not been assessed for an association with montelukast and may contain duplicates. ^ Each report may have multiple PTs PTs with 20 occurrences Indication with 15 occurrences COPD = Chronic obstructive pulmonary disease Death was reported as an outcome in 567 FAERS reports, which is approximately 5% of the total FAERS reports for montelukast. Reports were submitted to FDA consistently since approval in 1998; however, an increase in reports was noted in 2008 and This increase in reporting 79 of

80 was not consistent with the event dates reported. There was no increase in event dates noted in either 2008 or The most frequently reported preferred terms for reports with death as an outcome were related to suicide or pregnancy. Two of the frequently reported preferred terms were related to pregnancy and miscarriage (i.e., abortion spontaneous and maternal drug affecting foetus). Montelukast is currently labeled as Pregnancy Category B based on negative animal studies and no adequate, well-controlled studies in pregnant women. After approval, Merck established an informal pregnancy registry for montelukast by including an 800 number in the montelukast prescribing information to report prenatal exposure. Many of the reports reporting adverse events related to pregnancy and miscarriage in the death report series were from the Merck pregnancy registry. Of note, in 2006, Merck, DPARP, OSE, the Maternal Health Team, the Office of Pharmaceutical Science, and independent teratologist reviewed possible teratogenic risks associated with the use of montelukast due to 6 reports of congenital limb defects in infants born to mothers prescribed montelukast during their pregnancy. A causal relationship between the teratogenic events and montelukast could not be established. 13 Completed suicide was reported as a preferred term in 35% (196/567) a of the reports that reported death as outcome, and 1.6% (196/11649) of the total montelukast FAERS reports. Of the reports containing the preferred term Completed suicide and also reporting an age (n=170) b, the median age for completed suicides was 45 years, with a range of 7 years to 79 years. Eighty-nine of the 196 completed suicide reports were published in the Annual Report of American Association of Poison Control Centers National Poison Data System (AAPCC-NPDS). Frequently reported preferred terms for these reports included: toxicity to various agents (n=22); overdose (n=9); and cardio-respiratory arrest (n=7). These reports involved multi-drug overdoses and provided few details about the patients or their medication histories. Since the previous OSE review of neuropsychiatric events and completed suicides with montelukast use was completed in , 43 unique reports which contain the PT Completed suicide have been submitted to FAERS (excluding reports that were published in the AAPCC- NPDS annual report). Thirty-one of these reports submitted an age which ranged from 7 to 77 years. Twelve of the thirty-one reports were submitted for children ( 17 years). c Half of the reports (22/43) were submitted between June 13, 2008 (from previous OSE review) to January 1, 2010, which may be a result of stimulated reporting of the FDA communications regarding neuropsychiatric events released in 2008 and ,3 Appendix C contains a line listing with narrative for these 43 reports Overview of Data Mining a The 196 cases of completed suicide include reports previously described in the 2008 DPV review of montelukast and suicide. b This number represents a crude count of reports that have not been assessed for an association with montelukast and may contain duplicate reports. c Three of the twelve pediatric reports (FAERS case # ; ; and ) appeared in the 2009 DPV review of pediatric events with Singulair for the Citizen Petition of

81 The datamining results for montelukast are in Appendix E. The EB05 score for the top 8 PT terms (Allergic granulomatous angiitis, Mononeuritis, Pancoast s syndrome, Hypereosinophilic syndrome, Allergic respiratory disease, Eosinophilic myocarditis, Eosinophilic pneumonia, and Eosinophil count increased) are terms related to eosinophilic conditions, which are labeled events in the Warnings and Precautions section of the montelukast label. Other PT terms with high EB05 scores include neuropsychiatric events (e.g., Sleep terror, Self-esteem decreased, Nightmare, Morbid thoughts, Suicidal ideation, and Mood altered), which are adequately described in the label Overview of Literature Safety concerns have been raised and addressed by the FDA in the past regarding the increased risk of neuropsychiatric adverse events associated with the use of leukotriene-modifying agents, specifically, suicide and suicide attempts among patients with asthma. The FDA (Office of New Drugs and Office of Surveillance and Epidemiology) conducted several scientific reviews using data from the pre-marketing clinical trials and data from FDA s Adverse Event Reporting System (FAERS), and concluded that the clinical details of some post-marketing reports involving montelukast appeared consistent with a drug-induced effect. 6 A labeling change to all the leukotriene-modifying agents was made in 2009 to include a precaution in the drugprescribing information. In February of 2013, the Division of Epidemiology (DEPI) re-evaluated the possible association between leukotriene-modifying agents and suicide by evaluating recent publications and case control studies in order to quantify the suicide/risk attempt from leukotriene-modifying agents. The review noted that published clinical trials did not identify risk of suicide from leukotrienemodifying agents, a result likely due to the small sample size and low suicide rate. The review concluded that well-designed epidemiologic studies were lacking and that none of the literature identified at the time indicated the need for further regulatory action by the FDA. 14 For this review, an updated literature search was conducted from January 1, 2012 through December 18, A list of terms used in the search (please refer to Table 3, section 2.1.3) has not revealed any new evidence regarding serious events or safety concerns associated with the use of montelukast. The literature identified at this time does not indicate a need for further regulatory action by the FDA. Well-designed epidemiologic studies are currently lacking to quantify the level of risk of suicide/suicide attempt among asthma patients, including pediatric asthma patients, and therefore, continued monitoring of the literature is recommended. 2.3 DISCUSSION OF OVERVIEW OF POST-MARKETING DATA WITH MONTELUKAST A review of post-marketing data for montelukast did not identify any new safety issues that have not previously been reviewed by the FDA. The most often reported safety issues are related to neuropsychiatric events and Churg-Strauss Syndrome associated with montelukast use. These events are further reviewed and discussed in sections 3 and 4 of this review. The FAERS search identified 11,649 reports with montelukast from approval to October 31, Seventy-six percent of all reports indicated a serious outcome while 40% of all reports resulted in death, hospitalization, or were life-threatening. Death was reported as an outcome in approximately 5% (567/11649) of the total FAERS reports for montelukast. The most frequently 81 of

82 reported PTs included those for neuropsychiatric events: depression (n=1054), suicidal ideation (n=981), and abnormal behaviour (n=821). Completed suicide is reported in 1.6% (196/11649) of the total montelukast FAERS reports. These events are labeled in the prescribing information and the proposed OTC Drug Facts label with similar neuropsychiatric terms found in this review of FAERS. Of note, the term crying (n=421) is an unlabeled event, but could be a result of related PT terms associated with mood disturbances. The majority of fatal reports were in adults. The median age for the death report series was 53 years and 45 years in those reporting a completed suicide. The most frequent indication for montelukast use in the FAERS report series was asthma (53%). Allergy indications (PT: Multiple allergies, Rhinitis allergic, and Seasonal allergy) represented 10% (1244/11649) of FAERS reports. Since the review by DEPI in 2013, there has been no new literature published regarding serious events or safety concerns with regards to suicide/suicide attempts associated with montelukast use. However, there is a lack of well-designed epidemiologic studies that can lead to the quantification of the suicide/suicide attempt risk level among asthma patients, including, pediatric asthma patients. This runs parallel to the joint statement made by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) that there are no data from well-designed studies to indicate a link between Singulair and suicide [and] it is unknown whether there is an increased incidence of suicide in patients receiving Singulair. 15 At this time, there is no published article that indicates a need for further regulatory action by the FDA, however, continued monitoring of the literature is recommended. 3 NEUROPSYCHIATRIC EVENTS 3.1 METHODS AND MATERIALS To capture all the reports of neuropsychiatric events, we searched FAERS on December 12, 2013, using the FAERS search strategy in Table 1. To further characterize the reports, Empirica was used as a data managing tool. Audit trails for asthma and allergy indication PTs are in Appendix D. 1) We ran a Generic by Year 3D- DEI (Drug, Event, Indication) without litigation & foreign regulatory agencies removed (ID 11247) to identify 3D combinations that cannot be explained by any of the corresponding pair-wise associations. 2) We stratified the 680 PTs coded under the Psychiatric disorders SOC by indication (allergy-related or asthma-related). Reports with a D-E-I Interaction Signal Score > 1 were selected. 3) We then removed reports with an outcome of death or PT Completed suicide. 4) The time period of search was from March 27, 2008 (Date of previous review 6 of neuropsychiatric events) to October 31, RESULTS 82 of

83 Table 6 summarizes the FAERS reports of neuropsychiatric events with montelukast based on allergic and asthma-related PTs. This table uses a crude count of reports. For this review, the reports have not been assessed for an association with montelukast and may contain duplicate reports. Table 6. Crude Counts of FAERS Reports of Neuropsychiatric Events with Montelukast based on allergic and asthma related PT indications (excluding death outcome and completed suicide PT), received by FDA from March 27, 2008 to October 31, Indication: Allergic related PT Indication: Asthma related PT (n=551) Age (years) n=499 Mean 21 Median 11 Range 1-80 <18 years 323 (65%) Sex n=539 Male 274 Female 265 Initial FDA received date Event Date n= Country of reporter United States 535 Foreign of 207 (n=1879) n=1353 Mean 21 Median 11 Range 1-89 <18 years 997 (74%) n=1716 Male 888 Female n= United States 1533 Foreign

84 Report type Expedited 190 Direct 335 Periodic 26 Serious Outcomes* n=508 Life-threatening 50 Hospitalized 52 Disability 31 Required Intervention 12 Other 363 Frequently reported PTs, n=551 Abnormal behaviour (159), depression (155), suicidal ideation (145), aggression (143), anxiety (124), anger (91), crying (84), insomnia (73), nightmare (69), mood altered (57), irritability (54) Most frequently reported PTs in reports with a serious outcome, n=914 reports Depression (132), suicidal ideation (132), aggression (121), abnormal behaviour (120) anxiety (101), anger (71), crying (67), insomnia (59), mood swings (57), nightmare (54) Primary suspect medication Montelukast 546 Other medications 5 Most frequent indication for n=612 montelukast use Multiple allergies (223), hypersensitivity (162), seasonal allergy (103), rhinitis allergic (95), rhinitis (16), sinus disorder (13) Concomitant medications Associated with neuropsychiatric events (10) Expedited 1096 Direct 642 Periodic 141 n=1862 Life-threatening 192 Hospitalized 297 Disability 113 Congenital anomaly 2 Other serious 1258 n=1879 Suicidal ideation (512), depression (464), aggression (357), abnormal behaviour (344), anxiety (324), suicide attempt (254), insomnia (215) n=2811 reports Suicidal ideation (465), depression (380), aggression (288), abnormal behaviour (255), anxiety (255), suicide attempt (249), insomnia (178), nightmare (148), agitation (125), irritability (123), mood swings (117), crying (116), anger (112) Montelukast 1816 Other medications 63 n=1190 Asthma (1088), cough (29), bronchial hyperreactivity (25), asthma exercise induced (20), bronchitis (14), COPD (14) Associated with neuropsychiatric events (25) *Serious adverse drug experiences per regulatory definition (CFR ) include outcomes of death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events. Reports may include multiple outcomes. PTs with 50 occurrences for allergic indication; 200 occurrences for asthma indication PTs with 50 occurrences for allergic indication; 100 occurrences for asthma indication each report may have multiple PTs PTs with 10 occurrences 3.3 DISCUSSION The FAERS reports of neuropsychiatric events in Table 6 were mostly from the US. The patients in this report series for allergic and asthma related indications tended to be younger 84 of

85 (median age 11 years) compared to patients in the total FAERS report series (median age 31 years, Table 4). This is consistent with the drug use data that states among the 14.5 million pediatric patients aged 0-17 years old, pediatrics aged 6-14 years old accounted for the majority of patients at approximately 60% of total pediatric patients. 1 The most frequently reported neuropsychiatric PT when montelukast was used for allergy-related indication was Abnormal behaviour (n=159). Multiple allergies (PT) and Hypersensitivity (PT) were the most frequently reported indications for montelukast use among these patients. Among the 93 reports that provided information on concomitant drugs, only 10 reports stated the patient was taking concurrent medications that were associated with neuropsychiatric adverse events. The most frequently reported neuropsychiatric PT when montelukast was used for asthmarelated indication was suicidal ideation (n=512). There were 63 patients taking montelukast for asthma indication that were taking other suspect medications (predominately allergy medications). There were 25 patients taking concomitant medications that were associated with neuropsychiatric adverse events. Most of the neuropsychiatric PTs reported are labeled events with the exception of crying. However, crying may be a manifestation of reported PT terms Irritability and Mood swings. Although a mechanism of action for montelukast causing these neuropsychiatric events is unknown at the present time, it was important to convey the findings of FAERS data to the public on two occasions in 2008 and ,3 Patients and healthcare providers were advised to monitor for symptoms and to consider discontinuation of the drug in the event of these symptoms occurring. 4 CHURG-STRAUSS SYNDROME 4.1 METHODS AND MATERIALS FAERS Search Strategy The FDA Adverse Event Reporting System (FAERS) was searched with the strategy described in Table 7. Table 7. FAERS Search Strategy for Churg-Strauss Syndrome* Date of search November 15, 2013 Time period of search July 16, 2009^ - October 31, 2013 Product Terms Active Ingredient: Montelukast Montelukast sodium MedDRA Search Terms Preferred Term: Allergic granulomatous angiitis * See Appendix A for description of the FAERS database. ^ FAERS searched from date of previous review 9 to data lock date for this review. 4.2 RESULTS The FAERS search retrieved 149 reports. Table 8 summarizes the 149 FAERS reports of Churg- Strauss Syndrome (CSS) reported with montelukast for this report series. 85 of

86 Table 8. Crude Counts* of FAERS Reports of CSS with Montelukast use, received by FDA from July 16, 2009 to October 31, 2013 (N=149) Age (n=115) Mean 51 years Median 54 years Range 8-81 years <18 years 5% (6/115) Sex Male 57 Female 78 Unknown 14 Report year Country of reporter United States 49 Foreign 100 Report type Expedited 148 Direct 1 Serious Outcomes^ Death 1 Life-threatening 15 Hospitalized 90 Disability 15 Other serious 82 Indication Asthma 106 Sinusitis 2 Allergic rhinitis 1 Bronchitis 1 Hypersensitivity 1 Nasal polyp 1 Obstructive airway 1 Unknown 36 Concomitant steroid medication^ (n=85) Inhaled steroid 73 Oral steroid 25 History of Asthma Yes 118 No 4 Not reported 27 * These reports have not been assess for an association with montelukast and may contain duplicates. ^ Reports may report more than one outcome or steroid medication 4.3 DISCUSSION The FDA has been aware of the potential association of CSS and montelukast since the montelukast s approval in In addition, CSS has been included in the montelukast s prescribing information since approval. CSS (also known as eosinophilic granulomatosis with 86 of

87 polyangiitis) is a small and medium sized artery necrotizing vasculitis, most often occurring in patients with adult-onset asthma, allergic rhinitis, nasal polyposis, or a combination, with a mean age of onset of 48 years of age. 16 The American College of Rheumatology has proposed 6 criteria for the diagnosis of CSS, and the presence of 4 or more criteria is usually used for diagnosis. These criteria include: (1) asthma; (2) eosinophilia > 10% in peripheral blood, (3) paranasal sinusitis, (4) pulmonary infiltrates, (5) histological proof of vasculitis with extravascular eosinophils, and (6) mononeuritis multiplex. 17 Additional reviews of the potential association between CSS and montelukast have been performed since montelukast approval; however, since the underlying pathophysiology of CSS is poorly understood, the mechanism of action of medications to contribute to the development of CSS could not be identified. 4,18 The 2009 FDA response to the Petition acknowledged postmarket safety reports and published reports do show a potential association of CSS and montelukast, but causality could not be determined. 4 Reports of CSS with montelukast use continue to be submitted to FAERS, 149 reports since July 16, These reports were not further evaluated for an association with montelukast since the potential association of CSS with montelukast is well-documented. However, this review does not indicate any increased trend in severity or frequency of reporting. The current montelukast prescribing information adequately informs healthcare professionals of this potential association. In addition, the montelukast patient information sheet provided with the prescription adequately informs patients, in consumer-friendly language, of CSS. The patient information has a description of CSS, symptoms of CSS, and instructions for patients to contact their healthcare professional immediately if they experience these symptoms (see Appendix B). In contrast, the proposed OTC Drug Facts label for montelukast does not offer any information for consumers about the potential association with CSS, symptoms of CSS or what to do if symptoms develop. The NDA submission indicates Merck did not include this information on the Drug Facts label since there is insufficient information to establish a causal relationship with montelukast and CSS. Consideration should be given to include labeling for CSS on the OTC Drug Facts montelukast label because asthmatic patients potentially may use OTC montelukast and CSS can be described in consumer-friendly language as done in the Patient Information section of the prescription montelukast label. In addition, in general, early diagnosis of CSS improves survival. With treatment, the 1-year survival rate for CSS is 90%. 19 Although the proposed indication for the OTC montelukast does not include asthma, asthma is not contraindicated on the proposed Drug Facts label. The proposed label states, If you have asthma and allergies, you can use this product for your allergies if you are not taking another drug containing montelukast sodium. The potential exists that patients with asthma may use OTC montelukast, which increases the importance of including labeling for CSS. 5 CONCLUSION A review of post-marketing data for montelukast did not identify any new safety issues that have not been previously recognized and reviewed by the FDA. The most often reported safety issues 87 of

88 were related to neuropsychiatric events and Churg-Strauss Syndrome associated with montelukast use. However, there continues to be a lack of well-designed epidemiologic studies that can lead to the quantification of the suicide/suicide attempt risk level among patients using montelukast. The neuropsychiatric events appear to be adequately labeled in the proposed OTC montelukast Drug Facts label submitted with NDA ; however, the proposed OTC montelukast Drug Facts label lacks information about the potential association between montelukast use and Churg-Strauss Syndrome. 6 RECOMMENDATIONS Although approvability of an OTC montelukast product is beyond the scope of this review, DPV agrees with the proposed labeling for neuropsychiatric events on the OTC montelukast Drug Facts label submitted with NDA , but the Drug Facts label lacks information about CSS. Therefore, DPV recommends the following for consideration: If approved, add a statement to the OTC montelukast Drug Facts label Warnings Section and Consumer Leaflet for Churg-Strauss Syndrome using language that is similar to language found in the prescription montelukast Patient Information. Potential OTC labeling for Churg-Strauss Syndrome: Stop Use and ask your doctor if: you start to have pain in your joints you have a feeling of pins and needles or numbness of arms or legs you develop red-purple dots on the skin that look like a rash or bruise Sometimes people with asthma may develop a condition that makes their blood vessels become inflamed throughout their body (systemic vasculitis) when taking SINGULAIR Allergy. This sometimes happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered. 88 of

89 7 REFERENCES 1. Pham T. Singulair Drug Use Data. RCM December 23, U.S. Food and Drug Administration [intranet]. Early Communication about an Ongoing Safety Review of Montelukast (Singulair) 3/23/2008. [Updated: 18 April 2013; Cited 5 January 2014]. Available from: fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinfor mationforheathcareprofessionals/ucm htm 3. U.S. Food and Drug Administration [intranet]. Updated Information on Leukotriene Inhibitors: Montelukast (Singulair), Zarfirlukast (Accolate), and Zileuton (Zyflo, Zyflo CR) 8/28/2009. [Updated: 15 August 2013; Cited 5 January 2014]. Available from: fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformatio nforheathcareprofessionals/ucm htm 4. Seymour S. Memorandum to the Consultation for Citizen Petition FDA-2009-P DARRTS Reference ID: , TSI #837. May 25, Bonnel R, Nourjah P. Postmarketing Safety Review of Montelukast and Congenital Anomaly-Limb Reduction Defect. December 22, Green L, Mosholder A, Money D. AERS Post-marketing Safety Review: Mood, Cognitive, Perception, Sleep and Movement Adverse Events. NDA , NDA , NDA OSE RCM December 19, Wilson M. Labeling Submission for Singulair and disorientation. June 30, Ryan D. Fatal Anaphylaxis, Serious Skin Reactions, Immune Thrombocytopenia. November 17, Ryan D. Pharmacovigilance review of Singulair (montelukast) for Citizen Petition FDA-2009-P RCM May 14, Kalra D. Singulair and Stevens Johnson Syndrome and Toxic Epidermal Necrolysis. May 15, Jenni J. Association between leukotriene-modifying agents and suicide. February 27, Singulair label. Revised August Starke P. Medical Officer review of montelukast and congenital limb defects. NDA : SLR -039, NDA : SLR-041, NDA : SLR 019. October 5, Li J J. Review of the literature on the risk of suicide associated with leukotriene-modifying agents. FDA, OSE RCM February 27, Joint statement on FDA investigation of Singulair from the ACAAI and AAAAI. Eur Ann Allergy Clin Immunol 2008; Jun; 40 (2): Merck Manual [internet]. Gota C. Eosinophilic Granulomatosis with Polyangiitis (EGPA). c [Updated: April 2013; Cited: 12 January 2013]. Available from: merckmanuals.com/professional/musculoskeletal and connective tissue disorders/vasculitis/eosinophil ic granulomatosis with polyangiitis egpa.html?qt=churg%20strauss%20syndrome&alt=sh 17. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum Aug 1990; 33(8): Weller PF, Plaut M, Taggart V, Trontell A. The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 2001; 108: Medscape [internet]. Farid-Moayer M. Churg-Strauss Syndrome. c [Updated: 7 March 2013; Cited: 13 January 2014]. Available from: 89 of

90 8 APPENDICES 8.1 APPENDIX A. FDA ADVERSE EVENT REPORTING SYSTEM (FAERS) FDA Adverse Event Reporting System (FAERS) The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. The informatic structure of the database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation. Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The suspect products are coded to valid tradenames or active ingredients in the FAERS Product Dictionary (FPD). FDA implemented FAERS on September 10, 2012, and migrated all the data from the previous reporting system (AERS) to FAERS. Differences may exist when comparing case counts in AERS and FAERS. FDA validated and recoded product information as the AERS reports were migrated to FAERS. In addition, FDA implemented new search functionality based on the date FDA initially received the case to more accurately portray the follow up cases that have multiple receive dates. FAERS data have limitations. First, there is no certainty that the reported event was actually due to the product. FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough detail to properly evaluate an event. Further, FDA does not receive reports for every adverse event or medication error that occurs with a product. Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event. Therefore, FAERS data cannot be used to calculate the incidence of an adverse event or medication error in the U.S. population. Data Mining of FAERS using Empirica Signal Empirica Signal refers to the software that OSE uses to perform data mining analyses while using the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm. Data mining refers to the use of computer algorithms to identify patterns of associations or unexpected occurrences (i.e., potential signals ) in large databases. These potential signals can then be evaluated for intervention as appropriate. In OSE, the FDA Adverse Event Reporting System (FAERS) database is utilized for data mining. MGPS analyzes the records in FAERS and then quantifies reported drug-event associations by producing a set of values or scores that indicate varying strengths of reporting relationships between drugs and events. These scores, denoted as Empirical Bayes Geometric Mean (EBGM) values, provide a stable estimate of the relative reporting of an event for a particular drug relative to all other drugs and events in FAERS. MGPS also calculates lower and upper 90% confidence limits for EBGM values, denoted EB05 and EB95, respectively. Because EBGM scores are based on FAERS data, limitations relating to FAERS data also apply to data mining-derived data. Further, drug and event causality cannot be inferred from EBGM scores. 90 of

91 8.2 APPENDIX B. SELECTED SECTIONS OF THE SINGULAIR PATIENT INFORMATION What are the possible side effects of SINGULAIR? SINGULAIR may cause serious side effects. Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking SINGULAIR: agitation including aggressive irritability behavior or hostility memory problems attention problems restlessness bad or vivid dreams sleep walking depression suicidal thoughts and disorientation (confusion) actions (including suicide) feeling anxious tremor hallucinations (seeing or hearing things that are not really there) trouble sleeping Increase in certain white blood cells (eosinophils) and possible inflamed blood vessels throughout the body (systemic vasculitis). Rarely, this can happen in people with asthma who take SINGULAIR. This sometimes happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered. Tell your healthcare provider right away if you get one or more of these symptoms: a feeling of pins and needles or numbness of arms or legs a flu-like illness rash severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effects with SINGULAIR include: upper respiratory infection fever headache sore throat cough stomach pain diarrhea earache or ear infection flu runny nose sinus infection 91 of

92

93

94 A nurse reported her 56 year old sister, who had a pertinent medical history for asthma, allergies and no known drug allergy, was placed on therapy with montelukast for asthma (dose and duration not reported). The nurse could give no details regarding dates of montelukast use, but believed her sister had (b) (6) taken it for a "long time". Concomitant medication included "asthma inhalers" including as needed albuterol. It was reported that on the patient committed suicide by shooting herself during the course of montelukast sodium therapy. No further information is available. Completed Fluticasone/ FR-MERCK- suicide; 8) /22/2008 Salmeterol; 17 M Asthma Fluticasone Foreign 0809FRA00042 Intentional Singulair overdose A physician reported a 17 year old male patient was placed on montelukast 10 mg once a day for asthma in Concomitant therapy included fluticasone propionate 2 puffs daily started in 2002 for asthma. In Feb 2008, the patient and his family moved from France to Romania. There was no (b) (6) medical history of depression or anxiety or behaviour disorder. In, in the afternoon, the patient said that he was tired and he went to his bedroom for sleeping. By the end of the afternoon, the patient's father found his son dead (cyanosis+). The patient committed suicide by using 3 boxes of montelukast sodium (840 mg) and one box of fluticasone/salmeterol (diskus) and other drugs (no specified). The patient explained in a letter that he was tired and he was fed of the life. Autopsy was performed and did not show any specific anomalies. The cause of death was completed suicide with therapies overdose. The reporting physician felt that intentional overdose was related to therapy with montelukast sodium and fluticasone/salmeterol. US-MERCK- Completed 9) /31/2008 Singulair N/A N/A Not reported None reported USA 0810USA05003 suicide A physician stated a patient's mother heard that a child in her neighborhood was placed on therapy with montelukast sodium, chewable tablet for two weeks (dose and indication not reported) and committed suicide. Attempts are being made to verify the existence of an identifiable patient and reporter. Attempts to verify the existence of an identifiable patient have been unsuccessful. Completed suicide; Lung 10) Not Applicable 1/15/2009 Singulair 77 M Asthma None reported USA neoplasm malignant (b) (6) I saw a new clip on Fox news network about the drug singulair, that it could possibly cause suicidal tendencies. My father committed suicide on after being diagnosed with lung cancer. I did see one prescription that he had for singulair after going through some of his prescriptions. I am not sure how much he used. He did have a long history of asthma and used prescription medicines for a long time. Again I'm not sure how much of this drug he used. Just wanted to make a report. 11) Not Applicable 1/16/209 Singulair Completed suicide 76 M Chronic Obstructive Pulmonary Disease None reported A wife reported her husband had been on Singulair 10 mg for 3 years or longer for chronic obstructive pulmonary disease. He had been in the hospital (b) (6) (b) three times between (unknown cause for hospitalization). He was released from the hospital on Sunday, (6). He took his life on Monday afternoon. There was no note or explanation left by him before he committed suicide. They were happily married for fifty years. No other information was reported. Anxiety; 12) Not Applicable 1/26/2009 Singulair Completed Multiple Flonase; Intal 21 M Suicide; allergies; asthma inhaler; Proventil USA Depression; 94 of 207 USA 29

95

96 23) of 207 fracture; Influenza; Nocturia; Respiratory rate decreased; Weight decreased A physician and a medical assistant reported a 62 year old male ex-smoker (stopped in 1974) with no known drug allergies and with asthma, rhinitis allergic, gastro esophageal reflux disease, sleep apnea, periodic limb movement disorder, hypercholesterolemia and hypertension and a history of nasal polypectomy, appendectomy, tonsillectomy, coronary artery bypass graft three times in 2000 and a benign tumor removed from left knee received montelukast 10 mg once daily starting May 4, 2005, for asthma (duration not reported). Concomitant therapy included ciprofloxacin, esomeprazole, (b) (6) aspirin, fluticasone/salmeterol, fluticasone propionate, ezetimibe/simvastatin and amlodipine. On, the patient committed suicide. The physician stated that the patient had no history of depression. The family declined an autopsy and the remains were cremated. Medical records were obtained. US-MERCK- Completed Unspecified 20) /23/2009 Singulair N/A N/A Asthma USA 0906USA03426 suicide medications A physician reported a patient with "many issues" was placed on montelukast on an unspecified date for asthma (dose and duration not reported). The patient was taking other unspecified medications concomitantly. It was reported that "about four years ago", approximately in 2005, the patient committed suicide while taking montelukast. The patient sought unspecified medical attention. No other information reported. US-MERCK- Completed 21) /23/2009 Singulair 11 M Asthma None reported USA 0907USA04598 suicide A physician reported an 11 year old male received montelukast (dose and duration not reported) from an unspecified date for asthma. He suffered from (b) (6) depression from kids picking on him. Approximately "2 years ago" on the patient committed suicide and died. The physician did not feel there was any correlation with montelukast and did not want to file a report. No further information is available. US-MERCK- Completed 22) /10/2009 Singulair 55 M Not reported None reported USA 0909USA00472 suicide A physician reported a male in his late 50s received montelukast 10 mg once daily (duration and indication not reported). The patient committed suicide while taking montelukast. The physician thought it was important to note that he believed "there were some other things going on with this patient unrelated to his medication." A call was placed to the company rep that had a conversation with the physician, and the rep reported that in her conversation with the physician, he had mentioned that he had suggested the deceased s wife start on montelukast. The widow broke down and told the physician the story about her husband's suicide while on montelukast. No other information reported. US-MERCK- 1001USA /20/2010 Singulair Adverse event; Anxiety; Completed suicide; Depression N/A N/A Not reported None reported USA A parent group reported their children were treated with montelukast for unknown indication. The parents reported serious concerns based on their own children's adverse experiences with montelukast. On an unspecified date, their children suffered from physical symptoms and psychiatric disorders, 31

97

98 28) Not Applicable 4/16/2010 Singulair Asphyxia; Completed suicide 51 M Angioedema None reported Foreign The patient committed suicide by hanging on (b) (6) while taking Singulair 10 mg once daily. No other information reported. 29) Completed US-MERCK- 8/19/2010 Singulair suicide; 1008USA00975 Overdose N/A M Not reported None reported USA (b) (6) A physician reported a male patient was placed on montelukast 10 mg (duration and indication not reported) in. It was reported that in (b) (6), the patient committed suicide 6 months after starting therapy with montelukast, the patient died due to an illegal drug overdose. The physician believed that the patient's death was unintentional and had nothing to do with montelukast sodium. He refused to give the patient's date of death, and was not sure when the patient s last dose of montelukast was as the last prescribed refill was a while ago (date not reported). 30) / /28/2010 Singulair Completed suicide 51 M Hypersensitivity; Asthma Cetirizine; Lipitor Foreign Information has been received from a foreign agency concerning a 51 year old male patient who received montelukast 10 mg once a day for asthma and allergies (duration and start date not reported). Concomitant medications included: atorvastatin (LIPITOR) fore elevated cholesterol and cetirizine (REACTINE) for episodic angioedema. The patient completed suicide on an unreported date in The patient had no prior mental health problems, was very happy and had plans. There were no changes noted by the family or friends prior to the suicide. There was no interaction with other suspected drug. No further information is available. This was originally reported by a consumer. The agency considered that completed suicide and therapy with montelukast sodium were related. CA-MERCK- 1012USA03456 & CA-MERCK- 1012USA ) US-MERCK- Completed 3/7/2011 Singulair 1103USA00462 suicide 22 M Not reported None reported USA A nurse practitioner reported a 22 year old male received montelukast (dose, duration and indication not reported). On approximately (b) (6), the patient committed suicide and died. The patient did not seek medical attention. No further information is available. 32) US-MERCK- Completed 8/4/2011 Singulair 1107USA04085 suicide 13 M Asthma Advair Diskus USA A physician reported a 13 year old male received montelukast for asthma beginning in approximately 2001 (dose and duration not reported). Concomitant (b) (6) therapy included fluticasone/salmeterol (ADVAIR). On, the patient committed suicide and died. The physician further stated that he "was not seeing the patient at the time of the suicide because the family had moved out of the area and there was also a divorce that was occurring at the time of the suicide. No other information reported. Completed 33) suicide; US-MERCK- 12/27/2011 Singulair Depression; 1112USA03077 Suicidal ideation N/A M Not reported None reported USA A physician reported a male over 12 years old received montelukast 10 mg once daily for a long time (duration and indication not reported). The patient experienced severe depression, suicidal thoughts on an unspecified date. The patient had sought unspecified medical attention. No treatment was (b) (6) given for the adverse effects. The patient committed suicide in. No other information reported. 34) * US /8/2013 Acetaminophen; Cardio- 54 F Not reported None reported USA 98 of

99 1301USA Singulair; Duloxetine; Fenofibrate; Fluoxetine; Flurazepam respiratory arrest; Completed suicide This report has been received by Merck from a line listing from the AERS Database. This spontaneous report refers to a 54 years old female patient. The patient started therapy with montelukast (dose, duration, and indication not reported). Other suspect therapies included fenofibrate, fluoxetine, duloxetine, acetaminophen, and flurazepam. No other medications were reported. On an unknown date the patient experienced death by completed suicide and cardio-respiratory arrest. No details for death are available. 35) * US USA /11/2013 Advair; Singulair Asphyxia; Completed suicide 50 F Asthma Levothryroxine; Potassium This report was received by Merck from a Freedom of Information request to the FDA. A consumer reported a 50 year old female patient had been (b) (6) prescribed and was using both montelukast (dose not reported) and fluticasone/salmeterol (ADVAIR) (diskus) to treat asthma starting in (b) (6) She also battled anorexia nervosa for many years. She committed suicide by hanging on. She had never previously indicated any thoughts or intentions of suicide and was a practicing Catholic who raised their children in the same religion. She left behind their three beautiful children ages 11, 13 and 15. She was Christmas shopping that day with the reporter and their son. She had already bought gifts for the family. She was planning Christmas dinner and for their 11 year old daughter's birthday -Christmas day as well-. She had been taking these medications for approximately 9 months to one year. 36) * US Completed Hypersensitivity; 1/9/2013 Singulair 16 M Advair; Albuterol USA 0812USA00678 suicide Asthma This report was received by Merck from a Freedom of Information request to the FDA. On October 13, 2003, a 16 year old male patient was placed on montelukast 10 mg once daily (also reported as 10 mg daily as needed), for the treatment of allergies and asthma. Concomitant therapies included fluticasone/salmeterol (ADVAIR DISKUS) and albuterol, as needed when exercising. The patient usually exhibited asthma symptoms with strenuous exercise. The patient was a healthy, active and involved student in high school. The patient had his annual physical on an unspecified date (result unknown) where the physician noted the adolescent as well. The last prescription of montelukast was filled on April 17, On patient died by suicide after taking montelukast for approximately 3 years. Acetaminophen; Androgen receptor antagonist; Prinivil; US Completed 1/13/2013 Quetiapine 1301USA suicide fumarate; Salicylate meglumine; Singulair; Prochlorperazine 37) of 207 USA 61 F Not reported None reported USA A health professional reported a 61 year old female patient received montelukast (unknown dose, duration, and indication) along with other suspect therapies which include androgen receptor antagonist, prochlorperazine, lisinopril, salicylate meglumine, quetiapine fumarate, and acetaminophen. On an (b) (6), the 34

100 unknown date the patient committed suicide and died. No details for death are available. Bipolar disorder; 38) * Completed US /14/2013 Singulair suicide; Gun 1301USA shot wound; Personality change 17 M Asthma None reported USA This report has been received by Merck from the AERS Database. This spontaneous report refers to a 17 years old male patient who received montelukast for asthma (dose and duration not reported). No other medications were reported. On an unknown date, the patient experienced bipolar disorder, personality change, committed suicide and died. No details for death are available. 39) Completed US /21/2013 Singulair suicide; 1302USA Depression N/A M Hypersensitivity Advair; Spiriva USA A wife reported her husband (age not reported) received montelukast 10 mg (unknown frequency) for allergies beginning on July 23, Her husband was not suicidal at the time he started using montelukast, but became very depressed while on montelukast therapy. The concomitant therapies he received included fluticasone/salmeterol (ADVAIR) and tiotropium bromide (SPIRIVA). He committed suicide in (b) (6) and died. No other information reported. 40) US USA /22/2013 Singulair Abnormal behavior; Completed suicide; Irritability; Mood altered; Personality change; Poor quality sleep 12 F Rhinitis allergic; Asthma Advair; Dulera; Symbicort A physician assistant reported a 12 year old white female patient received montelukast 5 mg (frequency not reported) beginning on an unknown date in The patient's past medical history included asthma and allergic rhinitis but with no history of depression. On an unknown date in 2012, the patient switched to generic montelukast from brand Singulair. Beginning in September 2012, the patient experienced a change in mood, becoming irritable, moody, had trouble sleeping and developed a bad attitude. The patient was seen by the physician assistant on December 20, 2012 and the behavioral changes were reported by the patient s mother. Montelukast was discontinued, but the behavioral changes did not abate after stopping the drug. It was noted that the patient s compliance with montelukast was low. The concomitant medications included: ADVAIR (250 Microgram) twice daily from 16- OCT-2012 to 10-NOV-2012 for asthma, SYMBICORT (160 Microgram) twice daily from 20-NOV-2012 to 20-DEC-2012 for asthma and DULERA (100/5 microgram) 2 puffs twice a day from 20-NOV-2012 for asthma. On, the patient committed suicide. No other information reported. 41) Not Applicable 3/27/2013 Montelukast Advair Diskus; Completed 48 M Asthma Spiriva suicide Handihaler USA Suicide with handgun. No other information reported. 100 of 207 (b) (6) USA 35

101 42) US-MERCK- 1306USA /19/2013 Singulair Completed suicide; Depression; Mental disorder; Thinking abnormal N/A M Asthma Advair; Spiriva USA A consumer reported her husband of unknown age received montelukast 10 mg once daily for asthma since approximately April 2011 ( prescribed to him over two years ). He had a past medical history of chronic obstructive pulmonary disease, alcohol use (rare) and smoker who quit on July 11, His concomitant therapies included: Advair Diskus 500/50 mg and Spiriva handihaler capsule 18mcg. On an unknown date, he turned into a very depressed man. On (b) (6) 43) NSR_01298_ /17/2013, he committed suicide with a handgun. No other information reported. Completed Domperidone; suicide; Montelukast; Convulsion; Tramadol; Drug Tranexamic acid interaction; Hypoglycemia 36 N/A Not reported None reported Foreign Citation(s): Abadie D. Durrieu G. Roussin A. Montastruc JL. le Reseau Francais des Centres Regionaux de Pharmacovigilance. ("Serious" adverse drug reactions with tramadol: a pharmacovigilance survey in France]. Therapie 2013;68(2): Description of Event or Problem: It was reported in scientific literature by health professionals from France in a retrospective study of serious adverse effects from companies selling medications containing tramadol a 36 year old patient (unknown gender), with unknown history, ingested massive amounts of tramadol (unknown quantity), along with tranexamic acid, montelukast, and domperidone. The patient experienced hypoglycemia with seizures. The patient ingested the drugs in a reported suicide attempt, which resulted in death. No other information reported. This line contains a report and its duplicate report. Both reports were used to gather the information in the line listing. * These reports were gathered by Merck through Freedom of Information requests to the FDA or the public AERS database. They may include duplicates cases that were reported in the 2008 OSE review of montelukast and completed suicides. 101 of

102 8.4 APPENDIX D. AUDIT TRAILS FOR ASTHMA AND ALLERGY INDICATION PTS Asthma indication PTs: Case Series Name: Copy of 4610 Montelukast asthma indic and psych soc [551 cases] Query Logic: Return cases based on the following conditions and on the selection logic: (((((1 intersect 2 intersect 3 intersect 8) minus 4) minus 5) minus 6) minus 7) 1) Generic name equals 'Montelukast' 2) PT equals any of the following values: 'Feeling of despair', 'Abnormal dreams', 'Fear', 'Panic disorder', 'Affective disorder', 'Self esteem decreased', 'Selfinjurious ideation', 'Nightmare', 'Sleep terror', 'Mood swings', 'Thinking abnormal', 'Anger', 'Depression', 'Suicidal ideation', 'Violence-related symptom', 'Mood altered', 'Depressed mood', 'Anxiety', 'Oppositional defiant disorder', 'Aggression', 'Bipolar disorder', 'Panic attack', 'Screaming', 'Abnormal behaviour', 'Irritability', 'Crying', 'Morbid thoughts', 'Somnambulism', 'Negative thoughts', 'Emotional disorder', 'Self injurious behaviour', 'Mental disorder', 'Bruxism', 'Disturbance in attention', 'Insomnia', 'Suicide attempt', 'Frustration', 'Personality change', 'Intentional self-injury', 'Poor quality sleep', 'Enuresis', 'Affect lability', 'Stress', 'Sleep disorder', 'Decreased interest', 'Paranoia', 'Homicidal ideation', 'Attention deficit/hyperactivity disorder', 'Agitation', 'Social avoidant behaviour', 'Restlessness', 'Sleep talking', 'Tic', 'Initial insomnia', 'Middle insomnia', 'Obsessive thoughts', 'Obsessive-compulsive disorder', 'Hallucination', 'Suicidal behaviour', 'Amnesia', 'Completed suicide', 'Apathy', 'Hypersomnia', 'Autism', 'Hallucination', 'visual', 'Nervousness', 'Psychomotor hyperactivity', 'Somnolence' 3) Indication PT equals any of the following values: 'Food allergy', 'Hypersensitivity', 'Multiple allergies', 'Rhinitis', 'Rhinitis allergic', 'Seasonal allergy', 'Sinus disorder' 4) Indication PT equals any of the following values: 'Asthma', 'Asthma exercise induced', 'Asthma prophylaxis', 'Bronchial hyperreactivity', 'Bronchitis', 'Cough', 'Depression', 'Sinusitis', 'Wheezing' (or is null) 5) Generic name equals any of the following values: 'Albuterol', 'Albuterol And Ipratropium', 'Budesonide And Formoterol', 'Cromoglicic Acid', 'Fluticasone And Salmeterol', 'Formoterol', 'Formoterol And Mometasone', 'Ipratropium', 'Levalbuterol', 'Nedocromil', 'Omalizumab', 'Pirbuterol', 'Salmeterol', 'Theophylline', 'Zafirlukast', 'Zileuton' 6) PT equals any of the following values: 'Completed suicide', 'Death' 7) Outcome died equals 'YES' 8) FDA date is between '03/27/2008' and '10/31/2013', inclusive Allergy indication PTs: Case Series Name: Copy of 4610 Montelukast asthma indic and psyc soc [1879 cases] Query Logic: Return cases based on the following conditions and on the selection logic: ((((1 intersect 2 intersect 4 intersect 7) minus 3) minus 5) minus 6) 1) Generic name equals 'Montelukast' 2) PT equals any of the following values: 'Abnormal behaviour', 'Abnormal dreams', 'Affective disorder', 'Aggression', 'Agitation', 'Agoraphobia', 'Akathisia', 'Anger', 'Anhedonia', 'Anxiety', 'Anxiety disorder', 'Aphonia', 'Attention deficit/hyperactivity disorder', 'Bipolar disorder', 'Completed suicide', 'Conversion disorder', 'Crying', 'Decreased activity', 'Decreased interest', 'Depressed mood', 'Depression', 'Disturbance in attention', 'Dysphonia', 'Emotional disorder', 'Enuresis', 'Fear', 'Fear of death', 'Feeling guilty', 'Feeling of despair', 'Frustration', 'Hallucination', 'Hallucination, visual', 'Homicidal ideation', 'Initial insomnia', 'Insomnia', 'Intentional self-injury', 'Irritability', 'Major depression', 'Mental disorder', 'Mental impairment', 'Middle insomnia', 'Mood altered', 'Mood swings', 102 of

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111 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology (OSE) Office of Pharmacovigilance and Epidemiology (OPE) Epidemiology: Review of the Literature on the Risk of Suicide Associated with Leukotriene-modifying Agents Date: February 27, 2013 Reviewer(s): Jie Jenni Li, PhD, Epidemiologist, Division of Epidemiology II Team Leader Margie R. Goulding, PhD Epi. Team Leader, Division of Epidemiology II Division Director Judy A. Staffa, PhD, RPh Director, Division of Epidemiology Subject Association between leukotriene-modifying agents and suicide Drug Name(s): Leukotriene-modifying agents (LTMAs) (montelukast, zafirlukast, zileuton) Sponsors: OSE OSE RCM #: of 207

112 TABLE OF CONTENTS EXECUTIVE SUMMARY INTRODUCTION REVIEW METHODS AND MATERIALS REVIEW RESULTS CONCLUSION AND RECOMMENDATIONS REFERENCES of 207

113 EXECUTIVE SUMMARY Three leukotriene-modifying agents (LTMAs) (montelukast, zafirlukast, and zileuton) were approved in the late 1990s for long-term control of asthma. Safety concerns arose in 2008 regarding the increased risk of neuropsychiatric adverse events associated with LTMAs utilization, specifically suicide and suicide attempt among pediatric patients with asthma. FDA (OND and OSE) conducted several scientific reviews using data from the pre-marketing clinical trials and data from FDA s Adverse Event Reporting System (AERS), and concluded that the clinical details of some post-marketing reports involving montelukast appeared consistent with a drug-induced effect. A labeling change to all the LTMAs was made in 2009 to include a precaution in the drug-prescribing information. The objectives of the current review are (1) to evaluate the newly published nested case-control study (Schumock et. al. 2012) published in 2012, and (2) to identify other new publications in this area which attempt to quantify the level of risk of suicide/suicide attempt from LTMAs, in order to formulate an opinion on whether the current body of knowledge suggests the need for any further regulatory action by FDA. The nested case-control study (Schumock et al. 2012) identified 344 cases of suicide attempt and 3438 matched controls from an asthma cohort of pediatric patients in IMS claims data. The study results showed no association between use of LTMAs and an increased risk of suicide attempt. The study, however, is subject to residual confounding, and is low in statistical power. Further, a literature search targeting the period identified a conference abstract suggesting an increased risk of depression among asthma patients with montelukast exposure compared to asthma patients with exposure to inhaled corticosteroids. However, the study was not published in a full article as of the date of this literature review. Published clinical trials did not identify risk of suicide from LTMAs, a result likely due to the small sample size and low suicide rate. Taken together, well-designed epidemiologic studies are lacking to quantify the level of risk of suicide/suicide attempt among pediatric asthma patients. None of the literature identified at this time indicates a need for further regulatory action by FDA. Continued monitoring of the literature in this area is recommended. Literature review on luekotriene modifying agents and suicide of 207

114 1 INTRODUCTION Background. Three leukotriene-modifying agents (LTMAs, montelukast, zafirlukast, and zileuton) were approved in the late 1990s for long-term control of asthma. Safety concerns arose in 2008 regarding the increased risk of neuropsychiatric adverse events associated with LTMAs utilization, specifically suicide and suicide attempt among pediatric patients with asthma. The potential LTMA-suicide association is of concern because patients affected by asthma already are likely at a higher risk for depression, mood changes, and even suicide.[ 1 ] Further, asthma is common among children, and LTMAs are frequently used among the pediatric population due to the convenience of the oral dosage form. Regulatory history. To respond to the safety concern, FDA conducted several scientific reviews using data from the pre-marketing clinical trials, as well as data from FDA s Adverse Event Reporting System (AERS) (OSE RCM# ). Higher frequencies of insomnia, depression and abnormal behaviors were reported among LTMA users than non-users, although no increase in suicidal events was identified. Most of the cases were reported in children less than 16 years of age. FDA concluded that the clinical details of some post-marketing reports involving montelukast appeared consistent with a drug-induced effect. As a result, a labeling change to all the LTMAs was made in 2009 to include a precaution a in the drug-prescribing information. In 2011, OSE reviewed two published epidemiologic studies which identified no elevated risk of suicide.[ 2;3 ] (Jick et al and Shumock et al. 2011) The first study (Jick et al. 2009) identified no montelukast-related suicide cases from a cohort of 23,500 patients who had at least one montelukast prescription in the GPRD (now CPRD) database.[ 2;3 ] The OSE reviewer recommended caution in drawing conclusions based on this study, because the study was subject to limitations, such as small sample size, potentially incomplete capture of the outcomes in the electronic medical records, and lack of information on the baseline patient characteristics. The second study (Shumock et al. 2011) estimated the suicide rate (from the number of suicide deaths in each US county) conditional on LTMA use (from the number of prescriptions captured in the IMS Health database).[ 2;3 ] The primary limitation was that the study was ecologic in nature, and unable to draw any causal inferences about LTMA-related risk of suicide due to the lack of person level data. The objectives of the current review are (1) to evaluate the new Schumock et al. case-control study (Schumock et al 2012), and (2) to identify other recent publications in this area that attempt to quantify the level of risk of suicide/suicide attempt, in order to formulate an opinion on whether the current body of knowledge suggests the need for any further regulatory action by FDA. a Label for Montelukast (Singulair) as an example: Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Singulair. Post-marketing reports with Singulair use include agitation, aggressive behavior or hostility, anxiousness, depression, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Singulair appear consistent with a drug-induced effect. Literature review on luekotriene modifying agents and suicide of 207

115 2 REVIEW METHODS AND MATERIALS First, the Schumock et al article describing the nested case-control study was reviewed. Then a literature search was conducted in three databases (PubMed, EMBASE, and International Pharmaceutical Abstracts) to identify articles published between 2008 and The search strategy included the following terms: (leukotriene modifying agent OR leukotriene receptor antagonist OR montelukast OR zafirlukast OR zileuton) AND (suicide OR suicidal attempt OR suicidal thought OR psychiatric adverse event). A total of 23 abstracts were identified and screened for relevance. The full article review was limited to observational studies and clinical trials. In the end, 4 articles were reviewed in full. 3 REVIEW RESULTS 3.1 Shumock s nested case-control study (2012) Objectives. The study s objective was to examine the association between LTMAs and suicide attempts (SAs) in patients with asthma.[ 4 ] Cases and Controls. The case-control design was nested within a cohort of asthma patients aged 5-24 years old who were identified from the LifeLink Health Plan Claims Database (IMS Health, Inc.) by a diagnosis ICD-9-CM (International Classification of Diseases Ninth Revision Clinical Modification) code of 493.XX. The cohort was limited to those patients with at least 1 prescription claim for an asthma controller medication and at least 6 months of continuous enrollment before the index prescription date (index date). Cases of suicide attempt (SA) were defined as those who had an ICD-9-CM code between E950 and E959 recorded after the index date. The outcome was not validated by other means. Randomly selected control subjects were matched to each case (10:1 match) on age, sex, geographic region, and cohort entry time. Exposure. LTMA exposure was determined in the 180 days before the event date. The study determined the exposed period for each prescription based on the prescription fill date and the number of days supplied as recorded in prescription claims. Covariates. Potential covariates were assessed during the 6 months preceding the event date, including relative comorbidities (using ICD-9-CM codes) and medications (using National Drug codes, including anticonvulsants, antidepressants, antipsychotics, hypnotics, anxiolytics, and isotretinoin) that could have been associated with a higher risk of SAs. However, not all measured covariates were included in the final adjusted models which controlled only for bipolar disease, depression, other mental disorders, substance abuse, ED visits, previous psychological counseling and previous suicide attempts. Statistical Analysis. Conditional logistic regression was used to determine the crude and adjusted odds ratios (ORs) and 95% CIs for the association between LTMA exposure and SAs. In the adjusted analyses, variables were retained only if considered clinically significant (based on previous literature) or if they modified the risk estimate by greater than 10%. Literature review on luekotriene modifying agents and suicide of 207

116 Results. The study identified 344 cases of suicide attempt and 3438 matched controls from the selected asthma cohort (n=195,028). Cases were more likely than control subjects to have had previous SAs and to have previously received psychological counseling. Cases were also more likely to have been given a diagnosis of diseases that are associated with a higher risk of suicide, and to have been treated with medications that increase the risk of suicide, such as anticonvulsants, antidepressants, antipsychotics, anxiolytics and hypnotics. Cases had more ED visits with a diagnosis of asthma and were more likely to have had a prescription for an inhaled long-acting β-agonist in the past 6 months. Among cases, 5.5% were using a LTMA at the time of the SA compared with 6.5% of the control subjects, revealing a negative association (statistically non-significant) between current LTMA use and suicide attempt (adjusted odd ratio 0.70; 95% CIs ), controlling for bipolar disease, depression, other mental disorders, substance abuse, ED visits, previous psychological counseling and previous suicide attempts. However, subgroup analyses showed significantly higher risk (aor 5.15; 95% CIs ) in the older age group (19-24 years), but not in the other age groups (5-11 years and years). 3.2 Studies identified from the literature search A conference abstract based on a Korean population-based study reported a higher risk for depression in elderly asthma patients with LTMA exposure compared to exposure to inhaled corticosteroids (HR: 1.5; 95% CIs ).[ 5 ] However, a full article on the study had not been published as of the date of this review. No evidence of suicide risk from LTMAs was reported from clinical trials. An analysis based on three previously published clinical trials involving 504 montelukast-exposed patients revealed no negative effect on emotional well-being from montelukast among asthmatic adults.[ 6 ] However, the study was limited by the small number of patients enrolled. Merck also published an article on the suicidality in clinical trials of montelukast. The study was a result of scientific reviews requested by and in part specified by the FDA to examine the LTMAs-related suicide risk.[ 7 ] A broad descriptive review of all AEs as reported by study investigators identified no completed suicides in the 116 controlled clinical trials (20,131 montelukast patients and 17,633 placebo/active control patients). Events possibly related to suicidality were rare, and numbers of events were similar between montelukast and placebo/active control groups. An adjudication analysis of 41 selected trials (including 9,929 montelukast patients) identified one patient with a possibly suicidality-related adverse event (PSRAE) in the montelukast group and none in the placebo group. Finally, two published literature reviews on the adverse effects of LTMAs concluded that welldesigned epidemiology studies are lacking to determine the suicide risk associated with LTMA utilization.[ 8;9 ] Literature review on luekotriene modifying agents and suicide of 207

117 4 DISCUSSION Shumock s nested case-control study. The case-control study is subject to major limitations. First, the study is not powered enough to detect an elevated risk associated with the study medications. The reviewer estimates that the overall statistical power is below 60%, with even lower power for the age subgroup analyses. Even with low statistical power, the age subgroup of years still showed significantly higher risk. The age group of 5-11 years was too young to be included to study the outcome of suicide attempt, because suicidal behaviors are relatively rare in pre-adolescent children (one single event was reported in this study). Second, the study result is likely affected by residual confounding. The final adjusted models controlled only for bipolar disease, depression, other mental disorders, substance abuse, ED visits, previous psychological counseling and previous suicide attempts. Important potential confounders are left unadjusted or unmeasured, such as asthma severity, sinusitis and allergy history, and the use of medications known to increase the risk for suicide prior to the event date. Clinical trial studies. The negative results published in the clinical trials are unable to exclude the association between suicide and montelukast. Clinical trials usually enroll relatively small numbers of patients which are not powered to identify rare adverse events such as suicide among asthma patients with montelukast exposure. The trial participants often have less concomitant diseases and concomitant medication use than patients in the real world. In addition, children, especially younger children, are rarely studied in clinical trials. Measurements of psychiatric outcomes used in clinical trials most of the time do not meet research standards. FDA recommended measurements, such as the Columbia Classification Algorithm for Suicide Assessment (C-CASA) and Columbia-Suicide Severity Rating Scale (C-SSRS) have been underused in drug safety research, which result in probable misclassifications of the cases.[ 8 ] Study designs. It is challenging to distinguish the suicide effect attributable to the LTMA exposure from those attributable to other risk factors for suicide, such as asthma-induced depression and asthma severity. It is reported that asthma is associated with higher risk of suicide, independent of psychiatric comorbidities.[ 1 ] The incidence rate of depression and other suicide risk factors seem to be higher among asthma patients than among those without asthma. Higher asthma severity seems to be associated with more frequent psychiatric events. A casecontrol design might not be optimal to address the challenges mentioned above. A well-designed, large cohort study with propensity score matching could probably minimize the effects of baseline differences between the exposed and unexposed cohorts, and provide an estimate of the suicide effect attributable to the drug exposure only. Alternatively, a case-crossover study would be suitable because such a design minimizes the potential for confounding by comparing the risk of suicide attempt of the exposure period to that of the non-exposure period within the same individual. 5 CONCLUSION AND RECOMMENDATIONS The reported result of no association between LTMA utilization and risk of suicide attempt from the nested case-control study reviewed (Schumock et al. 2012) is questionable, because the study is limited by residual confounding and low statistical power. A further literature search targeting the period identified a conference abstract, but not full article, of a study suggesting Literature review on luekotriene modifying agents and suicide of 207

118 higher risk of depression from LTMA use among elderly asthma patients in Korea. Published clinical trials enrolled relatively small numbers of patients and are not powered to identify rare adverse events such as suicide among asthma patients with montelukast exposure. Taken together, well-designed epidemiologic studies are lacking to quantify the suicide risk related to the use of LTMAs. None of the published literature identified at this time indicates a need for further regulatory action by FDA. Continued monitoring of the literature in this area is recommended. Literature review on luekotriene modifying agents and suicide of 207

119 6 REFERENCES Reference List [1] Iessa N, Murray ML, Curran S, Wong IC. Asthma and suicide-related adverse events: a review of observational studies. Eur Respir Rev 2011;20: [2] Jick H, Hagberg KW, Egger P. Rate of suicide in patients taking montelukast. Pharmacotherapy 2009;29: [3] Schumock GT, Gibbons RD, Lee TA, Joo MJ, Valuck RJ, Stayner LT. Relationship between leukotriene-modifying agent prescriptions dispensed and rate of suicide deaths by county in the US. Drug Healthc Patient Saf 2011;3: [4] Schumock GT, Stayner LT, Valuck RJ, Joo MJ, Gibbons RD, Lee TA. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol 2012;130: [5] Chul Woo Rhee, Nam-Kyong Choi, Yoon-Ok Ahn, JoongyubLee, Byung Joo Park. Risk of Depression Associated with Use of Leukotriene Receptor Antagonist in Elderly Asthma Patients in Korea. Pharmacoepidemiology and Drug Safety 2011;20:S251. [6] Holbrook JT, Harik-Khan R. Montelukast and emotional well-being as a marker for depression: results from 3 randomized, double-masked clinical trials. J Allergy Clin Immunol 2008;122: [7] Philip G, Hustad C, Noonan G et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol 2009;124: [8] Manalai P, Woo JM, Postolache TT. Suicidality and montelukast. Expert Opin Drug Saf 2009;8: [9] Schumock GT, Lee TA, Joo MJ, Valuck RJ, Stayner LT, Gibbons RD. Association between leukotriene-modifying agents and suicide: what is the evidence? Drug Saf 2011;34: Literature review on luekotriene modifying agents and suicide of 207

120 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Drug Use Review Date: December 23, 2013 Reviewer: Team Leader: Deputy Director: Drug Name(s): Application Type/Number: Applicant/sponsor: Tracy Pham, Pharm.D. Drug Use Data Analyst Division of Epidemiology II Hina Mehta, Pharm.D. Drug Use Data Analysis Team Leader Division of Epidemiology II Laura Governale, Pharm.D., MBA Deputy Director for Drug Utilization Analysis Division of Epidemiology II Office of Pharmacovigilance and Epidemiology Office of Surveillance and Epidemiology Singulair (Montelukast) 10mg, 5mg, and 4mg Multiples Multiples OSE RCM #: **This document contains proprietary drug use data obtained by FDA under contract. The drug use data/information in this document has been cleared for public release.** of 207

121 CONTENTS Executive Summary Background Product Labeling Methods and Material Determining Settings Of Care Data Sources Used Results Patients Analyses Prescriptions Analyses Top Prescribing Specialties Indications for Use Discussion Conclusions... 8 APPENDIX 1: Tables and Graphs... 9 APPENDIX 2: Databases Description of 207

122 EXECUTIVE SUMMARY The Division of Nonprescription Clinical Evaluation (DNCE) is in the process of evaluating Merck s request for a partial prescription to over-the-counter (OTC) switch of Singulair 10mg tablet for the relief of symptoms of seasonal and perennial allergic rhinitis in adults. In support of this effort, this review from the Division of Epidemiology II (DEPI II) provides an analysis of the drug utilization patterns for montelukast, including brand and generic products, from the U.S. outpatient retail pharmacies for years Summary of Findings: The overall number of patients receiving prescriptions dispensed for montelukast increased by approximately 85% from year 2002 to year Moreover, the number of patients receiving prescriptions dispensed for montelukast among all patient age groups increased during the same examined time period. Approximately 33.3 million patients received prescriptions dispensed for montelukast from year 2002 to year 2012, cumulative; of these, adults aged 18 years and older accounted for the majority of total patients at approximately 58%. Among the 14.5 million pediatric patients aged 0-17 years old, pediatrics aged 6-14 years old accounted for the majority of patients at approximately 60% of total pediatric patients, followed by pediatrics aged 2-5 years old at 36%, years old at 14.5%, and 0-1 years old at 9%. The vast majority of pediatrics aged 0-1 years old, and 2-5 years old received prescriptions dispensed for montelukast 4mg. About three-quarters of pediatrics aged 6-14 years old received prescriptions dispensed for montelukast 5mg. The vast majority of pediatrics aged years old and adults aged 18 years and older received prescriptions dispensed for montelukast 10mg. These results show that the most commonly dispensed strength among each patient age group is consistent with the recommended dosage in the label. Since year 2008, the overall number of prescriptions dispensed for montelukast remained relatively steady at approximately 25 million prescriptions dispensed annually. Approximately 125 million prescriptions were dispensed for montelukast from year 2008 to year 2012, cumulative; of these, the majority of prescriptions were dispensed for montelukast 10mg at approximately 68% of total prescriptions, followed by montelukast 5mg at 19.5% and montelukast 4mg at 12%. During the same examined time period, Family Practice, General Practice, and Doctor of Osteopathy were the top prescribing specialty accounting for approximately 30% of total prescriptions dispensed for montelukast. Pediatricians and Internal Medicine specialists followed at approximately 20% and 16%, respectively, of total prescriptions. As reported from office-based physician offices, Asthma NOS was the top diagnosis associated with the use of montelukast among all patient age groups over the cumulative time period from year 2002 to year Allergic Rhinitis NOS was the second most mentioned diagnosis associated with the use of montelukast among all patient age groups. 1 BACKGROUND On September 6, 2013, Merck Consumer Care, Inc. submitted a New Drug Application (NDA) and requested a partial switch of Singulair 10mg tablet from prescription to over-the-counter for the indication of seasonal and perennial allergic rhinitis in adults. Merck also requested that the indication temporarily relieves itchy, watery eyes due to hay fever or other upper respiratory allergies be included in the labeling. The Division of Nonprescription Clinical Evaluation (DNCE) is in the process of 207

123 of assessing the safety reports associated with the use of Singulair and Merck s request for a partial prescription-to-otc switch. An Advisory Committee meeting is also tentatively scheduled in April or early May 2014 to discuss this application and the safety reports. In support of these efforts, the Division of Epidemiology II (DEPI II) was requested to provide the drug utilization patterns for montelukast for years PRODUCT LABELING Montelukast is a leukotriene receptor antagonist indicated for: 1) prophylaxis and chronic treatment of asthma in patient 12 months of age and older; 2) acute prevention of exercise-induced bronchoconstriction in patients 6 years of age and older; and 3) relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older. Montelukast is administered as: 1) once daily in the evening for patients 12 months and older who have asthma; 2) one tablet at least 2 hours before exercise for patients 6 years of age and older who have acute exercise-induced bronchoconstriction; 3) once daily for patients 2 years and older who have seasonal allergic rhinitis; 4) once daily for patients 6 months and older who have perennial allergic rhinitis; and 5) once daily in the evening for patients who have both asthma and allergic rhinitis. 1 Table 1 below provides the initial approval history and product labeling information of montelukast. Table 1. Montelukast s initial approval history and labeling information Product Strength and Formulation NDA/ANDA Initial NDA Approval Date Singulair and gerneric montelukast 10mg oral tablet NDA ; multiple ANDA 5mg chewable oral tablet 4mg chewable oral tablet 4mg oral granule packet NDA ; multiple ANDA NDA ; multiple ANDA NDA ; multiple ANDA Dosage by Age February 20, 1998 One tablet for patients 15 years of age and older February 20, 1998 One tablet for patients 6 to 14 years of age February 20, 1998 One tablet for patients 2 to 5 years of age July 26, 2002 One packet for patients 6 months to 5 years of age 2 METHODS AND MATERIAL 2.1 DETERMINING SETTINGS OF CARE The IMS Health, IMS National Sales Perspectives database (see Appendix 2 for full database description) was used to determine the various retail and non-retail channels of distribution for montelukast. In year 2012, approximately 81% of bottles/packages of montelukast were distributed to 1 U.S. Food and Drug Administration: Drugs@FDA. Singulair Approval History. Accessed in November Available at: fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=search.label ApprovalHistory#labelinfo of 207

124 outpatient retail pharmacies; 13% were to mail-order pharmacies; and 6% were to non-retail settings. 2 As a result, outpatient retail utilization patterns were examined. Data from non-retail and mailorder/specialty settings were not included in this review. 2.2 DATA SOURCES USED Proprietary drug utilization databases were used to conduct this analysis (see Appendix 2 for full database description). The IMS Health, Vector One : Total Patient Tracker (TPT) database was used to provide the nationally estimated number of patients receiving prescriptions dispensed for montelukast, stratified by patient age (0-1, 2-5, 6-14, 15-17, and 18+ years) and product strength, from U.S. outpatient retail pharmacies for years , annual and cumulative. The IMS Health, National Prescription Audit (NPA) database was used to provide the nationally estimated number of prescriptions dispensed for montelukast, stratified by product strength, from U.S. outpatient retail pharmacies for years , annual and cumulative. The top 10 specialties prescribing montelukast was also obtained from IMS Health, National Prescription Audit (NPA) for years , cumulative. The top 10 diagnoses associated with the use of montelukast, stratified by patient age (0-1, 2-5, 6-14, 15-17, and 18+ years), as reported from office-based physician practices in the U.S. for years , cumulative, was obtained from the Encuity Research, LLC., TreatmentAnswers with Pain Panel database. 3 RESULTS 3.1 PATIENTS ANALYSES Table 2 and Figure 1 in Appendix 1 provide the nationally estimated number of unique patients receiving prescriptions dispensed for montelukast, stratified by patient age and product strength, from U.S. outpatient retail pharmacies. The overall number of patients receiving prescriptions dispensed for montelukast increased by approximately 85% from approximately 3.5 million patients in year 2002 to 6.5 million patients in year During the same time period, the number of patients receiving prescriptions dispensed for montelukast increased by approximately 3-fold for pediatrics aged 0-1 years old, 53% for pediatrics aged 2-5 years old, 71% for pediatrics aged 6-14 years old, 86% for pediatrics aged years old, and 93% for adults aged 18 years and older (Table 2 and Figure 1). Over the cumulative time period from year 2002 to year 2012, approximately 33.3 million patients received prescriptions dispensed for montelukast; of these, the majority of patients were adults aged 18 years and older, accounting for approximately 58% (19.3 million patients) of total patients, followed by pediatric patients aged 0-17 years old at approximately 43% (14.5 million patients) of total patients. Among the pediatric population, patients aged 6-14 years old received the majority of prescriptions at approximately 60% (8.6 million patients) of pediatric patients. Patients aged 2-5 years old, years old, and 0-1 years old followed at approximately 36% (5.3 million patients), 14.5% (2.1 million 2 Source: IMS Health, IMS National Sales Perspectives. Year Data extracted October File: NSP montelukast DNCE channels xlsx of 207

125 patients), and 9% (1.3 million patients) of pediatric patients, respectively. These trends were the same for each of the examined year (Table 2). From year 2002 to year 2012, cumulative, the vast majority of patients aged 0-1 years old (1.3 million patients, 98% of 0-1 years old patients) and 2-5 years old (4.4 million patients, 84% of 2-5 years old patients) received prescriptions dispensed for montelukast 4mg. Approximately three-quarters of patients aged 6-14 years old (6.6 million patients, 76.5% of 6-14 years old patients) received prescriptions dispensed for montelukast 5mg. The vast majority of patients aged years old (2.0 million patients, 95% of years old patients) and 18 years and older (19.2 million patients, 99% of 18+ years old patients) received prescriptions dispensed for montelukast 10mg. Among patients aged 0-1 years old (4,900 patients) and 2-5 years old (34,400 patients), less than 1% of patients in these respective age groups received prescriptions dispensed for montelukast 10mg. Among patients aged 6-14 years old, approximately 28% of patients in this age group (2.4 million patients) received prescriptions dispensed for montelukast 10mg (Table 2). 3.2 PRESCRIPTIONS ANALYSES Table 3 in Appendix 1 provides the nationally estimated number of prescriptions dispensed for montelukast, stratified by product strength, from U.S. outpatient retail pharmacies. Approximately 125 million prescriptions were dispensed for montelukast for years , cumulative; of these, the majority of prescriptions were dispensed for montelukast 10mg at approximately 68% (85.3 million prescriptions), followed by montelukast 5mg at 19.5% (24.4 million prescriptions) and montelukast 4mg at 12% (15.4 million prescriptions). These trends were the same for all of the examined years. From year 2008 to year 2012, the overall number of prescriptions dispensed for montelukast remained relatively steady at approximately 25 million prescriptions dispensed annually. The number of prescriptions dispensed for montelukast 10mg (16.7 million 17.4 million prescriptions) and 5mg (4.8 million 4.9 million prescriptions) remained relatively steady. Meanwhile, the number of prescriptions dispensed for montelukast 4mg slightly decreased by approximately 11% from 3.3 million prescriptions in year 2008 to 2.9 million prescriptions in year TOP PRESCRIBING SPECIALTIES Table 4 in Appendix 1 provides the nationally estimated number of prescriptions dispensed for montelukast, stratified by prescribing specialty, from U.S. outpatient retail pharmacies for years , cumulative. Family Practice, General Practice, and Doctor of Osteopathy accounted for the highest proportion of dispensed prescriptions at approximately 30% (37.6 million prescriptions). Pediatricians, Internal Medicine, and Allergy/Immunology specialists followed at approximately 20% (24.9 million prescriptions), 16% (20.1 million prescriptions), and 9% (11.7 million prescriptions), respectively, of total prescriptions. 3.4 INDICATIONS FOR USE Table 5 in Appendix 1 provides the top 10 diagnoses in terms of drug use mentions 3 associated with the use of montelukast, stratified by patient age, as reported from office-based physician practices. 3 The term "drug uses" to refer to mentions of a drug in association with a diagnosis during an office-based patient visit. This term may be duplicated by the number of diagnosis for which the drug is mentioned. It is important to note that a "drug use" does not necessarily result in prescription being generated. Rather, the term indicates that a given drug was mentioned during an office visit of 207

126 Diagnoses associated with the use of montelukast were coded according to the International Classification of Diseases (ICD-9-CM) and 95% confidence intervals were calculated for the estimates. From year 2002 to year 2012, cumulative, Asthma NOS (ICD-9 code 493.9) was the top diagnosis associated with the use of montelukast among all patient age groups. Asthma NOS accounted for approximately 42% (916,000 uses, 95% CI 773,000 to 1.1 million uses) of uses among patients aged 0-1 years old, 49% (5 million uses, 95% CI 4.7 million to 5.4 million uses) of uses among patients aged 2-5 years old, 55% (11.1 million uses, 95% CI 10.6 million to 11.6 million uses) of uses among patients aged 6-14 years old, 55% (2.2 million uses, 95% CI 2 million to 2.5 million uses) of uses among patients aged years old, and 52% (26.7 million uses, 95% CI 25.9 million to 27.5 million uses) of uses among patients aged 18 years and older. Allergic Rhinitis NOS (ICD-9 code 477.9) was the second most mentioned diagnosis associated with the use of montelukast among all patient age groups. Allergic Rhinitis NOS accounted for approximately 19% (406,000 uses, 95% CI 311,000 to 502,000 uses) of uses among patients aged 0-1 years old, 20% (2.1 million uses, 95% CI 1.9 million to 2.3 million uses) of uses among patients aged 2-5 years old, 22% (4.4 million uses, 95% CI 4.1 million to 4.7 million uses) of uses among patients aged 6-14 years old, 21% (857,000 uses, 95% CI 718,000 to 996,000 uses) of uses among patients aged years old, and 17% (8.7 million uses, 95% CI 8.2 million to 9.1 million uses) of uses among patients aged 18 years and older. 4 DISCUSSION The analyses in this review indicate that the number of patients receiving prescriptions dispensed for montelukast among all patient age groups appears to have increased since year 2002; however, over the last 5 years from 2008 to 2012, the overall number of annual dispensed prescriptions and patients on montelukast has remained steady. The majority of patients receiving prescriptions dispensed for montelukast were aged 18 years and older. Montelukast 4mg was dispensed the most to pediatrics aged 0-1 years old and 2-5 years old, while montelukast 5mg was dispensed the most to pediatrics aged 6-14 years old, and montelukast 10mg was dispensed the most to pediatrics aged years old and adults aged 18 years and older. These results show that the most commonly dispensed strength among each patient age group is consistent with the recommended dosage in the label. Even though montelukast 10mg was used off-label among pediatric patients younger than 15 years of age, less than 1% each of pediatrics aged 0-1 years old and 2-5 years old, and approximately 28% of pediatrics aged 6-14 years old received prescriptions dispensed for montelukast 10mg. Findings from this review should be interpreted in the context of the known limitations of the databases used. Based on the IMS Health, IMS National Sales Perspectives, sales data showed that the majority of montelukast bottles/packages were distributed to outpatient retail pharmacies in year These data do not provide a direct estimate of use but do provide a national estimate of units sold from the manufacturer to various channels of distribution. The amount of product purchased by these retail and non-retail channels of distribution may be a possible surrogate for use, if we assume that facilities purchase drugs in quantities reflective of actual patient use. We focused our analyses on only the outpatient retail pharmacy settings, therefore these estimates may not apply to other settings of care, such as mail-order/specialty pharmacies, clinics, and hospitals, in of 207

127 which these products are used. The estimates provided are national estimates, but no statistical tests were performed to determine statistically significant changes over time or between products. Therefore, all changes over time or between products should be considered approximate, and may be due to random error. Indications for use were obtained using a monthly survey of 3,200 office-based physicians. Although these data are helpful to understand how drug products are prescribed by physicians, the small sample size and the relatively low usage of these products limits the ability to identify trends in the data. In general, physician survey data are best used to identify the typical uses for the products in clinical practice, and patient or prescription data are best used to evaluate utilization trends over time. Results should not be overstated when nationally projected estimates of annual uses or mentions fall below 100,000 as the sample size is very small with correspondingly large confidence intervals. 5 CONCLUSIONS The overall number of patients receiving prescriptions dispensed for montelukast increased by approximately 85% from year 2002 to year 2012; however, over the last 5 years from 2008 to 2012, the number of prescriptions dispensed and patients on montelukast remained relatively steady. During year 2012, approximately 6.5 million patients received prescriptions dispensed for montelukast, and approximately 25 million prescriptions were dispensed from outpatient retail pharmacies in the U.S. Adults aged 18 years and older accounted for the majority of total patients receiving prescriptions dispensed for montelukast. The majority of patients aged years old and 18 years and older received prescriptions dispensed for montelukast 10mg. Although montelukast 10mg is used off-label among pediatric patients younger than 15 years of age, its use appears to be considerably low compared to the most commonly used strength, and that the most commonly dispensed strength among each patient age group is consistent with the recommended dosage in the label. Moreover, Asthma NOS was the top diagnosis associated with the use of montelukast among all patient age groups, followed by Allergic Rhinitis NOS of 207

128 APPENDIX 1: TABLES AND GRAPHS Table 2. Nationally estimated number of unique patients receiving prescriptions dispensed for montelukast, stratified by patient age and product strength, from U.S. outpatient retail pharmacies, years Time Period in Year Cumulative 1/ /2012 N % N % N % N % N % N % N % N % N % N % N % N % Total Patients 3,537, % 4,814, % 5,617, % 5,971, % 6,569, % 7,398, % 6,686, % 6,254, % 6,623, % 6,389, % 6,547, % 33,314, % 0-17 years 1,518, % 2,090, % 2,535, % 2,605, % 2,789, % 3,153, % 2,770, % 2,536, % 2,685, % 2,569, % 2,598, % 14,450, % 0-1 years 42, % 83, % 129, % 130, % 161, % 194, % 166, % 144, % 157, % 145, % 134, % 1,276, % 4mg 38, % 79, % 126, % 128, % 159, % 192, % 164, % 142, % 156, % 143, % 133, % 1,253, % 5mg 3, % 4, % 3, % 2, % 2, % 3, % 2, % 1, % 1, % 1, % 1, % 25, % 10mg % % % % % % % % % % % 4, % 2-5 years 461, % 645, % 808, % 800, % 835, % 926, % 792, % 708, % 744, % 708, % 706, % 5,252, % 4mg 342, % 503, % 650, % 651, % 687, % 770, % 669, % 604, % 639, % 611, % 609, % 4,389, % 5mg 139, % 169, % 192, % 181, % 182, % 192, % 151, % 127, % 133, % 123, % 123, % 1,341, % 10mg 3, % 4, % 4, % 4, % 4, % 4, % 3, % 2, % 2, % 2, % 2, % 34, % 6-14 years 915, % 1,223, % 1,456, % 1,515, % 1,613, % 1,826, % 1,626, % 1,508, % 1,583, % 1,526, % 1,567, % 8,647, % 5mg 665, % 886, % 1,056, % 1,098, % 1,182, % 1,351, % 1,213, % 1,141, % 1,197, % 1,165, % 1,201, % 6,616, % 10mg 246, % 320, % 364, % 372, % 379, % 409, % 343, % 294, % 328, % 300, % 298, % 2,392, % 4mg 47, % 77, % 108, % 123, % 138, % 161, % 151, % 144, % 144, % 143, % 152, % 966, % years 165, % 229, % 267, % 292, % 320, % 357, % 316, % 293, % 316, % 305, % 308, % 2,096, % 10mg 155, % 217, % 253, % 277, % 302, % 336, % 295, % 271, % 295, % 283, % 284, % 1,986, % 5mg 12, % 15, % 17, % 19, % 22, % 26, % 25, % 26, % 27, % 28, % 31, % 182, % 4mg % % % % % % % % % % % 5, % 18+ years 2,028, % 2,737, % 3,115, % 3,398, % 3,815, % 4,277, % 3,946, % 3,744, % 3,897, % 3,784, % 3,923, % 19,306, % 10mg 2,005, % 2,710, % 3,089, % 3,373, % 3,787, % 4,247, % 3,922, % 3,721, % 3,878, % 3,766, % 3,903, % 19,164, % 5mg 25, % 29, % 27, % 27, % 29, % 31, % 26, % 24, % 20, % 19, % 21, % 201, % 4mg 3, % 4, % 5, % 4, % 5, % 6, % 5, % 4, % 3, % 3, % 3, % 42, % UNKNOWN AGE 4, % 4, % 474 <0.1% 283 <0.1% 138 <0.1% 133 <0.1% 59 <0.1% 408 <0.1% 7, % 1,995 <0.1% 90 <0.1% 16,542 <0.1% Source: IMS Health, Vector One : Total Patient Tracker (TPT). Years Data extracted November Files: TPT montelukast 4mg age xlsx; TPT montelukast 4mg age aggregate xlsx; TPT montelukast 5mg age xlsx; TPT montelukast 5mg age aggregate xlsx; TPT montelukast 10mg age xlsx; TPT montelukast 10mg age aggregate xlsx; TPT montelukast all strength 0-17 age xlsx; TPT montelukast all strength 0-17 age aggregate xlsx; TPT montelukast all strength age xlsx; TPT montelukast all strength age aggregate xlsx *Due to the possibility of double counting patients who are receiving treatment over multiple periods in the study, unique patient counts may not be added across time periods. Summing across patient age bands is not advisable and will result in overestimates of patient counts of 207

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130 Table 4. Nationally estimated number of prescriptions dispensed for montelukast, stratified by top 10 prescribing specialties, from U.S. outpatient retail pharmacies, cumulative years Cumulative 1/ /2012 TRx % TOTAL MONTELUKAST PRESCRIPTIONS 125,100, % FP/GP/DO 37,627, % PED 24,945, % IM 20,065, % ALLERGY/IMMUNOLOGY 11,693, % NURSE PRACTITIONER 7,214, % PUD 7,013, % PHYSICIAN ASSISTANT 4,281, % OTOLARYNGOLOGY 3,294, % SPECIALTY UNSPECIFIED 3,218, % CARDIOLOGY 715, % ALL OTHERS 5,028, % Source: IMS Health, National Prescription Audit. Years Data extracted November Files: NPA montelukast DNCE top 10 MD xlsx; NPA montelukast DNCE total MD xlsx of 207

131 Table 5. Top 10 diagnoses associated with the use of montelukast, stratified by patient age, as reported from office-based physician practices in the U.S., cumulative years Cumulative 1/ /2012 Cumulative 1/ /2012 Uses (000) 95% CI Uses (000) % Uses (000) 95% CI Uses (000) % Total Market 90,177 88,754-91, % Total Market 90,177 88,754-91, % 0-1 years 2,183 1,961-2, % years 4,108 3,805-4, % 4939 ASTHMA NOS , % 4939 ASTHMA NOS 2,244 2,019-2, % 4779 ALLERGIC RHINITIS NOS % 4779 ALLERGIC RHINITIS NOS % 7862 COUGH % 7862 COUGH % 4720 CHRONIC RHINITIS % 9953 ALLERGY, UNSPECIFIED % 5191 OTH DIS TRACHEA /BRON % 4739 CHRONIC SINUSITIS NOS % 4739 CHRONIC SINUSITIS NOS % 4938 OTHER FORMS OF ASTHMA % 9953 ALLERGY, UNSPECIFIED % 4900 BRONCHITIS NOS % 7860 DYSPNEA/RESPIRATORY ABN % 4659 ACUTE URI NOS % 4661 ACUTE BRONCHIOLITIS % 7860 DYSPNEA/RESPIRATORY ABN % 4860 PNEUMONIA, ORGANISM NOS % 4720 CHRONIC RHINITIS % All Others % All Others % 2-5 years 10,218 9,739-10, % 18+ years 51,282 50,210-52, % 4939 ASTHMA NOS 5,039 4,702-5, % 4939 ASTHMA NOS 26,714 25,939-27, % 4779 ALLERGIC RHINITIS NOS 2,078 1,862-2, % 4779 ALLERGIC RHINITIS NOS 8,686 8,245-9, % 7862 COUGH % 4960 CHR AIRWAY OBSTRUCT NEC 2,925 2,669-3, % 9953 ALLERGY, UNSPECIFIED % 9953 ALLERGY, UNSPECIFIED 2,505 2,268-2, % 4739 CHRONIC SINUSITIS NOS % 4739 CHRONIC SINUSITIS NOS 2,071 1,855-2, % 4720 CHRONIC RHINITIS % 7862 COUGH 1,423 1,244-1, % 7860 DYSPNEA/RESPIRATORY ABN % 4900 BRONCHITIS NOS 1, , % 4900 BRONCHITIS NOS % 7860 DYSPNEA/RESPIRATORY ABN % 5191 OTH DIS TRACHEA /BRON % 4720 CHRONIC RHINITIS % 4781 NASAL & SINUS DIS NEC % 4781 NASAL & SINUS DIS NEC % All Others , % All Others 4,389 4,075-4, % 6-14 years 19,984 19,314-20, % UNKNOWN AGE 2,401 2,169-2, % 4939 ASTHMA NOS 11,074 10,575-11, % 4939 ASTHMA NOS 1,246 1,079-1, % 4779 ALLERGIC RHINITIS NOS 4,403 4,089-4, % 4779 ALLERGIC RHINITIS NOS % 9953 ALLERGY, UNSPECIFIED % 9953 ALLERGY, UNSPECIFIED % 7862 COUGH % 7862 COUGH % 4739 CHRONIC SINUSITIS NOS % 4960 CHR AIRWAY OBSTRUCT NEC % 4900 BRONCHITIS NOS % 4739 CHRONIC SINUSITIS NOS % 4938 OTHER FORMS OF ASTHMA % 7860 DYSPNEA/RESPIRATORY ABN % 7860 DYSPNEA/RESPIRATORY ABN % 5191 OTH DIS TRACHEA /BRON % 4720 CHRONIC RHINITIS % 4720 CHRONIC RHINITIS % 5191 OTH DIS TRACHEA /BRON % 4900 BRONCHITIS NOS % All Others 1,494 1,311-1, % All Others % Source: Encuity Research LLC., TreatmentAnswers. Years Data extracted November File: Encuity montelukast DNCE age dx xlsx of 207

132 APPENDIX 2: DATABASES DESCRIPTION IMS Health, IMS National Sales Perspectives : Retail and Non-Retail The IMS Health, IMS National Sales Perspectives measures the volume of drug products, both prescription and over-the-counter, and selected diagnostic products moving from manufacturers into various outlets within the retail and non-retail markets. Volume is expressed in terms of sales dollars, eaches, extended units, and share of market. These data are based on national projections. Outlets within the retail market include the following pharmacy settings: chain drug stores, independent drug stores, mass merchandisers, food stores, and mail service. Outlets within the non-retail market include clinics, non-federal hospitals, federal facilities, HMOs, long-term care facilities, home health care, and other miscellaneous settings. IMS Health, Vector One : Total Patient Tracker (TPT) The IMS, Vector One : Total Patient Tracker is a national-level projected audit designed to estimate the total number of unique patients across all drugs and therapeutic classes in the retail outpatient setting over time. TPT derives its data from the Vector One database which integrates prescription activity from a sample received from payers, switches, and other software systems that may arbitrage prescriptions at various points in the sales cycle. Vector One receives over 1.9 billion prescription claims per year, representing over 158 million unique patients. Since 2002 Vector One has captured information on over 15 billion prescriptions representing over 356 million unique patients. IMS Health, National Prescription Audit (NPA) The National Prescription Audit (NPA TM ) measures the retail outflow of prescriptions, or the rate at which drugs move out of retail pharmacies into the hands of consumers via formal prescriptions in the United States. The NPA audit measures both what is prescribed by the physician and what is dispensed by the pharmacist. Data for the NPA audit is a national level estimate of the drug activity from retail pharmacies. NPA TM receives over 2.7 billion prescription claims per year, captured from a sample of the universe of approximately 57,000 pharmacies throughout the U.S. The pharmacies in the database account for most retail pharmacies and represent nearly 80% of retail prescriptions dispensed nationwide. The type of pharmacies in the sample are a mix of independent, retail, chain, mass merchandisers, and food stores with pharmacies, and include prescriptions from cash, Medicaid, commercial third-party and Medicare Part-D prescriptions. Data are available on-line for 72- rolling months with a lag of 1 month. Encuity Research, LLC., TreatmentAnswers with Pain Panel Encuity Research, LLC., TreatmentAnswers and TreatmentAnswers with Pain Panel is a monthly survey designed to provide descriptive information on the patterns and treatment of diseases of 207

133 encountered in office-based physician practices in the U.S. The survey consists of data collected from over 3,200 office-based physicians representing 30 specialties across the United States that report on all patient activity during one typical workday per month. These data may include profiles and trends of diagnoses, patients, drug products mentioned during the office visit and treatment patterns. The Pain Panel supplement surveys over 115 pain specialists physicians each month. With the inclusion of visits to pain specialists, this will allow additional insight into the pain market. The data are then projected nationally by physician specialty and region to reflect national prescribing patterns of 207

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135 Table of Contents 1. Background Regulatory Activity Regarding Consumer Studies Consumer Studies Overview of the Consumer Studies Design and Conduct of the Consumer Studies Targeted LC Study Design and Conduct Adolescent Study Design and Conduct SOLID Study Design and Conduct Consumer Study Results and Discussion Targeted LC Study Results Adolescent Study Results SOLID Study Results Self-selection Label Comprehension Discussion Adequacy of Neuropsychiatric Labeling Potential for Off-label Pediatric Use Potential for Off-label Asthma Use Additional Commentary on the SOLID Study Study Methodology Mitigation Secondary and Additional Objectives Conclusion Appendix: Additional Analyses Performed by the Agency on the SOLID Study of 207 2

136 Table of Tables Table 1. Currently approved indications for prescription Singulair... 4 Table 2. Consumer studies submitted in support of NDA for OTC marketing of Singulair Allergy... 8 Table 3. Targeted LC Study: Percent of subjects with correct response (primary endpoints, general population allergy sufferers) Table 4. Targeted LC Study: Percent of subjects with correct response (low literacy allergy sufferers) Table 5. Adolescent Study: Percent of subjects with correct self-selection (primary endpoint) Table 6. Adolescent Study: Percent of subjects with correct response (primary comprehension objectives, allergy sufferers) Table 7. SOLID Study: Percent of subjects with correct self-selection (general population asthma sufferers) Table 8. SOLID Study: Percent of subjects with correct response (comprehension objectives related to asthma) Table 9. SOLID Study: Percent of subjects with correct response (comprehension objective related to potential off-label pediatric use) Table 10. Targeted LC Study: Percent of subjects with correct response (primary objectives, general population allergy sufferers) Table 11. Adolescent Study: Percent of subjects with correct response (subgroups among allergy sufferers) Table 12. SOLID Study: Percent of subjects with correct and incorrect self-selection (general population asthma sufferers, Cohorts 1 and 2 combined) Table 13. SOLID Study: Percent of subjects with correct and incorrect self-selection (Cohort 3 low literacy asthma sufferers) Table 14. SOLID Study: Percent of subjects with correct response (impact of a priori mitigation in Cohorts 1 and 2) Table 15. SOLID Study: A priori mitigation categories Table 16. SOLID Study: Percent of subjects with correct self-selection (general population asthma sufferers) Table 17. SOLID Study: Percent of subjects with correct response (label comprehension, secondary objectives) Table 18: SOLID Study: Percent of subjects with correct response (general population asthma sufferers) Table 19. SOLID Study: Percent of subjects with correct response (low literacy asthma sufferers)^ Table 20. SOLID Study: Comprehension rates for subjects who stated Singulair Allergy was appropriate to personally use^ Table of Figures Figure 1. SOLID Study: Subject disposition Figure 2. SOLID Study: Warning on back of tested outer carton not for asthma treatment of 207 3

137 1. Background Montelukast (Singulair) is currently marketed for prescription use for four indications (Table 1). Table 1. Currently approved indications for prescription Singulair Indication Prophylaxis and chronic treatment of asthma Acute prevention of exercise-induced bronchoconstriction (EIB) Relief of symptoms of allergic rhinitis (AR) Seasonal allergic rhinitis (SAR) Perennial allergic rhinitis (PAR) Indicated Population >12 months >6 years >2 years >6 months Merck is proposing to market montelukast to OTC consumers for only two of the four Rx indications (SAR and PAR), and only in a subset of the current Rx population -- adults 18 years and older. As a prescription medication, adults > 18 years and adolescents years are directed to use one 10-mg tablet daily (same dose for asthma and allergic rhinitis); younger children are administered lower doses. 1 Singulair was approved for asthma treatment and prevention in Additional indications were approved in 2002 (SAR), 2005 (PAR), and 2012 (EIB). Starting in 2007, the prescription label and patient information for Singulair were updated to include neuropsychiatric adverse events. The current prescription label 2 includes the following text: Excerpts from Current Rx Label: WARNINGS AND PRECAUTIONS (in the Highlights): Neuropsychiatric events have been reported with SINGULAIR. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur. WARNINGS AND PRECAUTIONS (in the Full Prescribing Information): 5.4 Neuropsychiatric Events Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, 1 6 to 14 years: one 5-mg chewable tablet; 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules; 6 to 23 months: one packet of 4-mg oral granules 2 fda.gov/drugsatfda docs/label/2013/021409s043lbl.pdf 137 of 207 4

138 aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur [see Adverse Reactions (6.2)]. ADVERSE REACTIONS (in the Full Prescribing Information): 6.2 Postmarketing Experience (see footnote) 3 2. Regulatory Activity Regarding Consumer Studies During development, FDA expressed concern that: A. Labeling may not adequately communicate to consumers (i) the potential for neuropsychiatric events and (ii) the recommended course of action should neuropsychiatric adverse event(s) occur. B. Adolescents 15 to 17 years may self-administer Singulair Allergy for labeled and off-label uses. C. OTC asthma sufferers may use Singulair Allergy off-label for the asthma and EIB indications. In 2007, FDA s Division of Nonprescription Clinical Evaluation and the Sponsor began discussions on the OTC switch development program. Highlights of these interactions are outlined below. 3 Excerpts from Current Rx Label: (continued) 6.2 Postmarketing Experience (relevant excerpts) The following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor [see Warnings and Precautions (5.4)]. Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures. 138 of 207 5

139 October 22, 2007 pre-ind meeting with FDA: The Agency noted that prescription Singulair has the asthma (including exercise induced bronchospasm) and allergic rhinitis indications. The Agency expressed concern that if only the allergic rhinitis indication were switched, Singulair may be used by OTC consumers for the asthma and EIB indications. The Agency indicated that the sponsor would need to provide data to alleviate its concerns: consumer studies will be required to demonstrate appropriate self-selection and comprehension that this product should be used for allergic rhinitis and not asthma. Upon review of the label comprehension and self-selection study protocols, a determination will be made whether an actual use study is needed. The sponsor acknowledged the potential asthma consumer use issue and stated that this issue will be a focus of their research. As the sponsor preferred to use the Singulair trade name for an OTC product because of consumer recognition, it would examine whether this trade name potentially contributes to the consumer association of montelukast with asthma and therefore lead to self-selection or dosing errors. The Agency questioned if prescription Singulair is primarily used in patients with asthma who also have allergic rhinitis. The sponsor indicated that the product is intended for use in the OTC setting for patients with allergic rhinitis and no asthma. August 27, 2008: The Sponsor submitted a draft self-selection/actual use protocol. March 25, 2009 FDA Advice Letter regarding the submitted protocol: The Agency indicated that the objectives and endpoints of the self-selection/actual use study protocol were not clear. Based on the information provided to date and our current knowledge of the drug product, the Agency did not see the need for an actual use study if the sponsor were able to conduct a well-designed self-selection study. The Agency advised the sponsor to complete the label comprehension study and make any necessary label changes before proceeding with a self-selection study. The Agency suggested that the self-selection study include two cohorts: (1) asthmatics who have been treated with Singulair (either currently or in the past), and (2) asthmatics who have never been treated with Singulair. Each cohort would need to have an adequate number of asthmatics with allergies and asthmatics without allergies. The low literacy population would need to be wellrepresented of 207

140 February 7, 2013 pre-nda meeting with FDA: The Agency suggested that the sponsor propose language to warn consumers about neuropsychiatric events that can occur with Singulair use, and how to respond if they experience such an event. The Agency also suggested that the sponsor consider a consumer leaflet to inform consumers about the neuropsychiatric issue. The Agency advised about the need to assess the comprehension of the neuropsychiatric event warning (including the comprehension of what consumers should do if they experience a neuropsychiatric adverse event). The Agency recommended that subjects age 15 and older be assessed for comprehension and self-selection, if the sponsor planned to propose to label the product for adolescents years of age in a subsequent submission. The Agency was concerned that Singulair may be used off-label by adolescents; furthermore, adolescents may self-administer the medication. The Agency recommended that a self-selection and label comprehension study be performed in adolescents to collect the appropriate data on self-selection and the potential for misuse -- before the product is available OTC. The Agency indicated that the objective of understanding that consumers should not take another montelukast sodium product along with Singulair Allergy should be one of the sponsor s primary communication objectives. 3. Consumer Studies 3.1 Overview of the Consumer Studies To address FDA s concerns, the Sponsor conducted research and submitted reports for three consumer studies in support of the NDA for Singulair Allergy (Table 2). 3.2 Design and Conduct of the Consumer Studies Targeted LC Study Design and Conduct The Targeted Label Comprehension (LC) Study was a single-visit study designed to address the Agency s concern about adequate labeling regarding neuropsychiatric events. The study was conducted in 480 adults with self-reported history of indoor/outdoor allergies. A total of 84 subjects with depression and 151 low-literate 4 subjects were 4 Scored <60 on Rapid Estimate of Adult Literacy in Medicine (REALM) test, representing a health literacy level of 8 th grade or below 140 of 207 7

141 Table 2. Consumer studies submitted in support of NDA for OTC marketing of Singulair Allergy Study Referred to as N (total, GP, low literate) Description [ Concerns the Study Was Designed to Address ] Enrollees Study 13007: the Targeted LC 480, A single-visit, label comprehension study Adults, self-reported Singulair Allergy (Label 361,* evaluating comprehension of history of Targeted Label Comprehension) 151^ neuropsychiatric event warnings proposed indoor/outdoor Comprehension Study for the Drug Facts Label (DFL) allergies Study [ Neuropsychiatric labeling ] # of sites 10 Study 13023: Singulair Allergy Targeted Self- Selection and Warning Interpretation Study in Adolescents Ages Study 12246: Singulair OTC Label Interpretations and Decisions the Adolescent Study the SOLID Study 350, 260, , 733**, 163^^ A single-visit study evaluating appropriate self-selection based on labeled age, and interpretation of the neuropsychiatric event warnings in the DFL [ Off-label pediatric use, Neuropsychiatric labeling ] A single-visit study evaluating selfselection among subjects with asthma, and comprehension of proposed DFL text relating to asthma [ Off-label asthma use, Off-label pediatric use ] Adolescents 15 to 17 years, self-reported history of indoor/outdoor allergies Adults with selfreported history of asthma (with or without indoor/outdoor allergies) GP: general population; ^119 low literate augments + 32 low literates from the GP; ^^87 low literate augments + 40 low literates from Cohort low literates from Cohort 2; *84 with, 277 without, self-report of doctor diagnosis of depression; **384 have ever used (Cohort 1), 349 have never used (Cohort 2), Singulair. Of the 384, 70 were asthma-only sufferers, 314 were asthma and allergy sufferers; Of the 349, 71 were asthma-only sufferers, 278 were asthma and allergy sufferers; of 207 8

142 enrolled. The primary objective was to assess comprehension of two specific warnings for use on the outer carton of the nonprescription product: Stop use and ask a doctor if: you experience unexpected changes in behavior, thoughts, or mood you experience unexpected changes or problems when you sleep Subjects were presented with scenarios 5 and asked questions about the scenarios. For each scenario, subjects were asked the follow-up question ( Why do you say that? ). Subjects who mentioned side effects were asked a second follow-up question ( What do you mean by side effect? ). Responses to the initial question and follow-up question(s) were considered in assessing the degree of comprehension Adolescent Study Design and Conduct The Adolescent Study was a single-visit, combined self-selection / label comprehension study designed primarily to address the Agency s concern about potential off-label use by adolescents. The study enrolled 350 adolescents 15 to 17 years of age with self-reported history of indoor/outdoor allergies, including 90 low-literacy subjects. The self-selection primary objective was to assess if subjects could make a correct selfselection decision not to select the product based on the labeled age. The Drug Facts Label (DFL) that was tested had the following text: Directions adults 18 years of age and older / 1 tablet daily; not more than 1 tablet in 24 hours children under 18 years of age / do not use The adolescent subjects were given the package and DFL to read, and then asked the selfselection question: Is this medicine ok for you to use? All subjects were then asked an open-ended question: Why do you say that? Based on the age of subjects (15-17 years) and the proposed target age in the DFL (>18 years), all subjects were expected to not self-select to use Singulair Allergy. Subjects who answered yes or don t know to the self-selection question were asked follow-up 5 Scenario for behaviors, thoughts, or mood: Kara is usually a calm and relaxed person. She has allergies and has been using Singulair Allergy for the past several days. She has suddenly started feeling extremely agitated and nervous. According to the label, what, if anything, should Kara do? Scenario for sleep: Gary has allergies and has been using Singulair Allergy for the past week. He used to sleep very well, but in the last week, he has started waking up in the middle of the night with unusual nightmares. According to the label, what, if anything, should Gary do? 142 of 207 9

143 questions regarding what condition would be treated 6 and whether he / she were more likely to take the product on your own or ask someone first 7 ; subjects who responded that they would ask their parents or guardians were mitigated to a Correct self-selection (mitigation described a priori in the protocol). The label comprehension primary objectives included assessment of: A. what, if any, action adolescents would take if they started feeling different than usual if using Singulair Allergy. B. whether adolescents could correctly interpret the following proposed DFL language regarding potential neuropsychiatric effects: unexpected changes in behavior, thoughts, or mood and unexpected changes or problems when you sleep For these objectives, subjects were asked, If you were using this medicine and started feeling different than you usually do, what if anything, would you do? followed by two open-ended questions: What does the phrase unexpected changes in behavior, thoughts or mood mean to you? What does the phrase unexpected changes or problems when you sleep mean to you? SOLID Study Design and Conduct The SOLID Study was a single-visit, combined self-selection / label comprehension study designed to address the Agency s concern about potential off-label use for asthma. The Study enrolled 820 adults with self-reported history of asthma, with or without indoor / outdoor allergies. Enrollees included 384 subjects who had ever used Singulair (Cohort 1), 349 subjects who had never used Singulair (Cohort 2), and 163 low-literate subjects (Cohort 3). Figure 1 provides an overview of subject disposition. There was a substantial difference in the total number of Asthma-only subjects (N=141, 70+71) and Asthma & Allergies subjects (N=592, ) enrolled and analyzed. 6 What if anything would you use this product to treat? 7 You said that this product would be ok for you to use. Would you be more likely to take this on your own or would you ask someone first? 143 of

144 Figure 1. SOLID Study: Subject disposition Subjects initially enrolled N=836 Cohort 1 N=384* GP Asthma Have used Singulair Cohort 2 N=349** GP Asthma Never used Singulair Cohort 3 N=163*** Low Literate Asthma^ Subgroup 1 N=70 Asthma-only Subgroup 2 N=314 Asthma & Allergies Subgroup 3 N=71 Asthma-only Subgroup 4 N=278 Asthma & Allergies *385 enrolled, 1 removed from analysis; **356 enrolled, 7 removed from analysis; ***171 enrolled, 8 removed from analysis; GP: general population; ^includes 87 augments, 40 from Cohort 1, 36 from Cohort 2 Source: Study Report Recruits who answered in the following manner during screening were categorized as Asthma-only when enrolled: Yes when asthma was mentioned as a condition in this question: Have you ever experienced any of the following conditions? (You do not have to have been diagnosed by a doctor). 8 No when Indoor allergies or pet allergies (caused by dust, mold, dust mites, animals, dander, etc.) was mentioned as a condition in the above question. No when Seasonal allergies (caused by pollen, trees, grass, weeds, hay fever, etc also called outdoor allergies ) was mentioned as a condition in the above question. Recruits who answered in the following manner during screening were categorized as Asthma & Allergies when enrolled: Yes when asthma was mentioned as a condition, and Yes when either indoor or outdoor allergies (or both) was mentioned as a condition when asked if the condition were ever experienced. 8 Other conditions mentioned were glaucoma, heartburn, and diabetes. 144 of

145 Regarding off-label asthma use, the primary objectives included assessment of A. appropriate self-selection and B. comprehension of the following proposed DFL text related to asthma: Warnings Do not use to treat asthma. Asthma can be a life-threatening condition, and you should follow your doctor s directions. When using this product if you are currently taking asthma medicines, do not stop taking them For the self-selection objective, subjects were given a Singulair Allergy package and allowed to review the carton information at their own pace. Upon indicating that they had finished reviewing the carton information, subjects were asked, Is this product appropriate for you, personally, to use or not? (Question [Q] 1). The labeling was accessible during all interview questions. Subjects who responded Yes or indicated uncertainty were asked What, if anything, would you, personally, use this product to treat? (Q1_1). All subjects were asked Why do you say that? (Q2) and What led you to make that decision? (Q3). Following a literacy assessment, label comprehension was assessed by asking subjects questions consisting of scenarios to hypothetical situations. 9 Initial Correct self-selection assessed by the sponsor included both Yes, appropriate for me to take as well as No, not appropriate for me to take, depending on the subject. Assignment of the initial Correct or Incorrect self-selection code was based on the gestalt of the responses to all four questions (Q1, Q1_1, Q2, Q3). 10 Self-selection responses were then mitigated using predefined criteria (described a priori in the protocol) to allow apparently incorrect self-selection decisions to be considered correct self-selection decisions when taking into context the totality of subjects responses. Whether there was a medical risk associated with the responses was also a factor in 9 Scenario for Do not use to treat asthma : Karen has asthma. She would like to use this product to treat her asthma. According to the product label, is it okay for Karen to use this product to treat her asthma? Scenario for Do not stop using asthma medicine : David has allergies and asthma. He is currently taking prescription montelukast sodium to treat his allergies and asthma. He would like to use this product to treat his allergies along with prescription montelukast sodium to help treat his asthma. According to the product label, is it okay or not okay for David to use this product along with prescription montelukast sodium? 10 Sponsor s response to FDA s April 3, 2014 information request 145 of

146 final classification of Correct or Incorrect self-selection. Post-hoc mitigation was also performed for mitigating factors that were not predicted in advance of enrollment. Regarding off-label pediatric use, another primary objective of the SOLID study assessed comprehension of the following DFL statement: Directions children under 18 years of age / do not use Subjects were presented with the following scenario and question: Kim has a 12-year old daughter. Kim would like to give her daughter Singulair Allergy to treat her allergies. According to the product label, is it okay or not okay for Kim to give this product to her 12-year old daughter to treat her allergies? For all label comprehension objectives, subjects were asked the follow-up question Why do you say that? after providing a response to the question regarding the scenario. Responses to the question about the scenario and to the follow-up question were used to assess the degree of comprehension. 3.3 Consumer Study Results and Discussion Targeted LC Study Results In the Targeted LC Study, protocol-specified target thresholds for the primary objectives 11 were met (Table 3) for the general population. Comprehension in low literacy subjects was not a primary endpoint (no target threshold). Nevertheless, comprehension for both objectives in the low literacy subjects appears somewhat lower than in the general population (Table 4). 11 > 90% for the lower limit of the 2-sided 95% exact confidence interval. Sponsor s rationale for this threshold: Neuropsychiatric events have been observed in post-marketing reports in adult, adolescent, and pediatric patients taking Rx Singulair. These reports include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Singulair appear consistent with a drug-induced effect. (Sponsor s response to FDA s March 20, 2014 information request) 146 of

147 Table 3. Targeted LC Study: Percent of subjects with correct response (primary endpoints, general population allergy sufferers) Correct Objectives Stop use and ask a doctor -- if you experience unexpected changes in behavior, thoughts, or mood PE, ratio 97.5%, 352/361 LB 95.3% Stop use and ask a doctor -- if you experience unexpected changes or problems when you sleep 97.0%, 350/ % PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report Table 4. Targeted LC Study: Percent of subjects with correct response (low literacy allergy sufferers) Correct Objectives PE, ratio LB Stop use and ask a doctor -- if you experience unexpected changes in behavior, thoughts, or mood 90.1%, 136/ % Stop use and ask a doctor -- if you experience unexpected changes or problems when you sleep 86.8%, 131/ % PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report Adolescent Study Results Regarding self-selection in the Adolescent Study (Table 5), The initial Correct self-selection based on age was 57.7% (202/350). The post-mitigation Correct self-selection rate was 84.3% (295/350), with a lower bound (LB) of the 2-sided 95% confidence interval of 80.0%. Even with the mitigation, the protocol-specified target threshold of 90% 12 was not met. 12 Sponsor s rationale for this threshold: Rx Singulair 10 mg is indicated for patients down to 15 years of age and the OTC label will be for adults 18 years and up. In spite of the medical risk being low if an adolescent would use this product in an OTC setting, a >90% threshold was established to ensure that labeling directive was understood by adolescents, years of age. (Sponsor s response to FDA s March 20, 2014 information request) 147 of

148 Table 5. Adolescent Study: Percent of subjects with correct self-selection (primary endpoint) Correct PE, ratio LB Initial 57.7%, 202/ % Final (post-mitigation) 84.3%, 295/350 PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval; Source: Adapted from Study Report % Regarding label comprehension, the target thresholds for the primary objectives 13,14 were met (Table 6). 13 > 90% for the lower limit of the 2-sided 95% exact confidence interval (applies to all objectives in Table 4) Sponsor s rationale for threshold for interpretation of unexpected changes: Rx Singulair 10 mg is indicated for patients down to 15 years of age and the OTC label will be for adults 18 years and up. Neuropsychiatric events have been observed in post-marketing reports in adult, adolescent, and pediatric patients taking Rx Singulair. These post-marketing reports include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Singulair appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events and be instructed to notify their prescriber if these changes occur. 3 Although adolescents ages are not indicated on the OTC label, this will ensure that there was comprehension among this audience of the potential for these AEs in the event the product is used off-label among teens years of age. (Sponsor s response to FDA s March 20, 2014 information request) 14 Sponsor s rationale for threshold for action if feeling different: Rx Singulair 10 mg is indicated for patients down to 15 years of age and the OTC label will be for adults 18 years and up. A safe intended action is defined as a response in which the adolescent subject would communicate a potential drug-related effect to a parent or family member, doctor or pharmacist or would stop use of the drug. >90% threshold was established to ensure that labeling directive was understood by adolescents, years of age. (Sponsor s response to FDA s March 20, 2014 information request) 148 of

149 Table 6. Adolescent Study: Percent of subjects with correct response (primary comprehension objectives, allergy sufferers) Correct Objectives Safe intended action indicated in response to: If you were taking this medicine and started feeling different than you usually do, what, if anything, would you do? PE, ratio 96.6%, 338/350 LB 94.1% Correct interpretation of: unexpected changes in behavior, thoughts, or mood 95.1%, 333/ % unexpected changes or problems when you sleep 95.7%, 335/350 PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report % SOLID Study Results See Appendix 1 (Tables 18, 19, and 20) for additional analyses performed by the Agency. Note that the Agency s analyses were based on the sponsor s determination of both the correctness of the subject s self-selection decision and the subject s comprehension of the various label comprehension objectives. Data presented in section are from the SOLID Study report Self-selection As assessed by the Sponsor, protocol-specified target thresholds for the primary objectives 15 were met for one of the two general-population cohorts (Table 7): 15 > 90% for the lower limit of the 2-sided 95% exact confidence interval Sponsor s rationale for this threshold: Subjects with asthma should not select to use Singulair Allergy for their asthma. A threshold of > 90% was assigned because asthma is a life-threatening condition and patients should be under a doctor s care. (Sponsor s response to FDA s March 20, 2014 information request) 149 of

150 Table 7. SOLID Study: Percent of subjects with correct self-selection (general population asthma sufferers) Correct Self-selection PE, ratio LB Final (post-mitigation) Cohort 1 (ever used Singulair) 91.7%, 352/ % Cohort 2 (never used Singulair) Cohort 3 (100% low literates) Initial (pre-mitigation)* Cohort 1 Cohort %, 336/ %, 148/ %, 306/ %, 302/ % 85.3% 75.3% 82.5% Cohort %, 124/ % *Classification of self-selection decision as initially correct or incorrect was based on review of the responses to the self-selection question and to the follow-up questions (Q1, Q1_1, Q2, Q3): Q1: (Asked of all subjects): Is this product appropriate for you, personally, to use of not? Q1_1 (Only asked if potential positive response at Q1 or uncertainty): What, if anything, would you, personally, use this product to treat? Q2 (Asked of all subjects): Why do you say that? Q3 (Asked of all subjects): What led you to make that decision? PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report The sponsor reports that by combining and weighting Cohorts 1 and 2 equally an approach not specified in the protocol - the target threshold would be met (Table 12, PE 93.9% correct (688/733), LB 91.9%). The sponsor considers this approach conservative based on the projection that the representative population of potential users of Singulair Allergy in the OTC setting would include only a small proportion of current or previous Rx Singulair users and is more likely to skew toward current Singulair non-users (as in Cohort 2). However, because this combined analysis was a post-hoc analysis that was not pre-specified, it is difficult to determine if the combined analysis met the performance threshold because the type I error is not controlled. Self-selection in low literacy subjects was not a primary endpoint. Final, post-mitigation correct self-selection in low literacy asthma sufferers, as assessed by the Sponsor, was similar to that for the general population (Table 7). 150 of

151 Label Comprehension One of two primary comprehension objectives regarding asthma, Do not use to treat asthma, did not meet the protocol-specified target threshold 16, 17 for either general population cohort (1 or 2) (Table 8). The other concept regarding asthma medicine met the protocol-specified target threshold 18 for both general population cohorts (1 and 2). With respect to healthcare behaviors, 48% (394/820) of the total sample reported that they saw their doctor at most once a year for their asthma. Label comprehension in low literacy subjects was not a primary endpoint. Nevertheless, the low literate subjects (Cohort 3) demonstrated even poorer comprehension of do not use to treat asthma than the general population (Table 8) raising significant concern regarding potential off-label use of Singulair Allergy in the low literate population. Notably, the outer carton used in the consumer testing program included a banner similar to the following on the back side of the carton, at the top, just above the DFL (Figure 2). Figure 2. SOLID Study: Warning on back of tested outer carton not for asthma treatment THIS PRODUCT IS ONLY FOR ALLERGIES. DO NOT USE TO TREAT ASTHMA. (bolded, all capital letters, highlighted in yellow, and partially underlined). Source: Study Report > 90% for the lower limit of the 2-sided 95% exact confidence interval (applies to all concepts in Table 7) 17 Sponsor s rationale for threshold for Do not use to treat asthma : Rx Singulair is a leukotriene receptor antagonist indicated for prophylaxis and chronic treatment of asthma in patients 12 months of age and older. Rx Singulair is also used as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom as-needed short acting β- agonists provide inadequate clinical control of asthma. Singulair should not be substituted abruptly for inhaled or oral corticosteroids. Asthma is a serious medical condition and should be managed by a healthcare professional. (Sponsor s response to FDA s March 20, 2014 information request) 18 Sponsor s rationale for threshold for Do not stop taking asthma medicine : Rx Singulair is a leukotriene receptor antagonist indicated for prophylaxis and chronic treatment of asthma in patients 12 months of age and older. Singulair should not be substituted abruptly for inhaled or oral corticosteroids. Sudden stoppage of short acting β-agonists or inhaled corticosteroids could escalate to asthma flare up. Rx Singulair is also indicated as add-on therapy in patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom as-needed short acting β-agonists provide inadequate clinical control of asthma. Singulair should not be substituted abruptly for inhaled or oral corticosteroids. Asthma is a serious medical condition and should be managed by a healthcare professional. (Sponsor s response to FDA s March 20, 2014 information request) 151 of

152 Table 8. SOLID Study: Percent of subjects with correct response (comprehension objectives related to asthma) Correct Concept Tested Do not use to treat asthma Cohort 1 PE, ratio 91.7%, 352/384 LB 88.4% Cohort %, 322/ % Cohort %, 129/ % Do not stop taking asthma medicine Cohort 1 94%, 361/ % Cohort %, 335/ % Cohort %, 143/ % PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report The primary comprehension objective regarding age-appropriate use met the protocolspecified target threshold (Table 9). 19 In low literacy subjects (not a primary endpoint), comprehension of the target population age appears similar, though slightly lower (Table 9). 19 Sponsor s rationale for threshold for Children under 18 years of age / do not use : Rx Singulair also has pediatric indications and is used for prophylaxis and chronic treatment of asthma in patients 12 months of age and older. Singulair 10 mg tablet is approved for Rx use in patients 15 years or older. For this age range the medical consequences were considered to be of lower risk. However, for patients below 15 years of age, lower different doses are indicated. Thus the medical consequences were considered to be of higher risk. (Sponsor s response to FDA s March 20, 2014 information request) 152 of

153 Table 9. SOLID Study: Percent of subjects with correct response (comprehension objective related to potential off-label pediatric use) Correct Concept Tested PE, ratio LB Children under 18 years of age / do not use Cohort %, 368/ % Cohort 2 Cohort %, 338/ %, 149/ % 86.0% PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report Discussion This section is organized by topic area rather than by study. First, we discuss the adequacy of proposed DFL text regarding neuropsychiatric events in the DFL based on the results of two studies (Targeted LC and the Adolescent Studies). Second, we discuss the potential for off-label pediatric use based on the results of two studies (Adolescent and SOLID Studies). Third, we discuss the potential for off-label use for asthma based on the results of the SOLID Study Adequacy of Neuropsychiatric Labeling Together, the Targeted LC Study and the Adolescent Study appear to show that consumers 15 years and older (general population [GP] and low literates) generally understand: a) the proposed labeling concepts regarding potential neuropsychiatric effects and b) what action to take if such effects are experienced -- when directed to read the label. For the Targeted LC Study, the study report indicates that subjects coded as Complete comprehension either (i) correctly responded to the initial scenario and the follow-up question, or (ii) provided an incorrect response initially but provided a correct response to the follow-up question. Subjects coded as Partial comprehension by the sponsor may not have responded correctly initially but demonstrated a credible level of understanding of the possible risk associated with the scenario at the follow-up question; subjects who responded correctly initially but provided a general response at the follow-up were also coded as having Partial comprehension. 153 of

154 It appears that respondents were ultimately assessed as having correctly comprehended the warnings if they stated either stop use or ask a doctor were coded as having Partial comprehension. Our understanding is that they did not have to cite both stop use and ask a doctor to be ultimately assessed as having demonstrated comprehension. It appears that over 25% of the subjects were assessed as partially comprehending the neuropsychiatric event warnings tested (Table 10). Table 10. Targeted LC Study: Percent of subjects with correct response (primary objectives, general population allergy sufferers) Q# Objectives Q2 Stop use and ask a doctor if if you experience unexpected changes in behavior, thoughts, or mood Correct PE, ratio LB Demonstrated Comprehension Complete comprehension Partial Comprehension 97.5%, 352/ %, 249/ %, 103/ % Q4 Stop use and ask a doctor if you experience unexpected changes or problems when you sleep Demonstrated Comprehension Complete comprehension Partial Comprehension 97.0%, 350/ %, 249/ %, 101/ % Q#: Question number; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report Note that the Targeted LC Study assessed the ability of respondents to comprehend the neuropsychiatric warnings when directed to read the DFL. It did not assess if the typical allergy sufferer would read the DFL when considering whether to use this medication. Whether or not subjects had a doctor diagnosis of depression did not appear to affect comprehension scores in the Targeted LC Study. Other potential subgroups that might have been recruited were individuals with depression that had not necessarily been formally diagnosed by a healthcare professional. Finally, the precise wording of the Targeted LC Study questions may have helped to cue the correct answers as the hypothetical scenarios presented dramatically different before and after scenarios that were also specifically connected in the question to the time period in which the medicine had been taken: 154 of

155 Q2: Kara is usually a calm and relaxed person. She has allergies and has been using Singulair Allergy for the past several days. She has suddenly started feeling extremely agitated and nervous. According to the label, what should Kara do? Q4: Gary has allergies and has been using Singulair Allergy for a week. He used to sleep very well, but in the last week he has started waking up in the middle of the night with unusual nightmares. According to the label, what if anything should Gary do? It is possible that behavioral changes resulting from use of this product may be more subtle than those described above (e.g., if a consumer is usually not calm and relaxed before he/she decides to take the medicine). Moreover, it is also possible that consumers may not ascribe any behavioral changes that they do detect to the medicine specifically. The adequacy of proposed DFL text regarding (a) potential neuropsychiatric events and (b) appropriate action to take if such effects are experienced is an important issue we ask the committee to consider Potential for Off-label Pediatric Use While adults generally appeared to comprehend that it would not be appropriate to give Singulair Allergy to a 12 year old (SOLID Study, Table 9), many year olds did not correctly self-select not to use Singulair Allergy labeled for adult use (Adolescent Study, Table 5). In the Adolescent Study, the follow-up question that was asked for mitigation purposes may be unrealistic in an OTC setting: adolescents 15 to 17 years of age seriously considering use of Singulair Allergy would likely not be prompted to ask an adult in many, if not most, OTC settings. Thus, mitigation using the subjects answers to this question may have biased the results in favor of a higher correct self-selection rate. The mitigations of the initial self-selection score were based not on information volunteered by the adolescent subjects, but rather by subjects response to the direct question Would you be more likely to take this product on your own or ask someone first? (Adolescents who thus stated that they would ask someone first were then mitigated to be correct). This question was somewhat artificial in that it compelled the subjects to think about something (whether to ask a parent) that they ordinarily might not have thought about when selecting to use an allergy medicine. It is not clear that subjects who said they would ask a parent (particularly since their parent was sitting in the next room) actually would ask their parent or guardian in real life. Moreover, given the other labeling constraints such as not using for asthma, it would have been useful to assess (for those who said they would ask their parents) those parents assessment of whether the product was appropriate for their children to take. The sponsor asserts that it is highly unlikely that adolescents will purchase this product independently. While that may be true, the product may be purchased by adults and found 155 of

156 in home medicine cabinets. Also, as with the SOLID Study, the Adolescent Study did not appear to assess what subjects would say they would do with respect to current Rx asthma medications, where relevant. It is possible that subjects with asthma and subjects who have used prescription Singulair for asthma might mistakenly choose to use Singulair Allergy for asthma. When considering age as the primary criteria for correct self-selection, these and other subgroups analyzed had similar point estimates to the general population of adolescents (Table 11). Table 11. Adolescent Study: Percent of subjects with correct response (subgroups among allergy sufferers) Correct Self-selection PE, ratio LB Initial 57.7%, 202/350 Final (post-mitigation) Subjects with depression Subjects with asthma Subjects with low literacy Subjects who have used Rx Singulair for asthma Subjects who have used Rx Singulair for allergies 84.3%, 295/ % (n=15) 81.7% (n=89) 75.6% (n=68) 79.4% (n=27) 84.9% (n=45) 80.0% PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report Pediatric issues for the committee s consideration include (a) the likelihood of Singulair Allergy, labeled for adults only, to be used off-label in children and (b) whether adolescents could correctly self-select when considerations beyond age are taken into account Potential for Off-label Asthma Use While the target threshold for self-selection was met for one of the two general population cohorts (Table 7), both general population cohorts failed to meet the target threshold for the comprehension objective Do not use to treat asthma (Table 8). The low literate cohort was particularly deficient in comprehending the concept that Singulair Allergy is not for treatment of asthma (Table 8), despite the prominent warning on the back of the outer carton that the product is not for treatment of asthma (Figure 2). Although the target thresholds were met for comprehension of Do not stop taking asthma medicine, we question whether a sole label comprehension question can serve as the foundation for assuming that this behavior would not occur. Typically in a consumer drug development program, the key issues of clinical significance are tested first in label comprehension; after the label is optimized to maximize the probability of appropriate 156 of

157 behavior, there is additional testing with consumers. Label comprehension is considered to be a necessary, but not sufficient, step toward assessment of consumers actual behavior. An important issue for the committee s consideration is the appropriateness of OTC marketing of a drug currently with prescription indications for both asthma and allergies even if the asthma indication remains prescription only -- when one indication (asthma) requires physician care as it could be life-threatening, and the other indication (allergy) is highly prevalent among asthma patients. For the asthma patients with concomitant allergies who are already being prescribed montelukast sodium, Singulair may have been characterized by their physician as one medication in the asthma armamentarium, albeit for the allergy trigger. Many (~35-45%) asthma sufferers who reported having no indoor or outdoor allergies were considered appropriate to self-select OTC Singulair Allergy because they referenced experiencing allergy-like symptoms (see section below). The appropriateness of such individuals taking OTC Singulair Allergy is another important consideration for the committee s consideration. Concomitant Asthma and Allergy Of the 733 subjects in Cohorts 1 and 2 combined (Table 12), we note that: o 564 subjects responded Yes to whether the product is appropriate to use personally. o Of these 564 subjects, 475 were considered Correct for self-selection initially, and 532 were considered Correct for self-selection after a priori mitigation and post-hoc mitigation. o Thus, a minimum of 73% (532/733) of general population asthma sufferers enrolled in the SOLID study were deemed appropriate for self-selecting to use Singulair Allergy. Of the low literate asthma sufferers (Cohort 3), a minimum of 66% (108/163) of subjects were deemed appropriate for self-selecting to use Singulair Allergy (Table 13). Importantly, considering that all subjects enrolled in the SOLID study were asthma sufferers, these results could be interpreted to suggest that Singulair Allergy is appropriate OTC therapy for, at minimum, >70% of general population asthma sufferers who wish to treat concomitant allergy or allergy-like symptoms Asthma subjects without self-reported indoor or outdoor allergies were considered Correct in selfselecting to use Singulair Allergy if they experienced the symptom(s) listed on the Singulair Allergy label 157 of

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160 o Third, subjects were not asked whether they might continue their current asthma medication(s) while using Singulair Allergy. o Finally, of the 820 subjects (all 3 cohorts) enrolled in the SOLID study, 394 (48%) reported that they saw their doctor for asthma once per year or less. Whether availability of OTC Singulair Allergy would reduce interactions between patients and their healthcare providers for asthma care is not known. The adequacy of available data to support the appropriate use of Singulair Allergy in the OTC setting is an important issue we ask the committee to consider. 3.4 Additional Commentary on the SOLID Study In this section, we provide additional discussion on study methodology, the mitigation method, as well as secondary and additional objectives Study Methodology As described in section above, the SOLID Study does not appear to adequately address the question of whether asthma sufferers would use OTC Singulair Allergy to treat their asthma. In section below, we elaborate on subjects believing Singulair Allergy was appropriate for treating their allergy-like symptoms even though they selfreported having no allergies per se. Here, we elaborate on several additional points regarding the issue of treating asthma with Singulair Allergy (including some issues briefly mentioned in section ) and discuss methodological issues regarding the SOLID Study. 160 of 207 A. Singulair Allergy suggested as appropriate for vast majority of asthma sufferers: The methods (see D. below) and results (Table 12, Table 13 and associated discussion) could be interpreted to suggest that the vast majority of asthma sufferers also suffer from allergies (even if they do not initially self-report that they do, section below) and therefore it would be correct for almost all asthma sufferers to choose to use Singulair Allergy. B. Perceived linkages between allergies and asthma not queried: We reiterate that subjects were not probed about perceived linkages between allergies, or allergylike symptoms, and asthma. Subjects were also not asked whether they might ultimately treat their asthma by treating allergies or allergy-like symptoms that might or might not trigger the asthma. Rather, the study focused on asthmatics self-selection of Singulair as a standalone decision to deal with allergies or allergy symptoms (e.g., runny nose, congestion). As already mentioned, in some of these instances, subjects reported that they had no allergies per se. Thus, the SOLID study did not explore how these subjects linked if at all allergies or allergy 27

161 symptoms with their asthma, and whether they thought they might ultimately treat their asthma by treating the allergies or allergy symptoms that might or might not trigger the asthma. C. Decision regarding continuation of asthma medication not explored: Additionally, the SOLID study did not try to assess what subjects who self-selected to use the product would then think about or do with regard to continuing their asthma medication. Although this would have been most definitively assessed in an actual use study, it could have also been somewhat addressed in a self-selection study that had posed these additional questions. In a March 2009 correspondence, the Agency expressed that an actual use study is not needed if the sponsor were to conduct a well-designed self-selection study. D. Subgroup sizes ( Asthma-only vs. Asthma & Allergies ) different: In 2009, the Agency advised that each of two cohorts (differing in terms of previous Singulair use) would need to have an adequate number of asthmatics with allergies and asthmatics without allergies (section 2). As seen in Figure 1, the study that was fielded had 592 asthmatics with self-reported allergies ( Asthma & Allergies, ) and 141 asthmatics with no self-reported allergies ( Asthma-only, 70+71). The Sponsor explains the differences in cohort size as follows: The sample size for the asthma only and asthma with allergy subgroups were markedly different, because the incidence from multiple published studies report that about 80-90% of asthma sufferers experience co-morbid allergies. If we had enrolled similar numbers of asthma subjects with and without allergies, the combined results for each of the two main cohorts would not be representative of the population with asthma due to a disproportionate percentage of asthma-only sufferers. 24 E. Assertion that subject s knowledge allows for avoidance of asthma not validated: The Sponsor s assertion that asthma sufferers knowledge of their triggers allows them to avoid their condition is not validated by any question posed to subjects in this regard. F. Reason for Singulair prescription not explored: Although the SOLID study did ask whether subjects had used Singulair within the past year, it did not ask whether they had been prescribed Singulair for allergies or asthma. This information would have been useful when evaluating each subject s self-selection choice. G. Current concomitant medications not queried: Although the SOLID study did ask whether subjects had used Singulair (or other products) within the past year, it did not ask whether subjects were currently on Singulair or the other cited medications. This information would have been useful when evaluating each subject s self-selection choice. 24 Sponsor s response to FDA s March 24, 2014 information request 161 of

162 H. Low literates possibly not well represented: In 2009, the Agency advised that the low literacy population should be well represented (section 2 above). Although there was an augmented low literacy cohort (100% low literacy subjects), the low literacy population was not well represented in the general population cohorts which were the cohorts for the primary endpoints - the low literacy representation in these cohorts was only ~10%. Typically the Agency considers well designed studies to have a low literacy representation comparable to that in the general population. Based on a 2003 literacy survey, it appears that the percent of adults that are below basic in literacy level (the actual percent depending on the type of literacy tested) may be > 10%. 25 The self-selection and label comprehension point estimates for Cohort 3 (100% low literacy subjects) were in some instances lower than for the general population cohorts. I. Combined cohort possibly not representative of asthmatics: The Sponsor has proposed a post-hoc weighting alternative (combining the self-selection scores of both cohorts) that leads to self-selection scores that meet the pre-specified threshold (section ). The Sponsor asserts that if this product were to be approved for OTC marketing, former Rx Singulair users would comprise a small portion of the target market. While that may be the case, under this assumption, the overall sample should be representative of asthmatics with respect to demographics (see H above). J. Objective priority advice not heeded: In 2009, the Agency advised that Do not use along with prescription montelukast sodium should be a primary communications objective. In the SOLID Study, this objective was assessed as a secondary objective (see section below), without a target threshold Mitigation Table 12 and Table 13 demonstrate that the sponsor-assessed Correct self-selection includes many subjects who responded yes to Q1 ( Is this product appropriate for you, personally, to use or not? ). Table 12 illustrates that for the general population asthma sufferers, 475/564 yes answers were considered Correct during initial data analysis; by final analysis, 532/564 yes answers were considered Correct. For subjects who responded yes to Q1, a priori mitigations accounted for most of the allowed reclassification from Incorrect self-selection to Correct self-selection. In general, the Agency acknowledges that mitigations may be appropriate at times, as long as they are transparent in the data so that the Agency may conduct an independent analysis. Typically, study protocols contain a priori study mitigations, and sometimes post-hoc (not pre-specified in protocol) mitigations are also applied. It is also possible that mitigations may reverse a Correct assessment to an Incorrect assessment, though that occurs far less often than reversing an Incorrect assessment to a Correct assessment demographics.asp 162 of

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166 Sponsor s a priori mitigation category what was listed on the product label Cohort 1 Subgroup 1 (N=30) Cohort 1 Subgroup 2 (N=xx) # of subjects mitigated Cohort 2 Subgroup 3 (N=25) Cohort 2 Subgroup 4 (N=xx) Sponsor s rationale Sponsor s example Total* (N=84) would be interested in conditions purchasing. This would result in a (headaches). lost opportunity for the sponsor, but not a medical risk. Subject refers to When someone suffers from both Yes I can N/A 0 N/A 0 0 using product for both allergies and asthma, if their use this (0%) allergies and asthma allergies are under control, then because my their asthma would be under asthma is control. Doctors tell their patients triggered by to take Singulair to relieve their my allergies, which in turn would allergies. keep their asthma in check. *among all subjects enrolled in the SOLID study; includes low literate augments from Cohort 3; **Originally classified as Asthma-only categories, but response included within these as best fit by sponsor (Sponsor s response to FDA s April 3, 2014 information request) ^26 from Cohort 1, Subgroup from Cohort 2, Subgroup from low literate augment, Asthma-only, never Singulair + 8 Reconciled = 63. The sponsor explains that Reconciliation refers to Asthma & Allergies sufferers. According to the sponsor, When reviewing responses to all self-selection questions in the totality for these subjects, conservative coding of the gestalt led to the assessment of an initial incorrect selfselection code. However, the gestalt of the response posed no medical risk and an a priori mitigation category that was intended for asthma-only was determined to be applicable to them, even though they suffered from both asthma and allergies. (Sponsor s response to FDA s April 3, 2014 information request) Source: Study Report and sponsor s responses to FDA s information requests 166 of

167 Even after the Sponsor utilized all of the a priori mitigations and post-hoc mitigations such that yes this product is appropriate for me responses were changed to Correct when they had previously been Incorrect, Cohort 1 (ever used Singulair) still did not meet the a priori self-selection target threshold whereas Cohort 2 (never used Singulair) did (Table 16). Table 16. SOLID Study: Percent of subjects with correct self-selection (general population asthma sufferers) Cohort 1, N=384 Ever used Singulair Cohort 2, N=349 Never used Singulair Self-selection assessment PE, ratio LB PE, ratio LB Initial correct 79.7%, 306 / % 86.5%, 302 / % A priori mitigated correct 10.7%, 41 / %, 34 / 349 Post-hoc mitigated correct 1.3%, 5 / %, 0 / 349 Final correct 91.7%, 352 / % 96.3%, 336 / % PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report and sponsor s response to FDA s information request For low literacy subjects (Table 13), a similar, albeit slightly lower, percent of subjects were assessed by the sponsor as having a Correct self-selection response after mitigations (90.8%) when compared to asthma sufferers in the general population (Cohorts 1 and 2 combined, 93.9%). Of the 121 who initially answered yes to the selfselection question, only 90 subjects (74%) were initially assessed as a Correct selfselection. Primarily through a priori mitigations, the final Correct self-selection was raised to 89% (108/121) for low literates who initially answered yes to whether Singulair Allergy was appropriate for personal use. The SOLID Study appears to imply that Singulair Allergy is appropriate for not only most Asthma & Allergies sufferers, but also many Asthma-only sufferers (~35-45%) since asthma sufferers may have allergic symptoms even if they do not believe they have allergies (such is the case for ~35% of the Asthma-only subjects in Cohorts 1 (26/70) and 2 (23/71) (Figure 1 and Table 15). This implication is markedly different than the sponsor s assertion in 2007 that the product was intended for use in consumers with allergies only, and not asthma Secondary and Additional Objectives The label comprehension scores for the secondary objectives are shown below in Table 17. Note that Do not use along with prescription montelukast sodium achieved lower bounds of 84.6% and 82.2% for Cohorts 1 and 2, respectively. As stated in the regulatory background, the Agency advised the Sponsor that this assessment should be a primary, rather than a secondary, objective. If it had been a primary objective, the target threshold would not have been met if the threshold were 90%. 167 of

168 Table 17. SOLID Study: Percent of subjects with correct response (label comprehension, secondary objectives) Concept Tested Cohort Do not use along with prescription montelukast sodium Cohort 1 Correct response PE, ratio LB 88.3%, 339/ % Cohort 2 Okay to use Singulair Allergy to treat allergies along with asthma medicine Cohort 1 Cohort 2 Ask a doctor or pharmacist if not sure other medicine has montelukast sodium Cohort 1 Cohort %, 302/ %, 339/ %, 301/ %, 362/ %, 325/ % 84.6% 82.2% 91.5% 89.9% PE: point estimate; LB: lower confidence bound for a 2-sided exact 95% confidence interval Source: Study Report The Sponsor provides data supporting that nearly all subjects were aware of what to do in an emergent asthma event: (Multiple responses allowed) Use inhaler: 59.5% See/contact doctor or go to ER/hospital: 35.2% Use nebulizer or breathing treatment: 11.7% and that subjects knew what tends to trigger their asthma: 168 of 207 (Multiple responses allowed) Outdoor allergens: 58.8% Indoor allergens: 41.8% Exercise/exertion: 31.8% Animals/pet/dander: 21.3% Smoke: 14.9% Illness (flu/cold/sinus infection): 17.7% Perfumes/fragrances: 8.3% Stress: 7.9% Weather: 7.4% 35

169 The Sponsor asserts that this knowledge of triggers allows subjects to either avoid or manage their triggers, and therefore they know how to manage their condition and have a continued healthcare relationship with their healthcare professional. 3.5 Conclusion From the SOLID Study, the sponsor concludes that consumers with asthma can correctly self-select to use this product and understand the intended uses for Singulair as well as the key safety and risk messages on the product label. The sponsor asserts that subjects understand their asthma condition and triggers, and are under a physician s care for their asthma on a regular basis. Due to the limitations of the SOLID study and the various methodological issues discussed above, we do not completely align with the sponsor s conclusions regarding the SOLID study. 169 of

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171 Q9: Do not stop using asthma medicine Normal literacy Low literacy Q11: Do not use if under 18 years of age Normal literacy Low literacy Secondary objectives Q6: Okay to use Singulair Allergy to treat allergies along with asthma medicine Normal literacy Low literacy Q8: Do not use along with prescription montelukast sodium Normal literacy Low literacy Q10: Ask a doctor or pharmacist if not sure other medicine has montelukast Cohort 1: General population, ever Singulair user Subgroup 1: Subgroup 2: Asthma-only Asthma & Cohort 2: General population, never Singulair user Subgroup 3: Asthma-only Subgroup 4: Asthma & Allergies Allergies % (n/n) LB* % (n/n) LB* % (n/n) LB* % (n/n) LB* (9/13) (24/27) (9/15) (17/21) 96.5 (55/57) 84.6 (11/13) 98.2 (56/57) 84.6 (11/13) 86.0 (49/57) 84.6 (11/13) 91.2 (52/57) 61.5 (8/13) (272/287) (23/27) (276/287) (25/27) (259/287) (20/27) (259/287) (20/27) Normal literacy (53/57) (274/287) Low literacy (11/13) (24/27) * lower confidence bound for a 2-sided exact 95% confidence interval Source: FDA Statistics (55/56) (14/15) (54/56) (13/15) (43/56) (6/15) (49/56) (7/15) (52/56) (11/15) (246/257) (20/21) (252/257) (19/21) (236/257) (16/21) (232/257) (14/21) (242/257) (20/21) of

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173 Note: Table 20 includes subjects from all three cohorts who answered yes to Is this product appropriate for you, personally, to use or not? separated by cohorts. Cohort 3 is further grouped based on Singulair use. This table presents scores for primary and secondary objectives as well as informational endpoints for the label comprehension component of the SOLID Study. Table 20. SOLID Study: Comprehension rates for subjects who stated Singulair Allergy was appropriate to personally use^ General Population Low Literate Population Cohort 1: ever Singulair Cohort 2: never Singulair Cohort 3: ever Singulair user user user user Primary objectives Q4: Do not use to treat asthma Q9: Do not stop using asthma medicine Q11: Do not use if under 18 years of age Secondary objectives Q6: Okay to use Singulair Allergy to treat allergies along with asthma medicine Q8: Do not use along with prescription montelukast sodium Q10: Ask a doctor or pharmacist if not sure other medicine has montelukast Other Endpoints Q5A: Continue to see doctor for asthma as usual Q7A: What should be done in case of an % (n/n) LB* (%) 91.5 (280/306) 94.1 (288/306) 95.8 (293/306) 87.9 (269/306) 86.0 (263/306) 94.1 (288/306) 94.1 (288/306) 97.4 (298/306) % (n/n) LB* (%) (239/258) (247/258) (253/258) (231/258) (230/258) (239/258) (243/258) (250/258) (49/62) (50/62) (55/62) (45/62) (40/62) (54/62) (52/62) (58/62) % (n/n) LB* (%) Cohort 3: never Singulair (47/59) (54/59) (55/59) (44/59) (46/59) (53/59) (56/59) (59/59) % (n/n) LB* (%) asthma attack ^Subjects included in this table all responded yes to Is this product appropriate for you, personally, to use or not? (Q1) * lower confidence bound for a 2-sided exact 95% confidence interval Source: FDA Statistics of

174 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SINGULAIR safely and effectively. See full prescribing information for SINGULAIR. SINGULAIR (montelukast sodium) Tablets, Chewable Tablets, and Oral Granules Initial U.S. Approval: RECENT MAJOR CHANGES Warnings and Precautions Neuropsychiatric Events (5.4) 03/2013 Eosinophilic Conditions (5.5) 06/ INDICATIONS AND USAGE SINGULAIR is a leukotriene receptor antagonist indicated for: Prophylaxis and chronic treatment of asthma in patients 12 months of age and older (1.1). Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older (1.2). Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 6 months of age and older (1.3) DOSAGE AND ADMINISTRATION Administration (by indications): Asthma (2.1): Once daily in the evening for patients 12 months and older. Acute prevention of EIB (2.2): One tablet at least 2 hours before exercise for patients 6 years of age and older. Seasonal allergic rhinitis (2.3): Once daily for patients 2 years and older. Perennial allergic rhinitis (2.3): Once daily for patients 6 months and older. Dosage (by age) (2): 15 years and older: one 10-mg tablet. 6 to 14 years: one 5-mg chewable tablet. 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules. 6 to 23 months: one packet of 4-mg oral granules. Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). For oral granules: Must administer within 15 minutes after opening the packet (with or without mixing with food) (2.5) DOSAGE FORMS AND STRENGTHS SINGULAIR 10-mg Film-Coated Tablets SINGULAIR 5-mg and 4-mg Chewable Tablets SINGULAIR 4-mg Oral Granules (3) CONTRAINDICATIONS Hypersensitivity to any component of this product (4) WARNINGS AND PRECAUTIONS Do not prescribe SINGULAIR to treat an acute asthma attack (5.1). Advise patients to have appropriate rescue medication available (5.1). Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute SINGULAIR for inhaled or oral corticosteroids (5.2). Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR (5.3). Neuropsychiatric events have been reported with SINGULAIR. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur (5.4 and 6.2). Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events have been sometimes associated with the reduction of oral corticosteroid therapy (5.5 and 6.2). Inform patients with phenylketonuria that the 4-mg and 5-mg chewable tablets contain phenylalanine (5.6) ADVERSE REACTIONS Most common adverse reactions (incidence 5% and greater than placebo listed in descending order of frequency): upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at or FDA at FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Asthma 1.2 Exercise-Induced Bronchoconstriction (EIB) 1.3 Allergic Rhinitis 2 DOSAGE AND ADMINISTRATION 2.1 Asthma 2.2 Exercise-Induced Bronchoconstriction (EIB) 2.3 Allergic Rhinitis 2.4 Asthma and Allergic Rhinitis 2.5 Instructions for Administration of Oral Granules 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Acute Asthma 5.2 Concomitant Corticosteroid Use 5.3 Aspirin Sensitivity 5.4 Neuropsychiatric Events 5.5 Eosinophilic Conditions 5.6 Pheny ketonuria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Insufficiency 8.7 Renal Insufficiency 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Asthma 14.2 Exercise-Induced Bronchoconstriction (EIB) 14.3 Allergic Rhinitis (Seasonal and Perennial) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 174 of 207 Reference ID:

175 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Asthma SINGULAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older. 1.2 Exercise-Induced Bronchoconstriction (EIB) SINGULAIR is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older. 1.3 Allergic Rhinitis SINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 Asthma SINGULAIR should be taken once daily in the evening. The following doses are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet. For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules. For pediatric patients 12 to 23 months of age: one packet of 4-mg oral granules. Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion. 2.2 Exercise-Induced Bronchoconstriction (EIB) For prevention of EIB, a single dose of SINGULAIR should be taken at least 2 hours before exercise. The following doses are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet. For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet. An additional dose of SINGULAIR should not be taken within 24 hours of a previous dose. Patients already taking SINGULAIR daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and efficacy in patients younger than 6 years of age have not been established. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 2.3 Allergic Rhinitis For allergic rhinitis, SINGULAIR should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs. The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet. For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules. Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established. The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet. For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet. 175 of 207 Reference ID:

176 For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules. For pediatric patients 6 to 23 months of age: one packet of 4-mg oral granules. Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established. 2.4 Asthma and Allergic Rhinitis Patients with both asthma and allergic rhinitis should take only one SINGULAIR dose daily in the evening. 2.5 Instructions for Administration of Oral Granules SINGULAIR 4-mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 ml) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, SINGULAIR oral granules must not be stored for future use. Discard any unused portion. SINGULAIR oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. SINGULAIR oral granules can be administered without regard to the time of meals. 3 DOSAGE FORMS AND STRENGTHS SINGULAIR 10-mg Film-Coated Tablets are beige, rounded square-shaped tablets, with code MRK 117 or MSD 117 on one side and SINGULAIR on the other. SINGULAIR 5-mg Chewable Tablets are pink, round, bi-convex-shaped tablets, with code MRK 275 or MSD 275 on one side and SINGULAIR on the other. SINGULAIR 4-mg Chewable Tablets are pink, oval, bi-convex-shaped tablets, with code MRK 711 or MSD 711 on one side and SINGULAIR on the other. SINGULAIR 4-mg Oral Granules are white granules with 500 mg net weight, packed in a childresistant foil packet. 4 CONTRAINDICATIONS Hypersensitivity to any component of this product. 5 WARNINGS AND PRECAUTIONS 5.1 Acute Asthma SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with SINGULAIR can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist. 5.2 Concomitant Corticosteroid Use W hile the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids. 5.3 Aspirin Sensitivity Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal antiinflammatory agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)]. 5.4 Neuropsychiatric Events Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking 176 of 207 Reference ID:

177 and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur [see Adverse Reactions (6.2)]. 5.5 Eosinophilic Conditions Patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between SINGULAIR and these underlying conditions has not been established [see Adverse Reactions (6.2)]. 5.6 Phenylketonuria Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame), and mg per 4-mg and 5-mg chewable tablet, respectively. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment. The most common adverse reactions (incidence 5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis. Adults and Adolescents 15 Years of Age and Older with Asthma SINGULAIR has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo: 177 of 207 Reference ID:

178 Table 1: Adverse Experiences Occurring in 1% of Patients with an Incidence Greater than that in Patients Treated with Placebo SINGULAIR 10 mg/day (%) (n=1955) Placebo (%) (n=1180) Body As A Whole Pain, abdominal Asthenia/fatigue Fever Trauma Digestive System Disorders Dyspepsia Pain, dental Gastroenteritis, infectious Nervous System/Psychiatric Headache Dizziness Respiratory System Disorders Influenza Cough Congestion, nasal Skin/Skin Appendages Disorder Rash Laboratory Adverse Experiences* ALT increased AST increased Pyuria * Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, The frequency of less common adverse events was comparable between SINGULAIR and placebo. The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for SINGULAIR. Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. W ith prolonged treatment, the adverse experience profile did not significantly change. Pediatric Patients 6 to 14 Years of Age with Asthma SINGULAIR has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with SINGULAIR for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following events occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo. W ith prolonged treatment, the adverse experience profile did not significantly change. The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in pediatric patients 6 years of age and older, was consistent with the safety profile previously described for SINGULAIR. In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for SINGULAIR. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving SINGULAIR, the following events not previously observed with the use of SINGULAIR in this age group occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia. 178 of 207 Reference ID:

179 Pediatric Patients 2 to 5 Years of Age with Asthma SINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following events occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis. Pediatric Patients 6 to 23 Months of Age with Asthma Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established. SINGULAIR has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23 months of age receiving SINGULAIR, the following events occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo. Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with SINGULAIR with a frequency 1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week, placebocontrolled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies. Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis SINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. SINGULAIR administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency 2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection. Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis SINGULAIR has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical studies. SINGULAIR administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with SINGULAIR with a frequency 1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo. Pediatric Patients 6 Months to 14 Years of Age with Perennial Allergic Rhinitis The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia. Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration. Psychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor [see Warnings and Precautions (5.4)]. 179 of 207 Reference ID:

180 Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures. Cardiac disorders: palpitations. Respiratory, thoracic and mediastinal disorders: epistaxis, pulmonary eosinophilia. Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting. Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these occurred in combination with other confounding factors, such as use of other medications, or when SINGULAIR was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis. Skin and subcutaneous tissue disorders: angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria. Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps. General disorders and administration site conditions: edema. Patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)]. 7 DRUG INTERACTIONS No dose adjustment is needed when SINGULAIR is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SINGULAIR should be used during pregnancy only if clearly needed. Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see Nonclinical Toxicology (13.2)]. During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with SINGULAIR during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and SINGULAIR has not been established. 8.3 Nursing Mothers Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SINGULAIR is given to a nursing mother. 8.4 Pediatric Use Safety and efficacy of SINGULAIR have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Special Populations (12.3), and Clinical Studies (14.1, 14.2)]. The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug s effect are substantially similar among these populations. The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the 180 of 207 Reference ID:

181 disease course, pathophysiology and the drug s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age. The safety of SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment. The safety of SINGULAIR 4-mg and 5-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see Adverse Reactions (6.1)]. The safety of SINGULAIR 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults. The safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established. Growth Rate in Pediatric Patients A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of SINGULAIR on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included SINGULAIR 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between SINGULAIR and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the SINGULAIR, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for SINGULAIR minus placebo, beclomethasone minus placebo, and SINGULAIR minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1. Figure 1: Change in Height (cm) from Randomization Visit by Scheduled Week (Treatment Group Mean ± Standard Error* of the Mean) *The standard errors of the treatment group means in change in height are too small to be visible on the plot 8.5 Geriatric Use Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older 181 of 207 Reference ID:

182 individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required. 8.6 Hepatic Insufficiency No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency [see Clinical Pharmacology (12.3)]. 8.7 Renal Insufficiency No dosage adjustment is recommended in patients with renal insufficiency [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage with SINGULAIR. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. There have been reports of acute overdosage in post-marketing experience and clinical studies with SINGULAIR. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of SINGULAIR and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis. 11 DESCRIPTION Montelukast sodium, the active ingredient in SINGULAIR, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor. Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The empirical formula is C 35 H 35 ClNNaO 3 S, and its molecular weight is The structural formula is: Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile. Each 10-mg film-coated SINGULAIR tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax. Each 4-mg and 5-mg chewable SINGULAIR tablet contains 4.2 and 5.2 mg montelukast sodium, respectively, which are equivalent to 4 and 5 mg of montelukast, respectively. Both chewable tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. 182 of 207 Reference ID:

183 Each packet of SINGULAIR 4-mg oral granules contains 4.2 mg montelukast sodium, which is equivalent to 4 mg of montelukast. The oral granule formulation contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The cysteinyl leukotrienes (LTC 4, LTD 4, LTE 4 ) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT 1 ) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both earlyand late-phase reactions and are associated with symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity Pharmacodynamics Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD 4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD 4 -induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), SINGULAIR inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively. The effect of SINGULAIR on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received SINGULAIR, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received SINGULAIR, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of SINGULAIR. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies (14)] Pharmacokinetics Absorption Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg filmcoated tablet to fasted adults, the mean peak montelukast plasma concentration (C max ) is achieved in 3 to 4 hours (T max ). The mean oral bioavailability is 64%. The oral bioavailability and C max are not influenced by a standard meal in the morning. For the 5-mg chewable tablet, the mean C max is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning. For the 4-mg chewable tablet, the mean C max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The co-administration of the oral granule formulation with applesauce did not have a clinically significant effect on the pharmacokinetics of montelukast. A high fat meal in the morning did not affect the AUC of montelukast oral granules; however, the meal decreased C max by 35% and prolonged T max from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours. The safety and efficacy of SINGULAIR in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of SINGULAIR in patients with asthma was also demonstrated in clinical trials in which the 4-mg chewable tablet and 4-mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of SINGULAIR in patients with seasonal allergic rhinitis were demonstrated in clinical trials in 183 of 207 Reference ID:

184 which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion. The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated. Distribution Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues. Metabolism Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast. Elimination The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%). Special Populations Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of SINGULAIR in patients with more severe hepatic impairment or with hepatitis have not been evaluated. Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Gender: The pharmacokinetics of montelukast are similar in males and females. Race: Pharmacokinetic differences due to race have not been studied. Adolescents and Pediatric Patients: Pharmacokinetic studies evaluated the systemic exposure of the 4-mg oral granule formulation in pediatric patients 6 to 23 months of age, the 4-mg chewable tablets in pediatric patients 2 to 5 years of age, the 5-mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10-mg film-coated tablets in young adults and adolescents 15 years of age. The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents 15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients 15 years of age. The mean systemic exposure of the 4-mg chewable tablet in pediatric patients 2 to 5 years of age and the 5-mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4-mg chewable tablet should be used in pediatric patients 2 to 5 years of age. In children 6 to 11 months of age, the systemic exposure to montelukast and the variability of plasma montelukast concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4296 ng hr/ml [range 1200 to 7153]) was 60% higher and the mean C max (667 ng/ml [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng hr/ml [range 1521 to 4595]) and mean C max (353 ng/ml [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng hr/ml [range 2229 to 5408]) was 33% higher and the mean C max (562 ng/ml [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of montelukast in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above [see 184 of 207 Reference ID:

185 Adverse Reactions (6.1)]. The 4-mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age. Drug-Drug Interactions Theophylline, Prednisone, and Prednisolone: SINGULAIR has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of 100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Oral Contraceptives, Terfenadine, Digoxin, and Warfarin: In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of 100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR). Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants: Although additional specific interaction studies were not performed, SINGULAIR was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Cytochrome P450 (CYP) Enzyme Inducers: Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for SINGULAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with SINGULAIR. Effect of Montelukast on Cytochrome P450 (CYP) Enzymes: Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. Cytochrome P450 (CYP) Enzyme Inhibitors: In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil [see Overdosage (10)]. 185 of 207 Reference ID:

186 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay. In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose) Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Montelukast crosses the placenta following oral dosing in rats and rabbits [see Pregnancy (8.1)]. 14 CLINICAL STUDIES 14.1 Asthma Adults and Adolescents 15 Years of Age and Older with Asthma Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. The efficacy of SINGULAIR for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with SINGULAIR, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were nonsmokers who required approximately 5 puffs of inhaled β-agonist per day on an as-needed basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV 1 ) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV 1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving SINGULAIR was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects. The results of the U.S. trial on the primary endpoint, morning FEV 1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one SINGULAIR 10-mg tablet daily in the evening resulted in a statistically significant increase in FEV 1 percent change from baseline (13.0%-change in the group treated with SINGULAIR vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV 1 for SINGULAIR was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV 1 were similar. Figure 2: FEV 1 Mean Percent Change from Baseline (U.S. Trial: SINGULAIR N=406; Placebo N=270) (ANOVA Model) 186 of 207 Reference ID:

187 The effect of SINGULAIR on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2. Results on these endpoints were similar in the US study. Table 2: Effect of SINGULAIR on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model) SINGULAIR Placebo Endpoint N Baseline Mean Change from Baseline N Baseline Mean Change from Baseline Daytime Asthma Symptoms * (0 to 6 scale) β-agonist (puffs per day) * AM PEFR (L/min) * PM PEFR (L/min) * Nocturnal Awakenings (#/week) * * p<0.001, compared with placebo Both studies evaluated the effect of SINGULAIR on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on SINGULAIR experienced asthma attacks compared with patients on placebo (27.3%, p<0.001). In the US study, 7.8% of patients on SINGULAIR and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p=0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on SINGULAIR were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p<0.001). In the US study, 6.9% of patients on SINGULAIR and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p=0.196). Onset of Action and Maintenance of Effects In each placebo-controlled trial in adults, the treatment effect of SINGULAIR, measured by daily diary card parameters, including symptom scores, as-needed β-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in nonplacebo-controlled extension trials for up to one year. Withdrawal of SINGULAIR in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma. Pediatric Patients 6 to 14 Years of Age with Asthma The efficacy of SINGULAIR in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with SINGULAIR and 135 treated with placebo) using an inhaled β-agonist on an as-needed basis. The patients had a mean baseline percent predicted FEV 1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age 187 of 207 Reference ID:

188 was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins. Compared with placebo, treatment with one 5-mg SINGULAIR chewable tablet daily resulted in a significant improvement in mean morning FEV 1 percent change from baseline (8.7% in the group treated with SINGULAIR vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily as-needed inhaled β-agonist use (11.7% decrease from baseline in the group treated with SINGULAIR vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the montelukast and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14. Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months. Pediatric Patients 2 to 5 Years of Age with Asthma The efficacy of SINGULAIR for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with SINGULAIR. The median age was 4 years (range 2 to 6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black. W hile the primary objective was to determine the safety and tolerability of SINGULAIR in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, β-agonist use, oral corticosteroid rescue, and the physician s global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that SINGULAIR is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age. Effects in Patients on Concomitant Inhaled Corticosteroids Separate trials in adults evaluated the ability of SINGULAIR to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly. One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV 1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92.0% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-u.s.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with SINGULAIR resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p 0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of SINGULAIR to beclomethasone resulted in statistically significant improvements in FEV 1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to SINGULAIR alone or placebo alone as indicated by FEV 1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and as-needed β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) 188 of 207 Reference ID:

189 demonstrated that SINGULAIR, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of SINGULAIR in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of SINGULAIR on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see Warnings and Precautions (5.3)] Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of SINGULAIR, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebocontrolled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (SINGULAIR 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV 1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of SINGULAIR 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies. Table 3: Mean Maximum Percent Fall in FEV 1 Following Exercise Challenge in Study A (N=47) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1* SINGULAIR Placebo Treatment difference % for SINGULAIR versus Placebo (95% CI)* 2 hours (-12, -5) 8.5 hours (-9, -2) 24 hours (-7, -1) *Least squares-mean The efficacy of SINGULAIR 5-mg chewable tablets, when given as a single dose 2 hours before exercise for the prevention of EIB, was investigated in one multinational, randomized, double-blind, placebo-controlled crossover study that included a total of 64 pediatric patients 6 to 14 years of age with EIB. Exercise challenge testing was conducted at 2 hours and 24 hours following administration of a single dose of study drug (SINGULAIR 5 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV 1 following the 2 hours post-dose exercise challenge. A single dose of SINGULAIR 5 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise (TABLE 4). Similar results were shown at 24 hours post-dose (a secondary endpoint). Some patients were protected from EIB at 24 hours after administration; however, some patients were not. No timepoints were assessed between 2 and 24 hours post-dose. Table 4: Mean Maximum Percent Fall in FEV 1 Following Exercise Challenge in Pediatric Patients (N=64) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1* SINGULAIR Placebo Treatment difference % for SINGULAIR versus Placebo (95% CI)* 2 hours (-9, -1) 24 hours (-7, -1) *Least squares-mean 189 of 207 Reference ID:

190 The efficacy of SINGULAIR for prevention of EIB in patients below 6 years of age has not been established. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV 1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with SINGULAIR, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV 1 and mean time to recovery to within 5% of the pre-exercise FEV 1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. SINGULAIR did not, however, prevent clinically significant deterioration in maximal percent fall in FEV 1 after exercise (i.e., 20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of SINGULAIR. In pediatric patients 6 to 14 years of age, using the 5-mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose) Allergic Rhinitis (Seasonal and Perennial) Seasonal Allergic Rhinitis The efficacy of SINGULAIR tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with SINGULAIR tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry. The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0-3 categorical scale. Four of the five trials showed a significant reduction in daytime nasal symptoms scores with SINGULAIR 10-mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35.0 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received SINGULAIR tablets, loratadine, and placebo are shown in TABLE 5. The remaining three trials that demonstrated efficacy showed similar results. Table 5: Effects of SINGULAIR on Daytime Nasal Symptoms Score* in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean SINGULAIR 10 mg (344) Placebo (351) Active Control (Loratadine 10 mg) (599) (-0.21, -0.06) N.A (-0.31, -0.17) * Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale. Statistically different from placebo (p 0.001). The study was not designed for statistical comparison between SINGULAIR and the active control (loratadine). 190 of 207 Reference ID:

191 Perennial Allergic Rhinitis The efficacy of SINGULAIR tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received SINGULAIR 10-mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled. In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1.0% other origins. SINGULAIR 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 6); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing). Table 6: Effects of SINGULAIR on Daytime Nasal Symptoms Score* in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean SINGULAIR 10 mg (1000) Placebo (980) (-0.12, -0.04) N.A. * Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0-3 categorical scale. Statistically different from placebo (p 0.001). The other 6-week study evaluated SINGULAIR 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for SINGULAIR vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between SINGULAIR and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between SINGULAIR and placebo was with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was with a 95% CI of (-0.19, -0.01). 16 HOW SUPPLIED/STORAGE AND HANDLING No SINGULAIR Oral Granules, 4 mg, are white granules with 500 mg net weight, packed in a child-resistant foil packet. They are supplied as follows: NDC unit of use carton with 30 packets. SINGULAIR Tablets, 4 mg, are pink, oval, bi-convex-shaped chewable tablets. They are supplied as either No or No. 6628: No with code MRK 711 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit dose paper and aluminum foil-backed aluminum foil peelable blister packs of 100. No with code MSD 711 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant. 191 of 207 Reference ID:

192 SINGULAIR Tablets, 5 mg, are pink, round, bi-convex-shaped chewable tablets. They are supplied as either No or No. 6543: No with code MRK 275 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit dose paper and aluminum foil-backed aluminum foil peelable blister packs of 100 NDC bulk packaging high-density polyethylene (HDPE) bottles of 1000 with a non-childresistant white plastic closure with a wax paper/pulp liner, an aluminum foil induction seal, and silica gel desiccant. No with code MSD 275 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC bulk packaging high-density polyethylene (HDPE) bottles of 1000 with a non-childresistant white plastic closure with a wax paper/pulp liner, an aluminum foil induction seal, and silica gel desiccant. SINGULAIR Tablets, 10 mg, are beige, rounded square-shaped, film-coated tablets. They are supplied as either No or No. 6558: No with code MRK 117 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit dose paper and aluminum foil-backed aluminum foil peelable blister pack of 100 NDC bulk packaging high-density polyethylene (HDPE) bottles of 8000 with a non-childresistant white plastic closure with a wax paper/pulp liner, an aluminum foil induction seal, and silica gel desiccant. No with code MSD 117 on one side and SINGULAIR on the other: NDC unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant NDC bulk packaging high-density polyethylene (HDPE) bottles of 8000 with a non-childresistant white plastic closure with a wax paper/pulp liner, an aluminum foil induction seal, and silica gel desiccant. Storage Store SINGULAIR 4-mg oral granules, 4-mg chewable tablets, 5-mg chewable tablets and 10-mg filmcoated tablets at 25 C (77 F), excursions permitted to C (59-86 F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original package. Storage for Bulk Bottles Store bottles of 1000 SINGULAIR 5-mg chewable tablets and 8000 SINGULAIR 10-mg film-coated tablets at 25 C (77 F), excursions permitted to C (59-86 F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. W hen product container is subdivided, repackage into a well-closed, light-resistant container. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). 192 of 207 Reference ID:

193 Information for Patients Patients should be advised to take SINGULAIR daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled. Patients should be advised that oral SINGULAIR is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. Patients should be advised that, while using SINGULAIR, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed. Patients receiving SINGULAIR should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician. Patients should be instructed to notify their physician if neuropsychiatric events occur while using SINGULAIR. Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or nonsteroidal anti-inflammatory agents while taking SINGULAIR. Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame). Copyright Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. uspi-0476-mf-1306r of 207 Reference ID:

194 Patient Information SINGULAIR (SING-u-lair) (montelukast sodium) Tablets SINGULAIR (montelukast sodium) Chewable Tablets SINGULAIR (montelukast sodium) Oral Granules Read the Patient Information Leaflet that comes with SINGULAIR before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is SINGULAIR? SINGULAIR is a prescription medicine that blocks substances in the body called leukotrienes. This may help to improve symptoms of asthma and allergic rhinitis. SINGULAIR does not contain a steroid. SINGULAIR is used to: 1. Prevent asthma attacks and for the long-term treatment of asthma in adults and children ages 12 months and older. Do not take SINGULAIR if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. 2. Prevent exercise-induced asthma in people 6 years of age and older. 3. Help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). SINGULAIR is used to treat: outdoor allergies that happen part of the year (seasonal allergic rhinitis) in adults and children ages 2 years and older, and indoor allergies that happen all year (perennial allergic rhinitis) in adults and children ages 6 months and older. Who should not take SINGULAIR? Do not take SINGULAIR if you are allergic to any of its ingredients. See the end of this leaflet for a complete list of the ingredients in SINGULAIR. What should I tell my healthcare provider before taking SINGULAIR? Before taking SINGULAIR, tell your healthcare provider if you: are allergic to aspirin have phenylketonuria. SINGULAIR chewable tablets contain aspartame, a source of phenylalanine 194 of 207 Reference ID:

195 have any other medical conditions are pregnant or plan to become pregnant. Talk to your doctor if you are pregnant or plan to become pregnant, as SINGULAIR may not be right for you. are breast-feeding or plan to breast-feed. It is not known if SINGULAIR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking SINGULAIR. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how SINGULAIR works, or SINGULAIR may affect how your other medicines work. How should I take SINGULAIR? For anyone who takes SINGULAIR: Take SINGULAIR exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much SINGULAIR to take, and when to take it. Do not stop taking SINGULAIR or change when you take it without talking with your healthcare provider. You can take SINGULAIR with food or without food. See the information below in the section "How should I give SINGULAIR oral granules to my child?" for information about what foods and liquids can be taken with SINGULAIR oral granules. If you or your child misses a dose of SINGULAIR, just take the next dose at your regular time. Do not take 2 doses at the same time. If you take too much SINGULAIR, call your healthcare provider or a Poison Control Center right away. For adults and children 12 months of age and older with asthma: Take SINGULAIR 1 time each day, in the evening. Continue to take SINGULAIR every day for as long as your healthcare provider prescribes it, even if you have no asthma symptoms. Tell your healthcare provider right away if your asthma symptoms get worse, or if you need to use your rescue inhaler medicine more often for asthma attacks. Do not take SINGULAIR if you need relief right away from a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. Always have your rescue inhaler medicine with you for asthma attacks. Do not stop taking or lower the dose of your other asthma medicines unless your healthcare provider tells you to. For patients 6 years of age and older for the prevention of exercise-induced asthma: Take SINGULAIR at least 2 hours before exercise. Always have your rescue inhaler medicine with you for asthma attacks. If you take SINGULAIR every day for chronic asthma or allergic rhinitis, do not take another dose to prevent exercise-induced asthma. Talk to your healthcare provider about your treatment for exercise-induced asthma. Do not take 2 doses of SINGULAIR within 24 hours (1 day). For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 6 months of age and older with perennial allergic rhinitis: Take SINGULAIR 1 time each day, at about the same time each day. How should I give SINGULAIR oral granules to my child? Give SINGULAIR oral granules to your child exactly as instructed by your healthcare provider. 195 of 207 Reference ID:

196 Do not open the packet until ready to use. SINGULAIR 4-mg oral granules can be given: right in the mouth; or dissolved in 1 teaspoonful (5 ml) of cold or room temperature baby formula or breast milk; or mixed with 1 spoonful of one of the following soft foods at cold or room temperature: applesauce, mashed carrots, rice, or ice cream. Give the child all of the mixture right away, within 15 minutes. Do not store any leftover SINGULAIR mixture (oral granules mixed with food, baby formula, or breast milk) for use at a later time. Throw away any unused portion. Do not mix SINGULAIR oral granules with any liquid drink other than baby formula or breast milk. Your child may drink other liquids after swallowing the mixture. What is the dose of SINGULAIR? The dose of SINGULAIR prescribed for your or your child's condition is based on age: 6 to 23 months: one packet of 4-mg oral granules. 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules. 6 to 14 years: one 5-mg chewable tablet. 15 years and older: one 10-mg tablet. What should I avoid while taking SINGULAIR? If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or other medicines called non-steroidal anti-inflammatory drugs (NSAIDs) while taking SINGULAIR. What are the possible side effects of SINGULAIR? SINGULAIR may cause serious side effects. Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking SINGULAIR: agitation including aggressive irritability behavior or hostility memory problems attention problems restlessness bad or vivid dreams sleep walking depression suicidal thoughts and actions disorientation (confusion) (including suicide) feeling anxious tremor hallucinations (seeing or hearing trouble sleeping things that are not really there) Increase in certain white blood cells (eosinophils) and possible inflamed blood vessels throughout the body (systemic vasculitis). Rarely, this can happen in people with asthma who take SINGULAIR. This sometimes happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered. Tell your healthcare provider right away if you get one or more of these symptoms: a feeling of pins and needles or numbness of arms or legs a flu-like illness rash 196 of 207 Reference ID:

197 severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effects with SINGULAIR include: upper respiratory infection fever headache sore throat cough stomach pain diarrhea earache or ear infection flu runny nose sinus infection Other side effects with SINGULAIR include: increased bleeding tendency, low blood platelet count allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives and itching] dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits) palpitations nose bleed, stuffy nose, swelling (inflammation) of the lungs heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting hepatitis bruising, rash, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis) that may occur without warning joint pain, muscle aches and muscle cramps tiredness, swelling Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of SINGULAIR. For more information ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at FDA How should I store SINGULAIR? Store SINGULAIR at 59 F to 86 F (15 C to 30 C). Keep SINGULAIR in the container it comes in. Keep SINGULAIR in a dry place and away from light. General Information about the safe and effective use of SINGULAIR Medicines are sometimes prescribed for purposes other than those mentioned in Patient Information Leaflets. Do not use SINGULAIR for a condition for which it was not prescribed. Do not give SINGULAIR to other people even if they have the same symptoms you have. It may harm them. Keep SINGULAIR and all medicines out of the reach of children. This leaflet summarizes information about SINGULAIR. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SINGULAIR that is written for health professionals. For more information, call the Merck National Service Center at NSC-Merck ( ). What are the ingredients in SINGULAIR? 197 of 207 Reference ID:

198 Active ingredient: montelukast sodium Inactive ingredients: 4-mg oral granules: mannitol, hydroxypropyl cellulose, and magnesium stearate. 4-mg and 5-mg chewable tablets: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. People with Phenylketonuria: SINGULAIR 4-mg chewable tablets contain mg of phenylalanine, and SINGULAIR 5-mg chewable tablets contain mg of phenylalanine. 10-mg tablet: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating contains: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax. Copyright Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 12/2013 usppi-0476-mf-1306r of 207 Reference ID:

199