PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION

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1 PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr VIIBRYD TM vilazodone hydrochloride 10 mg, 20 mg, 40 mg tablets Antidepressant Forest Laboratories Canada Inc. 85 Enterprise Blvd., Suite 500 Markham, Ontario L6G 0B5 Date of Preparation: April 5, 2017 Submission Control No: VIIBRYD is a trademark of Forest Laboratories, LLC, an Allergan affiliate, used under license by Allergan Pharma Co Allergan. All Rights Reserved. VIIBRYD TM Product Monograph Page 1 of 41

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...4 WARNINGS AND PRECAUTIONS...4 ADVERSE REACTIONS...11 DRUG INTERACTIONS...16 DOSAGE AND ADMINISTRATION...20 OVERDOSAGE...21 ACTION AND CLINICAL PHARMACOLOGY...22 STORAGE AND STABILITY...25 DOSAGE FORMS, COMPOSITION AND PACKAGING...25 PART II: SCIENTIFIC INFORMATION...27 PHARMACEUTICAL INFORMATION...27 CLINICAL TRIALS...28 DETAILED PHARMACOLOGY...29 TOXICOLOGY...30 REFERENCES...34 PART III: PATIENT MEDICATION INFORMATION...35 VIIBRYD TM Product Monograph Page 2 of 41

3 Pr VIIBRYD TM vilazodone hydrochloride 10 mg, 20 mg, 40 mg tablets Antidepressant PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Dosage Form / Strength Tablets 10 mg, 20 mg, 40 mg Nonmedicinal Ingredients Colloidal silicon dioxide, FD&C Red #40 (10 mg only), FD&C Yellow #6 (20 mg only), FD&C Blue #1 (40 mg only), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide INDICATIONS AND CLINICAL USE Adults VIIBRYD (vilazodone hydrochloride) is indicated for the symptomatic relief of Major Depressive Disorder (MDD). The short-term efficacy of VIIBRYD was demonstrated in randomized, double-blind, placebocontrolled studies of 8 to 10-weeks (see CLINICAL TRIALS). Long-term maintenance efficacy has not been established. Physicians should periodically re-evaluate the usefulness of the drug for individual patients. Geriatrics (> 65 years of age): No dose adjustment is recommended on the basis of age (see WARNINGS AND PRECAUTIONS, Special Populations, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Pediatrics (< 18 years of age): No data is available to Health Canada; therefore, Health Canada has not approved an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). VIIBRYD TM Product Monograph Page 3 of 41

4 CONTRAINDICATIONS VIIBRYD (vilazodone hydrochloride) is contraindicated in: patients with known hypersensitivity to vilazodone or any of the excipients of the drug product. For a complete listing of excipients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. patients with concomitant use of Monoamine Oxidase Inhibitors (MAOIs) (see DRUG INTERACTIONS, WARNINGS AND PRECAUTIONS). Monoamine Oxidase Inhibitors (MAOIs) VIIBRYD increases serotonergic neurotransmission and must not be used in patients concomitantly taking, or having stopped taking for less than 14 days, monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic, methylene blue, a dye used in certain surgeries due to the risk of serious, sometimes fatal, drug interactions. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome or serotonin syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Therefore, at least 14 days should be allowed after discontinuing treatment with a MAOI before starting treatment with VIIBRYD (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome, and DOSAGE AND ADMINISTRATION). WARNINGS AND PRECAUTIONS POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM. Pediatrics: Placebo-Controlled Clinical Trial Data Recent analyses of placebo-controlled clinical trial safety databases from Selective Serotonin Reuptake Inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo. The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs. Adults and Pediatrics: Additional data There are clinical trials and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm and harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment. VIIBRYD TM Product Monograph Page 4 of 41

5 Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitationtype emotional and behavioural changes. An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients aged 18 to 24 years with psychiatric disorder showed an increased risk of suicidal behaviour with antidepressants compared to placebo. Discontinuation Symptoms Patients currently taking VIIBRYD (vilazodone hydrochloride) should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended (see DOSAGE AND ADMINISTRATION). Discontinuation of Treatment At the time that a medical decision is made to discontinue VIIBRYD, a gradual reduction in the dose, rather than an abrupt cessation, is recommended. There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor patients for these symptoms when discontinuing VIIBRYD. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate (see DOSAGE AND ADMINISTRATION, Discontinuing Treatment). General Bone Fracture Risk Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with VIIBRYD. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including VIIBRYD, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk VIIBRYD TM Product Monograph Page 5 of 41

6 factors for bone fractures. Carcinogenesis and Mutagenesis For animal data see TOXICOLOGY section. Cardiovascular Blood Pressure Patients with severe cardiac function impairment or with an identified risk of a serious cardiac arrhythmia, uncontrolled hypertension, or severe or unstable coronary heart disease were excluded from clinical trials with VIIBRYD. Caution should be exercised in treating patients with uncontrolled hypertension or with other cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure (see ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology and Haemodynamics). Dependence Dependence Liability VIIBRYD has been systematically studied in animals and did not demonstrate abuse or dependence potential. While VIIBRYD has not been systematically studied in humans for its potential for abuse, there was no suggested evidence of drug-seeking behaviour in the clinical studies. However, it is not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of VIIBRYD (e.g., development of tolerance, drug-seeking behaviour, increases in dose). Hematologic Abnormal Bleeding SSRIs and SNRIs, including VIIBRYD, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal antiinflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, ASA, or other drugs that affect coagulation (see DRUG INTERACTIONS). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g., thrombocytopenia). Hepatic/Biliary/Pancreatic Hepatic Impairment Based on a study conducted with VIIBRYD in patients with mild to moderate hepatic impairment, no impact was observed on the pharmacokinetics of vilazodone. Subsequently no VIIBRYD TM Product Monograph Page 6 of 41

7 dose adjustment is recommended for patients with mild or moderate hepatic impairment. Data in patients with severe hepatic impairment is limited; these patients were excluded from phase 3 clinical trials. Therefore caution should be exercised if patients with severe hepatic impairment are treated (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations). Renal Hyponatremia Hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/l have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Renal impairment The safety profile of vilazodone after a single oral dose of 20 mg did not differ in subjects with mild or moderate renal impairment when compared with subjects with normal renal function. Patients with severe renal impairment were not studied; VIIBRYD should be used with caution in these patients. No dose adjustment is recommended in patients with mild, moderate or severe renal impairment. Neurologic Seizures VIIBRYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Seizures are a potential risk with antidepressant drugs.viibryd should be prescribed with caution in patients with a seizure disorder. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including VIIBRYD, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John s Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD in clinical trials. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, VIIBRYD TM Product Monograph Page 7 of 41

8 delirium and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of VIIBRYD with MAOIs is contraindicated. VIIBRYD should not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking VIIBRYD. VIIBRYD should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS, MAOIs and DOSAGE AND ADMINISTRATION). Treatment with VIIBRYD should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated (see DRUG INTERACTIONS). Cognitive and Motor Disturbances The effects of vilazodone on the ability to drive or to operate machinery were not systematically evaluated in the vilazodone development program. Ophthalmologic Glaucoma As with other SSRIs/SNRIs, VIIBRYD can cause mydriasis and should be used with caution in patients with raised intraocular pressure or those with narrow-angle glaucoma. Psychiatric Suicide The possibility of a suicide attempt is inherent to Major Depressive Disorder (MDD) and may persist until significant remission occurs. Close supervision of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high risk patients. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania and other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or regimen. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions should be written for the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose with this drug (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). Activation of Mania/Hypomania VIIBRYD TM Product Monograph Page 8 of 41

9 Symptoms of mania/hypomania were reported in 0.1% of patients treated with VIIBRYD in short-term clinical studies of patients with MDD and in which patients with bipolar disorder were excluded. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use VIIBRYD cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania and VIIBRYD should be discontinued in any patient entering a manic phase. A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should be made only after patients have been adequately assessed to determine if they are at risk for bipolar disorder. It should be noted that VIIBRYD is not approved for use in treating bipolar depression. Electroconvulsive Therapy (ECT) The safety and efficacy of the concurrent use of VIIBRYD and ECT have not been studied, and therefore, caution is advisable. Special Populations Pregnant Women: The safety of VIIBRYD in human pregnancy has not been established. There are no adequate and well-controlled studies of VIIBRYD in pregnant women. When treating pregnant women with VIIBRYD, carefully consider whether the potential benefits outweigh the potential risks to the fetus (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions and TOXICOLOGY, Teratology Studies). Animal studies did not demonstrate a teratogenic effect of vilazodone, but lower fetal weight and delayed ossification were seen in rats at systemic exposures corresponding to approximately 48 times the Cmax at the maximum recommended human dose (40 mg/day) and in rabbits at approximately 17 times the Cmax at the maximum recommended human dose (see TOXICOLOGY). Nonteratogenic Effects: Post-marketing reports indicate that some neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of serotonergic antidepressants or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome). Infants exposed to SSRIs in pregnancy may have an increased risk for persistant pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent VIIBRYD TM Product Monograph Page 9 of 41

10 epidemiologic studies suggest a positive statistical association between SSRI use (including VIIBRYD) in pregnancy and PPHN. Other studies do not show a significant statistical association. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. If VIIBRYD is used until or shortly before birth, discontinuation symptoms in the newborn should be considered. Labour and Delivery: The effect of VIIBRYD on labour and delivery in humans is unknown. VIIBRYD should be used during labour and delivery only if the potential benefit outweighs the potential risk. Nursing Women: Vilazodone is excreted into the milk of lactating rats. The effect of VIIBRYD on lactation and nursing in humans is unknown. Breast feeding in women treated with VIIBRYD should be considered only if the potential benefit outweighs the potential risk to the child. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from VIIBRYD treatment, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Pediatrics (< 18 years of age): The safety and efficacy of VIIBRYD in the pediatric population have not been established. No patients below 18 years of age were included in the randomized, double-blind, placebo-controlled studies. VIIBRYD is not approved for use in pediatric patients (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). Geriatrics (> 65 years of age): Of the 3,007 patients in clinical studies with VIIBRYD, 65 (2.2%) were 65 to 70 years of age, and 378 (12.6%) were 55 to 64 years of age. An insufficient number of older patients were included in the randomized, double-blind, placebocontrolled studies to conclude whether the safety and efficacy in these patients differs from younger patients. Results from a single-dose (20 mg) pharmacokinetic study in elderly (65-80 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. As with any medicine, in the context of a greater potential for other concomitant medical conditions and drug therapies in elderly patients, caution should be exercised when treating the elderly. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see WARNINGS AND PRECAUTIONS, Hyponatremia, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). VIIBRYD TM Product Monograph Page 10 of 41

11 ADVERSE REACTIONS Adverse Drug Reaction Overview The safety of VIIBRYD (vilazodone hydrochloride) in major depressive disorder (MDD) was evaluated in 3,007 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 676 patient-years of exposure. Of the 3,007 VIIBRYD-treated patients, 2,408 were exposed to VIIBRYD in short-term, placebo-controlled studies. In the phase 3 placebo-controlled studies, the mean age of patients was 41 years (18-70 years) and of these patients, approximately 57% were women and 43% were men. In an open-label 52-week study at 40 mg once daily, 599 patients were exposed to VIIBRYD with 314 patients exposed for at least 6 months and 118 patients exposed for at least 12 months. The most commonly observed adverse reactions in VIIBRYD-treated MDD patients (n=1266) in placebo-controlled studies (incidence 5% and at least twice the rate of placebo) were: diarrhea, nausea, vomiting and insomnia. Adverse Reactions Reported as Reasons for Discontinuation of Treatment Overall, 7.3% of the patients who received VIIBRYD discontinued treatment due to an adverse reaction, compared with 3.5% of placebo-treated patients in these studies. The most common adverse reaction leading to discontinuation in at least 1% of the VIIBRYD-treated patients in the placebo-controlled studies was nausea (1.4%) and diarrhea (1.1%). Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The information presented in these sections was derived from studies of VIIBRYD in major depressive disorder including: 1) 4 placebo-controlled 8 to 10-week studies in 2233 patients, including 1266 receiving VIIBRYD; and 2) an open-label 52-week study of 599 patients. Patients in these studies were either titrated over one week to a dose of 20 mg daily or over two weeks to a dose of 40 mg daily of VIIBRYD. In these clinical trials, VIIBRYD was administered with food. Common Adverse Reactions in Placebo-Controlled MDD Studies Table 1 shows the incidence of common adverse reactions that occurred in 2% of VIIBRYDtreated MDD patients and at a greater rate than placebo-treated patients in the four placebocontrolled studies. Table 1 presents the adverse reactions of placebo and VIIBRYD as pooled data. VIIBRYD TM Product Monograph Page 11 of 41

12 Table 1: Adverse Reactions Occurring in 2% of VIIBRYD-treated Patients and at a greater rate than Placebo-treated Patients in MDD Placebo-Controlled Studies System Organ Class Preferred Term Placebo N=967 (%) VIIBRYD 20 mg/day N=288 (%) VIIBRYD 40 mg/day N=978 (%) Gastrointestinal disorders Diarrhea Nausea Dry mouth Vomiting Abdominal pain Dyspepsia Flatulence Gastroenteritis Abdominal distension Nervous system disorders Headache Dizziness Somnolence Paresthesia Psychiatric disorders Insomnia Abnormal dreams Restlessness General disorders Fatigue Cardiac disorders Palpitations <1 1 2 Metabolism and nutrition disorders Increased appetite Musculoskeletal and connective tissue disorders Arthralgia Investigations Increased weight Includes abdominal discomfort, abdominal pain upper, and abdominal pain. 2 Includes headache and tension headache 3 Includes restlessness, akathisia, and restless legs syndrome Sexual adverse reactions are presented in Table 2 Gastrointestinal The most frequent gastrointestinal events reported in vilazodone treated patients were diarrhea (28.1% vs 9.5% in placebo), nausea (23.4% vs. 6.8% in placebo) and vomiting (4.7% vs 1.7% in placebo). No serious adverse reactions occurred in the four placebo-controlled studies. The onset of diarrhea and nausea occurred mostly during the initial 2-week titration period and median duration was 5 days for nausea (mean duration of 15 days) and 8 days for diarrhea (mean duration of 19 days). Approximately half of the vomiting occurred in the initial 2 weeks of treatment and the median duration was 1 day (mean duration of 3.4 days). Adverse reactions related to gastrointestinal disorders led to discontinuation in 3.2% of all vilazodone-treated patients versus 0.6% of placebo patients. VIIBRYD TM Product Monograph Page 12 of 41

13 In the 52-week open label study, the most frequently occurring adverse events were diarrhea (35.7%), nausea (31.6%), dry mouth (11.0%) and vomiting (7.3%). The majority of events were either mild or moderate in intensity. Only one patient experienced serious gastrointestinal adverse event of duodenal stenosis. Adverse Events related to Gastrointestinal Disorders led to discontinuation in 4.0% of vilazodone treated patients in this 52-week study. Discontinuation symptoms Discontinuation symptoms were evaluated in 4 placebo-controlled trials (8 or 10 weeks in duration) following both abrupt discontinuation (2 studies) and gradual discontinuation over a 2- week period (2 studies). Discontinuation of vilazodone was associated with a somewhat greater incidence of adverse events vs. placebo in general. No specific adverse event occurred at a rate of 1% or greater and there was no discernible pattern seen with respect to specific system, organ, or class. When discontinuing Viibryd, a gradual reduction in the dose, rather than an abrupt cessation, is recommended whenever possible (see DOSAGE AND ADMINISTRATION, Discontinuation of Treatment). Cardiovascular parameters Blood Pressure VIIBRYD and placebo groups in MDD patients participating in the 4 placebo-controlled studies were compared with respect to mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in blood pressure or heart rate associated with VIIBRYD treatment. In a randomized, placebo- and positive-controlled, parallel group, ECG assessment study in 157 healthy subjects, serial blood pressure assessments were conducted. VIIBRYD treatment was associated with statistically significant, dose-dependent increases in systolic blood pressure at doses of 20 mg/day and higher and statistically significant, dose-dependent increases in diastolic blood pressure at doses of 40 mg/day and higher. The maximum mean difference from placebo in systolic blood pressure of 4.4 mmhg (90% CI 1.7, 7.2) for VIIBRYD 20 mg/day and 5.3 mmhg (90% CI 2.5, 8.1) for VIIBRYD 40 mg/day were observed. The maximum mean difference from placebo in diastolic blood pressure of 0.8 mmhg (90% CI -1.4, 3.0) for VIIBRYD 20 mg/day and 3.9 mmhg (90% CI 1.4, 6.3) for VIIBRYD 40 mg/day were observed (see ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography and Hemodynamics). In the pooled short-term studies in MDD, the mean change in systolic blood pressure from baseline to last assessment was 0.3 mmhg for all vilazodone doses combined and -0.2 mmhg for placebo. For vilazodone 20 mg alone the mean change was 0.2 mmhg. In the long term open-label 52 week study in MDD, the mean change in systolic blood pressure from baseline to last assessment was 0.4 mmhg for vilazodone 40 mg. Electrocardiograms At the end of the double-blind treatment period, mean changes in all ECG parameters (ventricular heart rate, QRS, PR, and QT intervals) were similar among vilazodone- and placebotreated patients. VIIBRYD TM Product Monograph Page 13 of 41

14 The effects of vilazodone on ECG interval and haemodynamic parameters were studied in a randomized, placebo- and positive-controlled, parallel group ECG assessment study performed in 157 healthy subjects (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics). Weight In the four placebo-controlled 8 to 10-week studies, slight mean changes in body weight were observed in the vilazodone 20-mg ( kg) and 40-mg ( kg) groups compared with placebo ( kg). The proportion of patients with a weight increase of 7% were 1.7% in 20 mg group, 1.3 % in 40 mg group and 1.0% in the placebo group. The proportion of patients with a weight decrease of 7% were 1.7% in 20 mg group, 0.7 % in 40 mg group and 0.7% in the placebo group. In the 52 week open-label study, mean weight increased mildly over time. The mean increase in weight from baseline at the last visit (mean duration: 31 weeks) for all patients who entered the study was 1.0 kg. However, the mean increase in weight from baseline at Week 52 was 1.7 kg. Weight change was generally consistent with the results from the four 8 or 10-week, placebocontrolled clinical studies. Sexual Function While changes in sexual function often occur as a manifestation of depression, they may also be a consequence of pharmacologic treatment. The incidence of self-reported adverse sexual reactions was low and similar to placebo in clinical studies, as measured by the total score on either the ASEX (Arizona Sexual Experiences Scale) or the CSFQ (Changes in Sexual Function Questionnaire). Reported effects were generally mild and transient in nature. Results from a 52- week open-label study were consistent with the findings from the placebo-controlled studies. Table 2 shows the incidence of adverse reactions associated with sexual dysfunction in the placebo-controlled studies. Table 2: Common Sexual Adverse Reactions Occurring in 2% of VIIBRYD-treated Patients and Greater than the Rate of Placebo-Treated Patients Preferred Term Males Females Placebo N=416 VIIBRYD 20 mg/day VIIBRYD 40 mg/day N=417 Placebo N=551 VIIBRYD 20 mg/day VIIBRYD 40 mg/day N=561 N=122 N=166 Abnormal Orgasm* <1% 2% 2% 0% 1% 1% Erectile dysfunction 1% 0% 3% Libido decreased <1% 3% 4% <1% 2% 2% Ejaculation disorder 0% 1% 2% Not applicable*includes abnormal orgasm and anorgasmia Because adverse reactions related to sexual function are believed to be voluntarily underreported, validated measures (the Arizona Sexual Experiences Scale and the Changes in Sexual Function Questionnaire) designed to identify sexual side effects of antidepressants were used prospectively in the placebo-controlled trials. Physicians should routinely inquire about possible sexual side effects (see CLINICAL TRIALS). VIIBRYD TM Product Monograph Page 14 of 41

15 Less Common Adverse Reactions Observed in Clinical Studies (< 2%) The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: Cardiac disorders: infrequent: tachycardia, ventricular extrasystoles Eye disorders: infrequent: dry eye, vision blurred; rare: cataract General disorders: frequent: feeling jittery, infrequent: feeling abnormal Metabolism and nutrition disorders: infrequent: decreased appetite Musculoskeletal and connective tissue disorders: frequent: muscle spasm Nervous System disorders: frequent: sedation, tremor; infrequent: dysgeusia, migraine Psychiatric disorders: infrequent: panic attack Skin and subcutaneous tissue disorders: infrequent: hyperhidrosis, night sweats Abnormal Hematologic and Clinical Chemistry Findings Laboratory Tests VIIBRYD has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology and urinalysis, as measured in placebo-controlled studies. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. Post-Market Adverse Drug Reactions The following adverse reactions have been identified during post-approval use of VIIBRYD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. These events include: General Disorders and Administration Site Conditions - irritability Psychiatric Disorders - hallucinations, suicide attempt, suicidal ideation, Anxiety, Agitation, Agression Skin and subcutaneous tissue disorders - rash, generalized rash, urticaria, drug eruption VIIBRYD TM Product Monograph Page 15 of 41

16 DRUG INTERACTIONS Serious Drug Interactions Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS. Overview Vilazodone is primarily metabolized by CYP3A4, with minor contributions from CYP2C19 and CYP2D6 (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics; DETAILED PHARMACOLOGY; DRUG INTERACTIONS, Drug-Drug Interactions - Potential for Other Drugs to Affect Vilazodone). Vilazodone is not a general inducer of CYP enzymes. In vitro studies indicate that vilazodone is a moderate inhibitor of CYP2C19 and CYP2D6 (see DRUG INTERACTIONS, Drug-Drug Interactions - Potential for Vilazodone to Affect Other Drugs). Drug-Drug Interactions Monoamine Oxidase Inhibitors (MAOIs) VIIBRYD is contraindicated in patients taking MAOIs (including the antibiotic linezolid and the dye methylene blue), or within at least 14 days of discontinuation of MAOIs (See CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOIs), WARNINGS AND PRECAUTIONS, Serotonin Syndrome and DOSAGE AND ADMINISTRATION, Switching to or from Monoamine Oxidase Inhibitor (MAOI) Antidepressants). Serotonergic Drugs Based on the mechanism of action of vilazodone and the potential for serotonin toxicity, also known as serotonin syndrome, caution is advised when VIIBRYD (vilazodone hydrochloride) is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, tryptophan, triptans, lithium, St-John s Wort, fentanyl and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine) (see WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome). Triptans (5HT 1 agonists) Cases of life-threatening serotonin syndrome have been reported during combined use of SSRIs/SNRIs and triptans. If concomitant treatment with VIIBRYD and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS AND PRECAUTIONS: Serotonin Syndrome). Lithium and tryptophan There have been reports of enhanced effects when antidepressants with serotonergic effect have been given together with lithium or tryptophan, therefore concomitant use of vilazodone with these medicinal products should be undertaken with caution. Central Nervous System (CNS)-Active Agents The risk of using VIIBRYD in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when VIIBRYD is prescribed in combination with other CNS-active drugs. VIIBRYD TM Product Monograph Page 16 of 41

17 Drugs Affecting Platelet Function (e.g., NSAIDs, ASA and other anticoagulants) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when VIIBRYD is initiated or discontinued (see WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding). Potential for Other Drugs to Affect Vilazodone Alcohol: Coadministration of VIIBRYD with ethanol did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmax nor terminal elimination rate of vilazodone was altered by coadministration with alcohol. Proton Pump Inhibitor: Coadministration of VIIBRYD with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmax nor terminal elimination rate of vilazodone was altered by coadministration with alcohol. Inhibitors of CYP3A4 Metabolism by CYP3A4 is a major elimination pathway for vilazodone. In a pharmacokinetics study, co-administration of VIIBRYD (5 or 10 mg) and a strong inhibitor of CYP3A4 (ketoconazole 200 mg) increased vilazodone plasma concentrations by approximately 50% (see Figure 1). The VIIBRYD dose should not exceed 20 mg if co-administered with a strong inhibitor of CYP3A4. The VIIBRYD dose should be readjusted to the original dose when strong CYP3A4 inhibitors are discontinued (see DOSAGE AND ADMINISTRATION). Inducers of CYP3A4 Concomitant use of VIIBRYD with a strong inducer of CYP3A4 (carbamazepine) decreased vilazodone systemic exposure by approximately 45% (see Figure 1). As knowledge of safety with doses > 40 mg is limited, no dosage adjustment is recommended (see DOSAGE AND ADMINISTRATION). Inhibitors of other CYP enzymes Concomitant administration of VIIBRYD with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. In vitro studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone. VIIBRYD TM Product Monograph Page 17 of 41

18 Inhibitors of P-glycoprotein transporters In vitro studies demonstrated that vilazodone is not a substrate of P-glycoprotein. Thus, concomitant administration of VIIBRYD with drugs that inhibit P-glycoprotein activity are not likely to affect the plasma exposure of vilazodone. Figure 1: Impact of Other Drugs on Vilazodone Pharmacokinetics Potential for Vilazodone to Affect Other Drugs Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19 Coadministration of VIIBRYD with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that VIIBRYD (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. VIIBRYD coadministration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. In vitro studies have shown that VIIBRYD is a moderate inhibitor of CYP2C19 and CYP2D6. Drugs metabolized by CYP2C8 Coadministration of VIIBRYD with a CYP2C8 substrate may lead to an increase in concentration of the other drug. In vitro studies suggest that VIIBRYD may inhibit the biotransformation of substrates of CYP2C8. The effect of VIIBRYD on CYP2C8 activity has not VIIBRYD TM Product Monograph Page 18 of 41

19 been tested in vivo. Induction of CYP isoforms VIIBRYD did not induce CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 or 3A5 in an in vitro study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms. Substrates of P-glycoprotein A study in healthy subjects demonstrated that VIIBRYD (40 mg) at steady-state had a slight, not clinically relevant effect (Cmax increased by approximately 18%, AUC0-t by 8%) on the single dose pharmacokinetics of digoxin (0.5 mg). Since digoxin has a narrow therapeutic range, monitoring is recommended. Drugs Highly Bound to Plasma Protein The interaction between vilazodone and other highly protein-bound drugs has not been evaluated. Because vilazodone is highly bound to plasma protein, administration of VIIBRYD to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug. Drug-Food Interactions VIIBRYD should be taken with food. VIIBRYD blood concentrations (AUC) in the fasted state can be decreased by approximately 50% compared to the fed state, and may result in diminished effectiveness in some patients (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption). Drug-Herb Interactions Interactions with herbs have not been established. St. John s Wort Concomitant use of antidepressants with serotonergic effect and herbal remedies containing St. John s Wort (Hypericum perforatum) may result in an increased incidence of adverse reactions including serotonin syndrome (see WARNINGS AND PRECAUTIONS). St. John s Wort is also known as an inducer of CYP3A4 (see DRUG-DRUG INTERACTION). Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions Alcohol: As with other psychotropic drugs, the use of alcohol by patients taking VIIBRYD is not recommended (see DRUG INTERACTIONS). VIIBRYD TM Product Monograph Page 19 of 41

20 DOSAGE AND ADMINISTRATION Dosing Considerations VIIBRYD (vilazodone hydrochloride) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). VIIBRYD should be taken with food. VIIBRYD blood concentrations (AUC) in the fasted state can be decreased by approximately 50% compared to the fed state, and may result in diminished effectiveness in some patients (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption). Recommended Dose and Dosage Adjustment Adults Initial Treatment of Major Depressive Disorder The recommended dose for VIIBRYD is 20 mg to 40 mg once daily with food. VIIBRYD should be initiated at a dose of 10 mg once daily for 7 days, followed by 20 mg once daily. Based on individual patient efficacy and tolerability, the dose may be increased from 20 mg to 40 mg once daily after 7 days. Therapeutic response is usually seen after 1-2 weeks of treatment. Dosing in Special Populations and Conditions Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Data in patients with severe hepatic impairment is limited; therefore caution should be exercised if patients with severe hepatic impairment are treated (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Renal Impairment No dose adjustment is recommended in patients with mild, moderate or severe renal impairment. Patients with severe renal were not studied therefore, VIIBRYD should be used with caution in these patients (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Geriatrics (> 65 years of age) No dose adjustment is recommended on the basis of age. Greater sensitivity of some older individuals cannot be ruled out. In the context of a greater potential for other concomitant medical conditions and drug therapies in elderly patients, caution should be exercised when treating the elderly (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics and ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Discontinuing Treatment Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as VIIBRYD. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing VIIBRYD. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider VIIBRYD TM Product Monograph Page 20 of 41

21 resuming the previously prescribed dose and decreasing the dose at a more gradual rate (see WARNINGS AND PRECAUTIONS, Dependence). Switching a Patient to or from Monoamine Oxidase Inhibitors (MAOIs) At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with VIIBRYD. Conversely, at least 14 days must be allowed after stopping VIIBRYD before starting an MAOI (see CONTRAINDICATIONS, MAOIs and WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome). Concomitant Use of CYP3A4 Inhibitors The VIIBRYD dose should not exceed 20 mg if co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole). The VIIBRYD dose should be readjusted to the original level when CYP3A4 inhibitors are discontinued (see DRUG INTERACTIONS). Concomitant Use of CYP3A4 Inducers Concomitant use of VIIBRYD with a strong inducer of CYP3A4 (carbamazepine 400 mg/day) decreased vilazodone systemic exposure by approximately 45%. As knowledge of safety with doses > 40 mg is limited, no dosage adjustment is recommended (see DRUG INTERACTIONS). Missed Dose In the event that a dose is missed, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regular time. The patient should not take two doses of VIIBRYD at the same time. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre. There is limited clinical trial experience regarding human overdosage with VIIBRYD (vilazodone hydrochloride). The adverse reactions associated with overdose of VIIBRYD at doses of mg as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation. Management of Overdose No specific antidotes for vilazodone are known. Management of overdose should consider the possibility of multiple drug involvement and should consist of treatment of clinical symptoms and relevant monitoring. Medical follow-up in a specialized environment is recommended. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations. VIIBRYD TM Product Monograph Page 21 of 41

22 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action VIIBRYD (vilazodone hydrochloride) is both a selective serotonin reuptake inhibitor and a partial agonist of the 5-hydroxytryptamine1A (5HT1A) receptors. The precise mechanism of the antidepressant effect of VIIBRYD is not fully understood but presumed to be related to enhancement of serotonergic activity in the central nervous system. Pharmacodynamics VIIBRYD selectively binds with high affinity to, and inhibits, serotonin reuptake sites (Ki=0.1 nm; IC50=1.6 nm). Viladozone also exhibits partial agonist activity at 5HT1A receptors (IC50=2.1 nm). Vilazodone is more selective for inhibition of serotonin reuptake than dopamine (Ki=37 nm ) or norepinephrine (Ki=56 nm) reuptake. Cardiac Electrophysiology and Haemodynamics The effects of vilazodone on ECG interval and haemodynamic parameters were studied in a randomized, placebo- and positive-controlled (moxifloxacin 400 mg), parallel group ECG assessment study performed in 157 healthy subjects to evaluate QT prolongation. Subjects randomized to vilazodone treatment (N=66) received sequential ascending doses of 10 mg/day, 20 mg/day, 40 mg/day, 60 mg/day, and 80 mg/day over a 15 day period, with each dose being administered for three days. ECG assessments were performed at 13 timepoints at baseline and on the third day of administration of the vilazodone at therapeutic doses of 20 mg and 40 mg and at supratherapeutic doses of 60 mg and 80 mg and at corresponding days in the control groups. Vilazodone was associated with a concentration-dependent increase in heart rate, with statistically significant differences from placebo at supratherapeutic doses of 60 mg/day and higher. On day 15, during treatment with vilazodone at supratherapeutic doses of 80 mg, statistically significant increases in ventricular heart rate were observed from 3-6 h post-dosing, with a maximum mean difference from placebo of 7.6 bpm (90% CI 5.9, 9.3) at 6 h. Vilazodone was associated with shortening of the PR interval at doses of 20 mg/day and higher. On day 9, during treatment with vilazodone 40 mg, statistically significant negative mean differences from placebo were observed at 10 of 13 timepoints, with a maximum mean difference from placebo of -5.9 ms (90% CI -7.8, -3.9) at 8 h. On day 15, during treatment with vilazodone 80 mg, statistically significant negative mean differences from placebo were observed at 10 of 13 timepoints, with a maximum mean difference from placebo of -8.2 ms (90% CI -10.3, -6.1) at 6 h. No consistent or dose-dependent effects on the QTc interval or QRS duration were observed. Vilazodone was associated with transient increases in systolic blood pressure at doses of 20 mg/day and higher. At 30 min post-dosing on the third day of each sequential ascending dose treatment, statistically significant mean differences from placebo in systolic blood pressure were observed with vilazodone. Statistically significant and dose-dependent increases in diastolic blood pressure were observed at vilazodone doses of 40 mg/day and higher (see Table 3). VIIBRYD TM Product Monograph Page 22 of 41