THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION. Addressing a Nighttime Condition With Daytime Consequences

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1 American Urological Association AUA NEWS THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION Addressing a Nighttime Condition With Daytime Consequences An ICU Theater program held in the Science & Technology Hall during the 2018 AUA Annual Meeting in San Francisco* Scott A. MacDiarmid, MD, FRCPSC Director, Bladder Control and Pelvic Pain Center Alliance Urology Specialists; Greensboro, North Carolina Clinical Associate Professor, Department of Urology The University of North Carolina at Chapel Hill; North Carolina Consultant for Avadel and speaker bureau Jennifer Miles-Thomas, MD, FPMRS Medical Director, Chesapeake Pelvic Health Center Partner, Urology of Virginia; Virginia Beach, Virginia Assistant Professor of Urology, Eastern Virginia Medical School; Norfolk, Virginia Consultant and speaker for Avadel Diane K. Newman, NDP, FAAN Co-Director, Penn Center for Continence and Pelvic Health Adjunct Professor of Urology in Surgery, Division of Urology University of Pennsylvania Medical Center; Philadelphia, Pennsylvania Consultant for Avadel Thomas Roth, PhD Director, Sleep Disorders and Research Center Henry Ford Hospital; Detroit, Michigan Consultant for Avadel *This was a promotional program directed by Avadel and not sponsored by the AUA.

2 2 SUPPLEMENT Introduction Nocturia affects nearly 50 million adults in the United States yet remains an under-recognized condition. 1,2 Only an estimated 26% of patients receive an accurate diagnosis of nocturia, and a mere 18% receive treatment.3 Often believed to be a natural part of aging or a symptom of other common urological illnesses like overactive bladder (OAB) or benign prostatic hyperplasia (BPH), most nocturia cases are caused by nocturnal polyuria, an overproduction of urine by the kidneys at night. 4 For decades, treatment options have offered limited benefit. 4 Left untreated, sleep disruptions due to nocturia have been shown to impair functioning, quality of life, and overall health and are associated with long-term illnesses like depression and cardiovascular disease. 5-8 TM (desmopressin acetate) Nasal Spray marks the first and only FDA-approved microdose nasal spray indicated to treat adults with nocturia due to nocturnal polyuria. 9,10 As a first-in-class product with no therapeutic equivalent, was studied in patients reflective of those seen in clinical practice. 11,12 A panel of leading healthcare providers in the fields of voiding disorders and sleep were assembled at the AUA 2018 annual meeting to offer their expertise on strategies to evaluate and treat this under-addressed condition. This supplement provides a summary of the issues discussed by this panel. Nocturia Is Underdiagnosed and Undertreated Nocturia is the most bothersome manifestation in patients with lower urinary tract symptoms. 13 It is generally defined as waking to void 2 or more times a night, a threshold derived from the point at which a majority of patients report bother. 14 It is not limited to any specific gender, age, or ethnicity, rather by the extent to which it is diagnosed and treated. 1 Of the nearly 50 million adults in the United States with nocturia, approximately 10 million receive a diagnosis, and only an estimated 1.5 million receive treatment. 1-3 This is due, in part, to 2 common misconceptions. First, that nocturia is simply a nuisance of the aging process, explaining why patients may fail to report it. 15 Second, clinicians may incorrectly mischaracterize nocturia to be merely a symptom of other common urological conditions like OAB and BPH, believing medications used to treat these issues are also addressing nocturia. 5 The burden of untreated nocturia is substantial. Nocturia affects multiple health-related quality-of-life parameters, and these aspects worsen with increasing nocturic episodes each night. 14 Sleep disruptions due to nocturia have been shown to impair quality of life, overall health, and work productivity. 5 In addition to its impact on a person s quality of life, nocturia is associated with numerous short-term and long-term health conditions. In the short-term, nocturia may contribute to reduced daytime energy, decreased concentration, and delayed reaction, which can contribute to higher rates of sick leave for patients with nocturia. 16 Over time, nocturia may contribute to depression, cardiovascular disease, fall-related fractures, and increased mortality. 6-8,17,18 These issues may be due in part to nocturia s profound disruption on sleep. Maintenance of a healthy sleep cycle is fundamental for daytime functioning. Sleep consists of 2 different states, rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. Deep, slow-wave, restorative sleep generally occurs during NREM sleep in the first 4 hours (Figure 1). 13 Waking during this time, even without loss of total amount of sleep, is more likely to lead to fatigue as well as increased discomfort and decreased pain threshold. 13 I find that patients don t proactively bring up nocturia. But I will question them about how often they are getting up at night, and explain that it s not a normal part of aging. It s important to ask them what s keeping them up at night. I also ask them what they ve done to address it. Diane Newman, NDP, FAAN

3 ADDRESSING A NIGHTTIME CONDITION WITH DAYTIME CONSEQUENCES 3 Since patients with 2 or more voids per night experience an average of only 2 to 3 hours of sleep before waking up to void, their nocturia disrupts the critical period where deep restorative sleep predominates. 19 Furthermore, once sleep is interrupted, the ability to fall back asleep can be impaired. In fact, one study showed that more than 40% of people with nocturnal awakenings had great difficulty resuming sleep. 20 This impact on sleep may explain the damaging effects nocturia has on overall health and quality of life. Figure 1. Sequences of States and Stages of Sleep on a Typical Night 13 Sequences of States and Stages of Sleep on a Typical Night Awake 1 Stages 2 3 REM REM REM REM REM Hours of Sleep Nocturnal Polyuria: The Most Common Cause of Nocturia Perhaps the greatest barrier to nocturia gaining recognition as a distinct condition, and subsequently receiving treatment, is the lack of understanding regarding its cause. The etiology of nocturia is multifactorial. 21 Psychological elements like depression and anxiety have been linked to nocturia. Urine production that exceeds functional bladder capacity can impair bladder storage, contributing to nocturia. Furthermore, behavioral choices like the timing, type, and quantity of fluid intake throughout the day can affect patients experience with nocturia. Of particular interest is polyuria (excessive urine production), which is further categorized by global polyuria (24-hour urine volume >40 ml/kg) and nocturnal polyuria, which is typically defined as nighttime urine production exceeding 20% to 33% (age-dependent) of 24-hour urine production. 4 While each of these factors can contribute a piece to an etiological puzzle, nocturnal polyuria is by far the most prevalent. 22 Approximately 80% of nocturia cases are due to nocturnal polyuria, an overproduction of urine by the kidneys at night. 4,22 Arginine vasopressin, a naturally occurring antidiuretic hormone that binds to receptors on renal cells, increases water reabsorption and reduces urine production. A reduction in vasopressin, therefore, results in an overproduction of urine at night and contributes to patients necessity for waking up to void. 5 Understanding this simple physiological cause of the overwhelming majority of nocturia explains why medications used to treat OAB and BPH as well as behavioral therapies have had questionable clinical benefit for patients. Anticholinergics, antimuscarinics, and beta-3 adrenergic agonists target the bladder while alpha-blockers target the prostate. They, therefore, don t target nocturnal polyuria in the kidneys. 4 Furthermore, until recently, there has not been an FDA-approved product indicated to treat this condition. 9,10 Many people (40%) have difficulty falling back to sleep. If you wake up frequently to void, your sleep is interrupted, not just by the time it takes to void, but also by the time it takes to fall back asleep. Jennifer Miles-Thomas, MD, FPMRS Please see Brief Summary of full Prescribing Information on pages 10 and 11 and Important Safety Information, including Boxed Warning regarding the risk of hyponatremia, on back cover.

4 4 SUPPLEMENT : The First and Only FDA-Approved Microdose Nasal Spray Indicated for the Treatment of Nocturia Due to Nocturnal Polyuria TM (desmopressin acetate) Nasal Spray is an innovative formulation combining the active ingredient desmopressin acetate and cyclopentadecanolide, a permeation enhancer. The emulsified formulation is ejected in a unique spray pattern structured by drug travel along the perimeter of the spray. This design enhances delivery to the nasal mucosa, helping to avoid pharynx clearing. At the mucosa, cyclopentadecanolide boosts desmopressin transport across the membranes and into circulation. 9,12 This delivery system allows for the use of a microdose of desmopressin while maintaining high bioavailability (8%) for a small peptide. Furthermore, this combination aids in maintaining consistent absorption and predictable pharmacokinetics, thus limiting variability from dose to dose. is available in 2 doses: 0.83 mcg and 1.66 mcg. 9,23 Following administration, the median time to peak plasma concentrations was 15 minutes for the 0.83 mcg dose and 45 minutes for the 1.66 mcg dose. Peak plasma concentrations remained below 10 pg/ml. As a vasopressin analog, is selective at V2 receptors found primarily on renal cells in the collecting ducts. 9 Activation of these receptors increases the formation of aquaporins, which allow water to move from the collecting duct back into the bloodsteam. This formation results in increased water reabsorption, thus concentrating the urine and reducing the amount of urine collected in the bladder during the night. 4 plasma levels were generally undetectable (below 2 pg/ml) 4 to 6 hours after administration, providing 2 points of clinical consideration. 9 First, that the antidiuretic effects take place during the core hours of sleep most critical for restoration. 13 Second, that the majority of the antidiuretic effect takes place prior to, and therefore doesn t interfere with, waking hours. Was Studied in Patients Reflective of Those Seen in Clinical Practice The efficacy and safety of were established across two 12-week, randomized, double-blind, placebo-controlled, multicenter studies that were conducted in North America. Patients at least 50 years old with 2 or more nocturic episodes per night for at least 6 months were screened (57% were men and 43% were women). Eighty percent of the patients enrolled in the study had nocturia due to nocturnal polyuria. Additionally, 21% had both nocturnal polyuria and OAB, and 31% had both nocturnal polyuria and BPH. At baseline, 1045 patients with nocturia due to nocturnal polyuria were randomized in a balanced ratio to 1.66 mcg, 0.83 mcg, or placebo. Both studies had similar design with a validated quality of life (QoL) instrument known as the INTU (Impact of Nighttime Urination) questionnaire, developed in collaboration with the FDA, used in Trial 1 only. In both studies, nocturnal polyuria was defined as nighttime urine production exceeding 33% of the 24-hour urine production. 9,24 This study population is representative of patients most likely to be affected by nocturia (adults at least 50 years of age with several nocturic episodes and concomitant OAB and BPH) and also those patients most at risk for hyponatremia. The clinical trials, therefore, reflect a level of insight into patient experience that may be seen in clinical practice. 9,24 Decreased the Number of Times Patients Woke Up During the Night to Urinate studies featured 2 co-primary efficacy endpoints in each of the 2 trials: (1) change in the mean number of nocturic episodes per night and (2) the percentage of patients who achieved at least a 50% reduction in nocturic episodes. The clinical trials also established a high standard, setting a 50% reduction in nocturic episodes as the benchmark to be considered a responder to treatment. Other clinical trials evaluating the efficacy of desmopressin defined a responder as one who experienced only a 33% reduction in nocturnal voids. 9,23,24

5 ADDRESSING A NIGHTTIME CONDITION WITH DAYTIME CONSEQUENCES 5 was effective at reducing the number of nocturic voids. Nearly 50% of patients using 1.66 mcg reduced the number of times they woke up by half or more. Specifically in Trial 1, the percentage of patients achieving at least a 50% reduction in nocturic episodes per night from baseline was 47%, 35%, and 27% for the 1.66 mcg, 0.83 mcg, and placebo arms, respectively. In Trial 2, the respective reductions were 49%, 41%, and 29% mcg produced a statistically significant effect in each trial, whereas 0.83 mcg produced a statistically significant effect in Trial 2 but not in Trial 1. While not clear why patients in the placebo arm experienced a decrease in nocturic episodes, one explanation is behavioral modifications. Although patients were not instructed to impose fluid restrictions on themselves, enrollment in the study may have influenced them to do so, regardless. 9,24 Further highlighting the reduction of nocturic episodes, analysis of pooled data showed nocturic episodes per night were reduced by 1.5, 1.4, and 1.2 for 1.66 mcg, 0.83 mcg, and placebo, respectively (Figure 2). Both doses of produced a statistically significant effect in the pooled analysis, and for responders taking the 1.66 mcg dose, the mean reduction was 2.1 voids per night. decreased the amount of times patients with nocturnal polyuria woke up during the night to urinate. 9,12 Figure 2. Decreased the Number of Times Patients Woke Up During the Night to Urinate Co-primary Efficacy Endpoint: Change in Mean Number of Nocturic Episodes per Night 9,12 LS Mean Change in Nocturic Episodes/Night (pooled data) mcg (pooled data) P< mcg (pooled data) P< Trial 1 (N=204) Trial 2 (N=145) Trial 1 (N=209) Trial 2 (N=145) Trial 1 (N=199) Trial 2 (N=143) Mean change from baseline Difference from placebo (95% CI) -0.3 (-0.4 to 0.0) -0.3 (-0.5 to -0.1) -0.3 (-0.5 to -0.1) -0.3 (-0.6 to -0.2) Abbreviations: CI, confidence interval; LS, least squares. Nocturnal polyuria is caused by the overproduction of urine, a condition caused by arginine vasopressin. We told patients to raise their legs (behavioral modifications) and focused on bladder and prostate issues, but none of these seemed to work. Thomas Roth, PhD Please see Brief Summary of full Prescribing Information on pages 10 and 11 and Important Safety Information, including Boxed Warning regarding the risk of hyponatremia, on back cover.

6 6 SUPPLEMENT (desmopressin acetate) Nasal Spray was also evaluated on several secondary efficacy endpoints: (1) change in percentage of nights with at most 1 nocturic episode, (2) percentage of nights with no nocturic episodes, (3) time to first nocturic episode, (4) mean reduction from baseline in nocturnal urine volume, and (5) change from baseline in overall impact score for the INTU questionnaire. 9,12,24 Because most patients experience bother with 2 nightly voids, it is important to evaluate the percentage of patients who awoke to void 1 or fewer times per night. 14 In Trial 1, the baseline percentage of nights with at most 1 nocturic episode was 1% for 1.66 mcg, 0.83 mcg, and placebo and increased to 44%, 40%, and 34%, respectively. In Trial 2, baseline percentage of nights with 1 or fewer voids was 1%, 2%, and 1% and increased to 45%, 40%, and 30% for the 1.66 mcg, 0.83 mcg, and placebo doses, respectively. For this endpoint, 1.66 mcg produced a statistically significant effect in each trial, whereas 0.83 mcg produced a statistically significant effect in Trial 2, but not in Trial 1. For most patients, the prevention of this second nightly void can reduce the bother experienced by nocturia. 9 In fact, for some patients taking, a portion of nights were free from nocturic episodes completely. Ten percent of nights were free from nocturic voids for patients using the 1.66 mcg dose compared to 4% of nights for those using placebo. 9 Patients taking were also able to stay in bed longer before waking up to void (Figure 3). 12 Prior to starting treatment, study subjects remained in bed an average of 2.4 hours before their first void. Following treatment with in a pooled analysis, the time to first nocturic episode from bedtime during the treatment period was 252, 240, and 210 minutes in the 1.66 mcg, 0.83 mcg, and placebo dosage groups, respectively. This means patients administered 1.66 mcg or 0.83 mcg had 4 or more hours of uninterrupted sleep after going to bed, the key threshold when deep, slow-wave, restorative sleep occurs. 12,13 Figure 3. Patients Taking Were Able to Stay in Bed Longer Before Waking Up to Void Secondary Efficacy Endpoint: Time to First Nocturic Episodes 12 Change from baseline +66 minutes 210 minutes 0.83 mcg Change from baseline +96 minutes 240 minutes 1.66 mcg Change from baseline +108 minutes 252 minutes Hours P<.0001 vs placebo. Baseline: 2.4 hours The first 4 hours of sleep are the most important for a restful night.13 The key time before you get your sleep interrupted is 4 hours. pushed out the time to first interrupted sleep to over 4 hours in both arms. Responders slept for over 5 hours before they had to get up to void. I think that s impressive data. Scott MacDiarmid, MD, FRCPSC

7 ADDRESSING A NIGHTTIME CONDITION WITH DAYTIME CONSEQUENCES 7 Because addresses the root cause of nocturnal polyuria overproduction of urine at night patients on also significantly reduced the amount of urine they produced at night. In a pooled analysis from a baseline of 805 ml, nocturnal urine volume was reduced by 302 ml, 239 ml, and 190 ml in the 1.66 mcg, 0.83 mcg, and placebo groups, respectively mcg produced a statistically significant effect in each trial. Additionally, 1.66 mcg responders showed an increased benefit, producing 360 ml less urine than they did at baseline. 12 Complementing these endpoints is an evaluation on the impact nocturia has on patients daily lives. The trial included a patient-reported outcome known as the Impact of Nighttime Urination (INTU) questionnaire. This 10-item questionnaire was developed and validated in consultation with the FDA to assess associations between treatment and the impact on quality of life. The 10 items are divided into daytime (6 items) and nighttime (4 items) domains. An overall score from 0 to 100 is generated from those items, with a higher score representing the greatest impairment in function. INTU was evaluated exclusively in Trial 1. 9,23,24 reduced the impact of the nighttime urination score by 45% from baseline (mean baseline score=33) for those in the 1.66 mcg arm. Those in the 0.83 mcg arm saw a reduction of 43% from their baseline score (baseline mean=30). In comparison, those in the placebo arm experienced a reduction from baseline (mean score=32) of 34% significantly reduced the impact of nocturia on patients daily lives. 9 Patients who completed the 12-week placebo-controlled studies were given the option to enroll in open-label extension trials, which demonstrated continued long-term efficacy through 40 weeks for 0.83 mcg in the OL-1 trial and 126 weeks for 1.66 mcg in the DB3-A2 trial. Reduction in nocturic episodes over this length of time shows the durability of when used over an extended period of time in patients with nocturnal polyuria (Figure 4). 12 Figure 4. Patients Taking Regularly for Up to 2 Years Experienced Sustained Reduction in Nocturic Episodes During That Corresponding Period Demonstrated Durable Long-Term Efficacy in Open-Label Extension Trials (40 and 126 Weeks) 12 Time (weeks) Change in Mean Number of Nocturic Episodes per Night From Baseline (n=302) (n=229) 0 (n=307) -1.3 (n=227) (n=223) (n=214) -1.6 (n=290) (n=285) (n=273) -1.7 (n=245) -1.7 (n=207) -1.7 (n=216) (n=197) (n=198) (n=180)(n=117) (n=116) (n=187)(n=184) OL-1 (40-week trial) 0.83 mcg -1.9 (n=106) -1.9 (n=97) -1.9 (n=97) -2.1 (n=48) DB3-A2 (126-week trial) 1.66 mcg (n=40) (n=33) -2.1 (n=48) -2.2 (n=18) -2.2 (n=9) Data presented are for patients with nocturia due to nocturnal polyuria in 2 phase 3, long-term, open-label studies. 12 Please see Brief Summary of full Prescribing Information on pages 10 and 11 and Important Safety Information, including Boxed Warning regarding the risk of hyponatremia, on back cover.

8 8 SUPPLEMENT The Rate of Severe Hyponatremia (Serum Sodium 125 mmol/l) Was Low With As with previous iterations of desmopressin, severe hyponatremia remains a risk of treatment. In (desmopressin acetate) Nasal Spray clinical trials, severe hyponatremia was defined as serum sodium level 125 mmol/l with or without symptoms or serum sodium level between 126 and 129 mmol/l with clinical symptoms associated with hyponatremia. The incidence of hyponatremia with was similar in men and women. Five patients taking 1.66 mcg (1.5%) and 1 patient taking placebo (0.3%) experienced serum sodium levels 125 mmol/l. No patients taking 0.83 mcg experienced severe hyponatremia. Of the 5 patients on 1.66 mcg with serum sodium 125 mmol/l, all were 65 years of age or older. Four were men. The onset of the hyponatremia ranged from 6 days to 12 weeks after the start of dosing. Four of these patients were taking a concomitant systemic or inhaled glucocorticoid. Furthermore, in a 126-week extension study, no patients using (1.66 mcg) experienced severe hyponatremia ( 125 mmol/l) through 126 weeks. 9,12,24 Serum sodium should be monitored prior to initiating therapy, within 7 days of starting treatment, approximately 1 month after initiating treatment or increasing the dose, and periodically after treatment as clinically appropriate. If a patient develops hyponatremia while taking, treatment may need to be temporarily or permanently discontinued, and treatment for the hyponatremia instituted, depending on the clinical circumstances, including the duration and severity of the hyponatremia. 9 In clinical studies, adverse reactions with occurred at an overall low rate. The most common treatment-related adverse events in clinical trials were nasal discomfort, nasopharyngitis, nasal congestion, sneezing, hypertension/blood pressure increased, back pain, epistaxis, bronchitis, and dizziness. The discontinuation rate due to adverse reactions was 4.0%, 4.4%, and 2.3% in patients taking 0.83 mcg, 1.66 mcg, and placebo doses, respectively. 9 : A Once-Nightly Nasal Spray Offering 2 Desmopressin Microdoses With No Therapeutic Equivalent is available in 2 microdoses: 1.66 mcg for patients <65 years of age who are not at increased risk for hyponatremia and 0.83 mcg for patients 65 years of age, or younger patients at increased risk for hyponatremia. 9 is administered as a once-nightly nasal spray. The recommended dose of is 1 spray in either nostril nightly approximately 30 minutes before going to bed. should be primed before using for the first time and re-primed if not used for more than 3 days. If a dose is missed, the dose should not be doubled at the next use. It is also important to recognize that 2 sprays of 0.83 mcg are not interchangeable with 1 spray of 1.66 mcg. Before opening, should be stored upright in a refrigerator, but after opening it can be stored upright at room temperature for up to 60 days. Both bottle strengths of contain 30 days of medication when used once each night. 9

9 ADDRESSING A NIGHTTIME CONDITION WITH DAYTIME CONSEQUENCES 9 Conclusion Recognizing nocturia as a distinct condition gives nearly 50 million adults in the United States with nocturia the hope of a proper diagnosis and treatment. 1,2 Predominantly caused by nocturnal polyuria, an overproduction of urine by the kidneys at night, nocturia s impact on healthy sleep cycles and patients quality of life cannot be overstated. 4,5,13 For decades, treatment options have provided limited benefit. 4,22 offers providers and their patients a new therapy: the first and only FDA-approved microdose nasal spray indicated to treat adults with nocturia due to nocturnal polyuria. 9,10 References: 1. Fitzgerald MP, Litman HJ, Link CL, McKinlay JB; BACH Survey Investigators. The association of nocturia with cardiac disease, diabetes, body mass index, age and diuretic use: results from the BACH survey. J Urol. 2007;177(4): Population distribution by age. Kaiser Family Foundation website. state-indicator/distribution-by-age. Accessed December 16, Oelke M, Anderson P, Wood R, Holm-Larsen T. Nocturia is often inadequately assessed, diagnosed and treated by physicians: results of an observational, real-life practice database containing 8659 European and US-American patients. Int J Clin Pract. 2016;70(11): Weiss JP. Nocturia: focus on etiology and consequences. Rev Urol. 2012;14(3-4): Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect of nocturia on sleep. Sleep Med Rev. 2011;15(2): Kupelian V, Wei JT, O Leary MP, Norgaard JP, Rosen RC, McKinlay JB. Nocturia and quality of life: results from the Boston Area Community Health Survey. Eur Urol. 2012;61(1): Cappuccio FP, Cooper D, D Elia L, Strazzullo P, Miller MA. Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. Eur Heart J. 2011;32(12): Lightner DJ, Krambeck AE, Jacobson DJ, et al. Nocturia is associated with an increased risk of coronary heart disease and death. BJU Int. 2012;110(6): [package insert]. Chesterfield, MO: Avadel Specialty Pharmaceuticals, LLC; US Food and Drug Administration. FDA approves first treatment for frequent urination at night due to overproduction of urine. ucm htm. Accessed April 5, US Food and Drug Administration. Orange Book Noctiva. Accessed April 5, Data on file. Avadel Specialty Pharmaceuticals, LLC. 13. Stanley N. The underestimated impact of nocturia on quality of life. Eur Urol. 2005;4(7)(suppl): Tikkinen KA, Johnson TM, Tammela TL, et al. Nocturia frequency, bother, and quality of life: how often is too often? A population-based study in Finland. Eur Urol. 2010;57(3): Fonda D. Nocturia: a disease or normal ageing? BJU Int. 1999;84(suppl 1): Abrams P. Nocturia: the effect on sleep and related health consequences. Eur Urol Suppl. 2005;3(6): Holm-Larsen T. The economic impact of nocturia. Neurourol Urodyn. 2014;33(suppl 1):S10-S Kupelian V, Fitzgerald MP, Kaplan SA, Norgaard JP, Chiu GR, Rosen RC. Association of nocturia and mortality: results from the Third National Health and Nutrition Examination Survey. J Urol. 2011;185(2): van Kerrebroeck P, Hashim H, Holm-Larsen T, Robinson D, Stanley N. Thinking beyond the bladder: antidiuretic treatment of nocturia. Int J Clin Pract. 2010;64(6): Ohayon MM. Nocturnal awakenings and comorbid disorders in the American general population. J Psychiatr Res. 2008;43(1): Wein A, Lose GR, Fonda D. Nocturia in men, women and the elderly: a practical approach. BJU Int. 2002;90(suppl 3): Weiss JP, van Kerrebroeck PE, Klein BM, Nørgaard JP. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol. 2011;186(4): Cohn JA, Kowalik CG, Reynolds WS, et al. Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol. 2017;10(12): Kaminetsky J, Fein S, Dmochowski R, et al. Efficacy and safety of SER120 nasal spray in nocturia patients pooled analysis of 2 randomized, double-blind, placebo-controlled phase 3 trials. J Urol doi: /j.juro [Epub ahead of print]. Figure 1 reprinted from Stanley N. The physiology of sleep and the impact of ageing. Eur Urol Suppl. 2005;3(6):17-23, with permission from Elsevier. PM-US-NTV Please see Brief Summary of full Prescribing Information on pages 10 and 11 and Important Safety Information, including Boxed Warning regarding the risk of hyponatremia, on back cover.

10 (desmopressin acetate) Nasal Spray The following is a brief summary. Please consult Full Prescribing Information for complete details. WARNING: HYPONATREMIA can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death. is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids. Ensure serum sodium concentrations are normal before starting or resuming. Measure serum sodium within 7 days and approximately 1 month after initiating therapy or increasing the dose, and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia. If hyponatremia occurs, may need to be temporarily or permanently discontinued. INDICATIONS AND USAGE is indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void. Nocturnal polyuria was defined in the clinical trials as nighttime urine production exceeding one-third of the 24-hour urine production. Before starting : Evaluate the patient for possible causes for the nocturia, including excessive fluid intake prior to bedtime, and optimize the treatment of underlying conditions that may be contributing to the nocturia. Confirm the diagnosis of nocturnal polyuria with a 24-hour urine collection, if one has not been obtained previously. Limitation of Use: has not been studied in patients less than 50 years of age. CONTRAINDICATIONS is contraindicated in patients with the following conditions due to an increased risk of severe hyponatremia: Hyponatremia or a history of hyponatremia [see Warnings and Precautions] Polydipsia Primary nocturnal enuresis [see Use in Specific Populations] Concomitant use with loop diuretics [see Warnings and Precautions] Concomitant use with systemic or inhaled glucocorticoids [see Warnings and Precautions, Drug Interactions] Renal impairment with an estimated glomerular filtration rate (egfr) below 50 ml/min/1.73 m 2 [see Use in Specific Populations] Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion During illnesses that can cause fluid or electrolyte imbalance, such as gastroenteritis, salt-wasting nephropathies, or systemic infection is contraindicated in patients with the following conditions because fluid retention increases the risk of worsening the underlying condition: Congestive heart failure (New York Heart Association Class II to IV) [see Warnings and Precautions] Uncontrolled hypertension WARNINGS AND PRECAUTIONS Risk of Hyponatremia: can cause hyponatremia [see Boxed Warning and Adverse Reactions]. Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest, or death. is contraindicated in patients at increased risk of severe hyponatremia, such as those with excessive fluid intake, those who have illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids [see Boxed Warning, Contraindications, and Drug Interactions]. Before starting or resuming, ensure that the serum sodium concentration is normal. Consider the 0.83 mcg dose as the starting dose for patients who may be at risk for hyponatremia. Scott MacDiarmid, MD, FRCPSC When is administered, fluid intake in the evening and nighttime hours should be moderated to decrease the risk of hyponatremia. Monitor the serum sodium concentration within 7 days and approximately 1 month of initiating or increasing the dose, and periodically thereafter. The frequency of serum sodium monitoring should be based on the patient s risk for hyponatremia. For example, more frequent monitoring is recommended for patients 65 years of age or older or those on concomitant medications that can increase the risk of hyponatremia, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), chlorpromazine, carbamazepine, and thiazide diuretics [see Drug Interactions]. If hyponatremia occurs, may need to be temporarily or permanently discontinued, and treatment for the hyponatremia instituted, depending on the clinical circumstances, including the duration and severity of the hyponatremia. Fluid Retention: can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Therefore, is contraindicated in patients with New York Heart Association Class II to IV congestive heart failure or uncontrolled hypertension [see Contraindications]. In addition, is not recommended in patients at risk for increased intracranial pressure or those with a history of urinary retention, and should be used with caution (e.g., monitoring of volume status) in patients with New York Heart Association Class I congestive heart failure. Concurrent Nasal Conditions: Discontinue in patients with concurrent nasal conditions that may increase systemic absorption of (e.g., atrophy of nasal mucosa, and acute or chronic rhinitis), because the increased absorption may increase the risk of hyponatremia. can be resumed when these conditions resolve. ADVERSE REACTIONS The following adverse reaction is described elsewhere in the labeling: Hyponatremia [see Boxed Warning and Warnings and Precautions] Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, the 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. Two randomized, double-blind, placebo-controlled, multicenter trials conducted in adults 50 years of age and older evaluated the efficacy and safety of nasal spray compared to placebo. At baseline, 1045 patients treated with 0.83 mcg or 1.66 mcg, or placebo, had nocturia due to nocturnal polyuria, wakening at least 2 times per night to urinate. Nocturnal polyuria was defined as nighttime urine production exceeding one-third of the 24-hour urine production. The mean age of the patients studied with nocturia due to nocturnal polyuria was 67 years with 42% between 50 and 64 years of age, and 58% aged 65 years and older. Fifty-seven percent were men and 43% were women. Caucasians comprised 79%, Blacks 12%, Hispanics 6%, and Asians 2% of the trial population. During these trials, serious adverse reactions were reported in 2%, 2%, and 3% of patients with nocturia due to nocturnal polyuria treated with 0.83 mcg, 1.66 mcg, and placebo, respectively. There was one case of hyponatremia in the 1.66 mcg group and one case in the placebo group classified as serious adverse reactions. Adverse Reactions Leading to Discontinuation: Among patients with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 4.0% with 0.83 mcg, 4.4% with 1.66 mcg, and 2.3% with placebo. Table 1 displays the most common adverse reactions leading to discontinuation in patients with nocturia due to nocturnal polyuria. Table 1: Most Common Adverse Reactions ( 2 Incidences) Leading to Discontinuation in Patients With Nocturia Due to Nocturnal Polyuria in 2 Double-Blind, -Controlled Clinical Trials Adverse Reactions 1.66 mcg (n=341) 0.83 mcg (n=354) (n=349) Hyponatremia/Blood Sodium Decreased 4 (1.2%) 3 (0.9%) 1 (0.3%) Nasal Discomfort 2 (0.6%) 0 3 (0.9%) Nasal Congestion 2 (0.6%) 0 0 Atrial Fibrillation 2 (0.6%) 0 0 Dizziness 0 2 (0.6%) 1 (0.3%) Dysuria 1 (0.3%) 2 (0.6%) 0 Most Common Adverse Reactions: Table 2 summarizes the most common adverse reactions reported by patients with nocturia due to nocturnal polyuria. This table shows adverse reactions reported in at least 2% of patients treated with and at a higher incidence with the 1.66 mcg dose than with placebo.

11 Table 2: Common Adverse Reactions (Reported by 2% of -Treated Patients and at a Higher Incidence With the 1.66 mcg Dose Than With ) in 2 Double-Blind, -Controlled Clinical Trials in Patients With Nocturia Due to Nocturnal Polyuria Adverse Reactions 1.66 mcg (n=341) 0.83 mcg (n=354) (n=349) Nasal Discomfort 20 (5.9%) 12 (3.4%) 17 (4.9%) Nasopharyngitis 13 (3.8%) 8 (2.3%) 10 (2.9%) Nasal Congestion 10 (2.9%) 5 (1.4%) 5 (1.4%) Sneezing 9 (2.6%) 8 (2.3%) 5 (1.4%) Hypertension/Blood Pressure Increased 9 (2.6%) 6 (1.7%) 4 (1.1%) Back Pain 8 (2.3%) 4 (1.1%) 3 (0.9%) Epistaxis 7 (2.1%) 7 (2.0%) 4 (1.1%) Bronchitis 7 (2.1%) 3 (0.8%) 3 (0.9%) Dizziness 6 (1.8%) 7 (2.0%) 5 (1.4%) No overall changes were observed in the safety profile during the open-label, uncontrolled extension trial with up to 126 weeks of follow-up. Hyponatremia: Table 3 shows the incidence of serum sodium concentrations below the normal range reported in the 2 placebo-controlled trials. Table 3: Hyponatremia in 2, Double-Blind, -Controlled Clinical Trials in Patients With Nocturia Due to Nocturnal Polyuria Serum Sodium Concentrations (mmol/l) 1.66 mcg (n=341) 0.83 mcg (n=354) (n=349) (12.3%) 33 (9.3%) 18 (5.2%) (2.1%) 8 (2.3%) (1.5%) 0 1 (0.3%) Of the 5 patients on 1.66 mcg with serum sodium 125 mmol/l, all were 65 years of age or older. Four were men. The onset of the hyponatremia ranged from 6 days to 12 weeks after the start of dosing. Four of these patients were taking a concomitant systemic or inhaled glucocorticoid and 3 were taking an NSAID. Sex: The incidence of hyponatremia with was similar in men and women. Age: Patients 65 years of age and older treated with had a higher incidence of hyponatremia compared to those younger than 65 years of age (see Table 4). Table 4: Hyponatremia, Based on Age, in 2 Double-Blind, -Controlled Clinical Trials in Patients With Nocturia Due to Nocturnal Polyuria Serum Sodium Concentrations (mmol/l) 1.66 mcg <65 years (n=146) 1.66 mcg 65 years (n=195) 0.83 mcg <65 years (n=148) 0.83 mcg 65 years (n=206) <65 years (n=144) 65 years (n=205) (9.6%) 28 (14.4%) 8 (5.4%) 25 (12.1%) 7 (4.9%) 11 (5.4%) (3.6%) 2 (1.4%) 6 (2.9%) (2.6%) (0.5%) DRUG INTERACTIONS No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions between and other medications. Drugs That May Cause Severe Hyponatremia: Concomitant use of and loop diuretics or systemic or inhaled glucocorticoids is contraindicated because of the risk of severe hyponatremia [see Boxed Warning, Contraindications, and Warnings and Precautions]. can be started or resumed 3 days or 5 half-lives after the glucocorticoid is discontinued, whichever is longer. Drugs That May Cause Water Retention: Monitor serum sodium more frequently in patients taking concomitantly with medications that may cause water retention and increase the risk for hyponatremia (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, opioid analgesics, NSAIDs, lamotrigine, and carbamazepine) [see Warnings and Precautions]. Drugs Administered Intranasally: The drug interaction potential between and other intranasally administered drugs has not been studied. is not recommended for use in patients who require treatment with other drugs via the nasal route. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary: There are no data with use in pregnant women to inform any drug-associated risks. No adverse developmental outcomes were observed in animal reproduction studies with administration of desmopressin during organogenesis to pregnant rats and rabbits at doses approximately <1 and 31 times, respectively, the maximum recommended human dose based on nasal surface area (see Data). is not recommended for the treatment of nocturia in pregnant women. Nocturia is usually related to normal physiologic changes during pregnancy that do not require treatment with. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: Desmopressin acetate did not cause fetal harm in teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day, which is approximately <1 times (rat) and 31 times (rabbit) the maximum recommended human dose based on nasal surface area. Lactation: Desmopressin is present in small amounts in human milk and is poorly absorbed orally by an infant. There is no information on the effects of desmopressin on the breastfed infant or on milk production. The development and health benefits of breastfeeding should be considered along with the mother s clinical need for and any potential adverse effects on the breastfed infant from or from the underlying maternal condition. Pediatric Use: is contraindicated for the treatment of primary nocturnal enuresis because of reports of hyponatremic-related seizures in pediatric patients treated with other intranasal formulations of desmopressin. Studies of have not been conducted in pediatric patients [see Contraindications]. Geriatric Use: Patients 65 years and older treated with had a higher incidence of hyponatremia compared to patients less than 65 years old treated with [see Warnings and Precautions, and Adverse Reactions]. Renal Impairment: Desmopressin is mainly excreted in the urine. The area under the concentration-time curve (AUC) and terminal half-life of desmopressin in renally impaired patients with an egfr below 50 ml/min/1.73 m 2 is 3- to 4-fold greater than in patients with an egfr above 50 ml/min/1.73 m 2. Therefore, is contraindicated in patients who have renal impairment with an egfr below 50 ml/min/1.73 m 2 [see Contraindications]. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of desmopressin has not been studied. OVERDOSAGE Signs of overdose may include effects from hyponatremia such as seizure, altered mental status, cardiac arrhythmias, and worsening edema. Other signs of overdose may include oliguria and rapid weight gain due to fluid retention [see Warnings and Precautions]. In case of overdosage, should be discontinued immediately, serum sodium should be assessed, and appropriate medical treatment initiated. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Hyponatremia: Inform patients that can cause hyponatremia, which may be lifethreatening. Inform patients to moderate fluid intake in the evening and nighttime hours, to monitor for symptoms of hyponatremia (such as headache, nausea or vomiting, restlessness, fatigue, drowsiness, dizziness, muscle cramping, or altered mental status), to undergo recommended serum sodium measurements, to inform their health care provider about new medications, and to stop during illnesses that can cause fluid or electrolyte imbalance [see Boxed Warning, Dosage and Administration, Contraindications, and Warnings and Precautions]. Nasal Conditions: Inform patients to discontinue if nasal conditions occur that may increase systemic absorption of (e.g., atrophy of nasal mucosa, and acute or chronic rhinitis). can be resumed when these conditions resolve [see Warnings and Precautions]. Priming and Dosing: Instruct patients to prime before using it for the first time by pumping 5 sprays into the air away from the face and to re-prime it by pumping 2 sprays into the air if the bottle has not been used in more than 3 days. Instruct patients not to administer 2 sprays of the 0.83 mcg dose. Manufactured for: Avadel Specialty Pharmaceuticals, LLC Chesterfield, MO Rev 03/2018 [Ref 12/2017] PM-US-NTV

12 When kidneys work overtime to produce too much urine at night, think To learn more about the first and only FDA-approved microdose nasal spray for adults with nocturia due to nocturnal polyuria, 1,2 visit IMPORTANT SAFETY INFORMATION WARNING: HYPONATREMIA See full prescribing information for complete boxed warning. (desmopressin acetate) Nasal Spray can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death. is contraindicated in patients at increased risk of severe hyponatremia. See Important Safety Information below for full contraindications. Ensure serum sodium is normal before starting or resuming. Measure serum sodium within 7 days and approximately 1 month after initiating therapy or increasing the dose, and periodically during treatment. More frequently monitor patients 65 years of age and those at increased risk of hyponatremia. If hyponatremia occurs, may need to be discontinued. INDICATIONS AND USAGE is a vasopressin analog indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void. Limitation of Use: Not studied in patients <50 years of age. CONTRAINDICATIONS is contraindicated in patients with the following conditions: hyponatremia or a history of hyponatremia, polydipsia, primary nocturnal enuresis, concomitant use with loop diuretics or systemic or inhaled glucocorticoids, estimated glomerular filtration rate <50 ml/min/1.73 m 2, syndrome of inappropriate antidiuretic hormone secretion (SIADH), during illnesses that can cause fluid or electrolyte imbalance, congestive heart failure (New York Heart Association Class II-IV), and uncontrolled hypertension. WARNINGS AND PRECAUTIONS Fluid retention: Not recommended in patients at risk of increased intracranial pressure or history of urinary retention. Monitor volume status in patients with NYHA Class I congestive heart failure. Nasal conditions: Discontinue in patients with concurrent nasal conditions that may increase absorption, until resolved. ADVERSE REACTIONS Common adverse reactions in clinical trials (incidence >2%) included nasal discomfort, nasopharyngitis, nasal congestion, sneezing, hypertension, back pain, epistaxis, bronchitis, and dizziness. DRUG INTERACTIONS Monitor serum sodium more frequently when is concomitantly used with drugs that may cause water retention and increase the risk for hyponatremia. USE IN SPECIFIC POPULATIONS Pregnancy: Use of is not recommended. Pediatric: Do not use for primary nocturnal enuresis in children. To report SUSPECTED ADVERSE REACTIONS, contact Avadel at or FDA at FDA-1088 or References: 1. [package insert]. Chesterfield, MO: Avadel Specialty Pharmaceuticals, LLC; US Food and Drug Administration. FDA approves first treatment for frequent urination at night due to overproduction of urine. gov/newsevents/newsroom/pressannouncements/ucm htm. Accessed February 26, Avadel Specialty Pharmaceuticals, LLC Avadel. All rights reserved. Chesterfield, MO PM-US-NTV