PRIOR AUTHORIZATION POLICY

POLICY: Desmopressin Products – Noctiva™ (desmopressin acetate nasal spray for intranasal use [0.83 mcg/0.1 mL and 1.66 mcg/0.1 mL] – Avadel)

APPROVAL DATE: 09/11/2019

OVERVIEW Noctiva, a vasopressin analog, is indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least two times per night to void.1 A limitation of use is that the agent has not been studied in patients < 50 years of age. Before initiating Noctiva it is recommended that the diagnosis of nocturnal polyuria has been confirmed with a 24-hour urine collection. It is recommended to check serum sodium concentrations prior to initiating or resuming Noctiva and throughout treatment. If hyponatremia occurs, Noctiva may need to be temporarily or permanently discontinued.

Safety Noctiva has a Boxed Warning regarding hyponatremia.1 Noctiva is contraindicated in patients with hyponatremia or among those with a history of hyponatremia. Also, patients with polydipsia or primary nocturnal enuresis should not use Noctiva. Do not administer Noctiva concomitantly with loop diuretics or with systemic or inhaled glucocorticoids. Patients with renal impairment with an estimated glomerular filtration rate below 50 mL/min/1.73 m2 should not use Noctiva. Those with known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion should not use Noctiva. Do not utilize Noctiva during illnesses that may cause fluid or electrolyte imbalance, such as gastroenteritis, salt-wasting nephropathies, or systemic infection. Noctiva is contraindicated in patients with congestive heart failure (CHF) [New York Heart Association {NYHA} class II to IV] or among those with uncontrolled hypertension because the fluid retention in these conditions increases the risk of worsening the underlying condition. Also, Noctiva 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 NYHA class I CHF. Noctiva 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. Trials involving Noctiva have not been performed in pediatric patients.

Other Desmopressin Therapies Nocdura® (desmopressin acetate sublingual tablets) is a vasopressin analog indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least two times per night to void.2 The FDA- approved dose in women is 27.7 mcg daily (25 mcg desmopressin), 1 hour before bedtime, given sublingually without water. The recommended dose in men is 55.3 mcg daily (50 mcg desmopressin), 1 hour before bedtime, administered sublingually without water. The pharmacokinetics of Nocdurna have not been established; however, overall mean bioavailability was 0.25% with higher sublingual desmopressin doses.

Many other desmopressin products are available in various formulations (oral tablets, nasal spray, injection).3-7 None of the agents are indicated for use in nocturia due to nocturnal polyuria.  DDAVP® tablets (desmopressin acetate oral tablets, generic [0.1 mg and 0.2 mg]) are indicated for use in central diabetes insipidus and primary nocturnal enuresis.4 Oral bioavailability is 0.16%.  DDAVP injection (desmopressin acetate injection, generic [4 mcg/mL]) is indicated for the treatment of hemophilia A and von Willebrand’s disease (type 1) [given by intravenous infusion],

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as well as for central (cranial) diabetes insipidus (administered subcutaneously or as a direct intravenous injection).4  DDAVP nasal spray (desmopressin acetate nasal spray [10 mcg per 0.1 mL]) and DDAVP rhinal tubule (0.1 mg per 1 mL) are indicated for use in central cranial diabetes insipidus.5,6 Stimate nasal spray (desmopressin acetate nasal spray [150 mcg per 0.1 mL]) is indicated for use in hemophilia A and von Willebrand’s Disease (type 1).6 Per Stimate product labeling, intranasal bioavailability is 3.3% to 4.1%.7

Noctiva delivers a much lower rate of desmopressin medication per spray (0.83 mcg or 1.66 mcg per spray) than either intranasal desmopressin product (approximately 10 times less than DDAVP nasal spray and around 100 times less than Stimate nasal spray).1 However, it is uncertain how the pharmacokinetic profile of Noctiva aligns with the other FDA-approved nasal desmopressin products because there are no comparative bioavailability studies and Noctiva contains a novel excipient, cyclopentadecanolide, which enhances absorption.1

Data with Oral Desmopressin in Nocturia Many reviews and clinical studies have investigated the effect of oral desmopressin in patients with nocturia.8-26 Desmopressin was superior to placebo in reducing the overall number of nocturnal voids.9 A Cochrane review of desmopressin for treating nocturia in men (2017) concluded that desmopressin may reduce the frequency of urination at night in many men compared with placebo when treated for 3 to 12 months.11 Other reviews also support the use of desmopressin in both tablet and orally disintegrating tablet formulations for patients with nocturia.12-14 Other studies also detailed the use of oral desmopressin in the management of nocturia in various clinical scenarios.15-26

Guidelines In 2011 a consensus statement was published regarding the evaluation and treatment of nocturia.27 Nocturnal polyuria is defined as nocturnal urine volume exceeding 20% of the total 24-hour urine volume in patients < 65 years of age and exceeding 33% of the total 24-hour urine volume in patients ≥ 65 years of age. Most patients initially respond to nocturia by engaging in one or more lifestyle modifications. The statement suggests that for patients whose nocturia is related to nocturnal polyuria, treatment that reduces nocturnal urine volumes may be appropriate. Due to the specific antidiuretic action of desmopressin, it is the pharmacological therapy of choice for patients with nocturia when nocturnal polyuria is present. Desmopressin appears well-tolerated with hyponatremia as the only potentially serious adverse event. Many patients diagnosed with benign prostatic hypertrophy (BPH) or overactive bladder (OAB) have comorbid nocturnal polyuria, which may be resistant to treatment with alpha1 blockers and/or anticholinergics. Therefore, for patients with BPH or OAB and concomitant nocturnal polyuria, combined use of desmopressin should be considered.

POLICY STATEMENT Prior authorization is recommended for prescription benefit coverage of Noctiva. All approvals are provided for the duration noted below. Due to the specialized skills required for evaluation and diagnosis of patients treated with Noctiva well as the monitoring required for adverse events and long-term efficacy, approval requires Noctiva to be prescribed by or in consultation with a physician who specializes in the condition being treated.

Automation: None.

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RECOMMENDED AUTHORIZATION CRITERIA Coverage of Noctiva is recommended in those who meet the following criteria:

FDA-Approved Indication

1. Nocturia due to Nocturnal Polyuria. Approve for 1 year if the patient meets all of the following criteria (A, B, C, D, E, F, G and H): A) The patient is ≥ 50 years of age; AND B) Noctiva is prescribed by or in consultation with a urologist, a geriatrician, or an endocrinologist; AND C) The diagnosis of nocturnal polyuria has been confirmed with a 24-hour urine collection before treatment initiation and the patient meets one of the following (i or ii): i. The nocturnal urine volume exceeds 20% of the total 24-hour urine volume in patients < 65 years of age; OR ii. The nocturnal urine volume exceeds 33% of the total 24-hour urine volume in patients ≥ 65 years of age; AND D) The patient has tried non-pharmacologic techniques or lifestyle interventions to manage the nocturia (e.g., nighttime fluid restriction, avoidance of caffeine and alcohol, earlier timing of medications, leg elevation and/or use of compression stockings); AND E) Prior to desmopressin therapy, the patient awakens at least two times per night to void; AND F) The patient has serum sodium concentrations within the normal range (135 to 145 mmol/L); AND G) The patient tried one of Nocdurna (desmopressin acetate sublingual tablets) or oral desmopressin acetate tablets (DDAVP tablets, generics); AND H) The prescribing physician has verified that the patient does not have the following conditions/circumstances in which use of Noctiva is not recommended (i, ii, iii, iv, v, or vi): i. Currently receiving loop diuretics (e.g., furosemide, torsemide, bumetanide); OR ii. Currently receiving systemic or inhaled glucocorticoids; OR iii. Renal impairment with an estimated glomerular filtration rate < 50 mL/min/1.73 m2; OR iv. New York Heart Association (NYHA) class II to IV congestive heart failure (CHF); OR v. Polydipsia; OR vi. Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

CONDITIONS NOT RECOMMENDED FOR APPROVAL Noctiva has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for non- coverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.)

1. Primary Nocturnal Enuresis. Use of Noctiva is contraindicated for the treatment of patients with primary nocturnal enuresis.1 Reports of hyponatremia-related seizures have occurred in pediatric patients treated with other intranasal formulations of desmopressin. Use of Noctiva has not been studied in pediatric patients. Desmopressin tablets (DDAVP tablets) are indicated for the management of primary nocturnal enuresis in pediatric patients.3

2. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available.

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REFERENCES 1. Noctiva™ nasal spray [prescribing information]. Chesterfield, MO: Avadel; December 2017. 2. Nocdurna® sublingual tablets [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals; June 2018. 3. DDAVP® tablets [prescribing information]. Parsipanny, NJ: Ferring Pharmaceuticals; December 2014. 4. DDAVP® injection [prescribing information]. Parsipanny, NJ: Ferring Pharmaceuticals; April 2015. 5. DDAVP® nasal spray [prescribing information]. Parsipanny, NJ: Ferring Pharmaceuticals; April 2015. 6. DDAVP® rhinal tube nasal solution [prescribing information]. Parsipanny, NJ: Ferring Pharmaceuticals; April 2015. 7. Stimate® nasal spray [prescribing information]. King of Prussia, PA: CSL Behring LLC; June 2013. 8. Smith A, Wein A. Current pharmacotherapy of nocturia. Expert Opin Pharmacother. 2013;14(7):885-894. 9. Cornu JN, Abrams P, Chapple CR, et al. A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management-a systematic review and meta-analysis. Eur Urol. 2012;62:877-890. 10. Sakalis VI, Karavitakis M, Bedretdinova D, et al. Medical treatment of nocturia in men with lower urinary tract symptoms: systemic review by the European Association of Urology guidelines panel for male lower urinary tract symptoms. Eur Urol. 2017;72:757-769. 11. Han J, Jung JH, Bakker CJ, et al. Desmopressin for treating nocturia in men. Cochrane Database Syst Rev. 2017 Oct 21;10:CD012059. 12. Friedman FM, Weis JP. Desmopressin in the treatment of nocturia: clinical evidence and experience. Ther Adv Urol. 2013;5(6):310-317. 13. Cvetkovic RS, Plosker GL. Desmopressin in adults with nocturia. Drugs. 2005;65(1):99-107. 14. Ebell MH, Radke T, Gardner J. A systematic review of the efficacy and safety of desmopressin for nocturia in adults. J Urol. 2014;192:829-835. 15. Song M, Hong BS, Chun JY, et al. Safety and efficacy of desmopressin for the treatment of nocturia in elderly patients: a cohort study. Int Urol Nephrol. 2014;46:1495-1499. 16. Berges R, Hofner K, Gadamke M, Oelke M. Impact of desmopressin on nocturia due to nocturnal polyuria in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). World J Urol. 2014;32:1163-1170. 17. Rovner ES, Raymond K, Andruczyk E, Juul KV. Low-dose desmopressin and tolterodine combination therapy for treating nocturia in women with overactive bladder: a double-blind, randomized controlled study. Low Urin Tract Symptoms. 2017 May 31. [Epub ahead of print]. 18. Juul KV, Malmberg A, van der Meulen E, et al. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU Int. 2017;119:776-784. 19. Lose G, Lalos O, Freeman RM, et al. Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind placebo- controlled study in women. Am J Obstet Gynecol. 2003;189(4):1106-1113. 20. Van Kerrebroeck P, Rezepour M, Cortesse A, et al. Desmopressin in the treatment of nocturia: a double-blind, placebo- controlled study. Eur Urol. 2007;52(1):221-229. 21. Wang CJ, Lin YN, et al. Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: a double-blind, placebo controlled, randomized study. J Urol. 2011;185(1):219-223. 22. Weiss JP, Zinner NP, Klein BM, Norgaard JP. Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial. Neurourol Urodyn. 2012;31(4):441-447. 23. Weiss JP, Herschorn S, Albei CD, Van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled parallel group study. J Urol. 2013;190(3):965-972. 24. Weiss JP, Herschorn S, Albei CD, et al. Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo-controlled parallel group study. J Urol. 2013;190(3):965-972. 25. Sand PK, Smochowski RR, Reddy J, et al. Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel group study. J Urol. 2013;190(3):958-964. 26. Juul KV, K, Klein MB, Norgaard JP. Long-term durability of the response to desmopressin in female and male nocturia patients. Neurourol Urodyn. 2013;32:363-370. 27. Weiss JP, Blaivas JG, Bliwise DL, et al. The evaluation and treatment of nocturia: a consensus statement. BJU Int. 2011;108:6-21.