NOCDURNA

NOCDURNA is indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void. In the NOCDURNA clinical trials nocturnal polyuria was defined as night-time urine production exceeding one-third of the 24-hour urine production. Before starting NOCDURNA: Evaluate the patient for possible causes for the nocturia, including excessive fluid intake prior to bedtime, and address other treatable causes of nocturia. Confirm the diagnosis of nocturnal polyuria with a 24-hour urine collection, if one has not been obtained previously. NOCDURNA 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. ( 1 )

NOCDURNA (desmopressin acetate) sublingual tablets are available as: 27.7 mcg of desmopressin acetate (equivalent to 25 mcg of desmopressin): White, round, sublingual tablet with " 25 " on one side. NDC 54436-325-30 Carton of 30 sublingual tablets (3 blister packs with 10 tablets each) 55.3 mcg of desmopressin acetate (equivalent to 50 mcg of desmopressin): White, round, sublingual tablet with " 50 " on one side. NDC 54436-350-30 Carton of 30 sublingual tablets (3 blister packs with 10 tablets each) Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature]. Keep in original package to protect from moisture and light. Use immediately upon opening individual tablet blister.

Dosing Information ( 2.1 ) : Women: 27.7 mcg daily, one hour before bedtime, administered sublingually without water Men: 55.3 mcg daily, one hour before bedtime, administered sublingually without water 2.1 Dosing Recommendations Before starting or resuming NOCDURNA assess the sodium concentration and only start or resume NOCDURNA in patients with a normal serum sodium concentration [see Warnings and Precautions (5.1) , Contraindications (4) ]. The recommended NOCDURNA dosage in: Women is 27.7 mcg once daily, one hour before bedtime, administered sublingually without water. Men is 55.3 mcg once daily, one hour before bedtime, administered sublingually without water. Keep the tablet under the tongue until it has fully dissolved. The recommended dose for women is lower than for men because women are more sensitive to the effects of NOCDURNA and had a higher risk of hyponatremia with the 55.3 mcg dose in clinical trials. Instruct patients to empty their bladder immediately before bedtime. Limit fluid intake to a minimum from 1 hour before until 8 hours after administration [ see Warnings and Precautions (5.1) and Patient Counseling Information (17) ] . 2.2 Sodium Monitoring Ensure serum sodium concentration is normal prior to initiating or resuming NOCDURNA. NOCDURNA is contraindicated in patients with hyponatremia or a history of hyponatremia [see Contraindications (4) ] . Check the serum sodium concentration within the first week and again at one month after initiating or resuming therapy. Periodically monitor serum sodium during NOCDURNA therapy, as clinically appropriate. More frequent serum sodium monitoring is recommended for patients 65 years and older and for those at risk of hyponatremia. If the patient develops hyponatremia, NOCDURNA 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 [ see Warnings and Precautions (5.1) ].

NOCDURNA is contraindicated in patients with the following conditions due to an increased risk of hyponatremia: Hyponatremia or a history of hyponatremia [see Warnings and Precautions (5.1) ] . Polydipsia Concomitant use with loop diuretics [see Warnings and Precautions (5.1) ] Concomitant use with systemic or inhaled glucocorticoids [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] Renal impairment with estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m 2 [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3) ]. 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 NOCDURNA is contraindicated in patients with the following conditions because fluid retention increases the risk of worsening the underlying condition: Heart failure [See Warnings and Precautions (5.2) ] Uncontrolled hypertension Hyponatremia or a history of hyponatremia ( 4 ) Polydipsia ( 4 ) Concomitant use with loop diuretics or systemic or inhaled glucocorticoids ( 4 ) Estimated glomerular filtration rate below 50 mL/min/1.73 m 2 ( 4 ) Syndrome of inappropriate antidiuretic hormone secretion (SIADH) ( 4 ) During illnesses that can cause fluid or electrolyte imbalance ( 4 ) Heart failure ( 4 ) Uncontrolled hypertension ( 4 )

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Fluid Restriction, Hyponatremia, Sodium Monitoring and Acute Illnesses Instruct patients to place one tablet under the tongue one hour before bedtime and to empty their bladder immediately prior to bedtime. The tablet should remain under the tongue until it dissolves. [see Dosage and Administration (2.1) ]. Advise patients to limit fluid intake to a minimum starting one hour prior to NOCDURNA administration and for eight hours following NOCDURNA administration. Advise patients to avoid caffeine and alcohol before bedtime [see Warnings and Precautions (5.1) ]. Inform patients that NOCDURNA may cause severe hyponatremia, which may be life-threatening, if it is not promptly diagnosed and treated. Inform them about the signs and symptoms associated with hyponatremia, to undergo recommended serum sodium measurements, and to inform their health care provider about new medications [see Warnings and Precautions (5.1) ]. Inform patients that NOCDURNA should be stopped during acute intercurrent illnesses that cause fluid or electrolyte imbalance [see Warnings and Precautions (5.2) ].

Monitor serum sodium more frequently when NOCDURNA is concomitantly used with drugs that may increase the risk of hyponatremia (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, thiazide diuretics, NSAIDs, lamotrigine, chlorpropamide and, carbamazepine). ( 7.1 ) 7.1 Drugs That May Increase the Risk of Hyponatremia Concomitant use of NOCDURNA and loop diuretics or systemic or inhaled glucocorticoids is contraindicated because of the risk of severe hyponatremia [see Boxed Warning , Contraindications (4) , and Warnings and Precautions (5.1) ] . NOCDURNA can be started or resumed three days or five half-lives after the glucocorticoid is discontinued, whichever is longer. Drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, opiate analgesics, thiazide diuretics, carbamazepine, lamotrigine, sulfonylureas, particularly chlorpropamide, and NSAIDs may increase the risk of hyponatremia. Monitor serum sodium more frequently in patients taking NOCDURNA concomitantly with these drugs and when doses of these drugs are increased [see Warnings and Precautions (5.1) ].

Studies with desmopressin have not been performed to evaluate carcinogenic potential. Desmopressin was not mutagenic in bacterial mutagenicity (Ames) and mouse lymphoma assays. Animal studies with desmopressin showed no impairment of fertility in male and female rats at doses up to 200 mcg/kg/day.

Risk Summary NOCDURNA 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 NOCDURNA. There are no data with NOCDURNA use in pregnant women to inform any drug-associated risks. No adverse developmental outcomes were observed in animal reproductive and developmental studies following administration of desmopressin acetate during organogenesis to pregnant rats and rabbits, at exposures 92- and 8- times, respectively, the maximum recommended dose in women, based on body surface area (mg/m 2 ) ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Desmopressin acetate, administered during organogenesis did not cause fetal harm in teratology studies in rats at intravenous doses up to 238 mcg/kg/day or in rabbits at subcutaneous doses up to 10 mcg/kg/day, representing 92- and 8-times, respectively, the maximum recommended dose in women of 27.7 mcg, based on body surface area (mg/m 2 ).

The safety and effectiveness of NOCDURNA have not been established in pediatric patients.

A total of 562 subjects 65 years or older were enrolled in the clinical trials, about 48% of the study population. Clinical studies of desmopressin have shown an increased risk of hyponatremia in patients 65 years of age or older compared to those younger than 65 years of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] .

The following adverse reaction is described elsewhere in the labeling: Hyponatremia [see Boxed Warning and Warnings and Precautions (5.1) ] Common adverse reactions (> 2% incidence) included dry mouth, hyponatremia or blood sodium decreased, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring at 1-888-337-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse event 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. The safety database includes three double-blind, placebo-controlled, multicenter, randomized trials of NOCDURNA and one open-label extension trial. Study 1 (CS40) (NCT01262456) enrolled only women, Study 2 (CS41) (NCT01223937) enrolled only men, Study 3 (CS29) (NCT00477490) enrolled men and women and Study 4 (CS31) (NCT00615836) was an extension of Study 3 for up to 3 years [see Clinical Studies (14) ]. At baseline, 196 women treated with NOCDURNA 27.7 mcg/day, 173 women given placebo, 195 men treated with NOCDURNA 55.3 mcg/day, and 213 men given placebo had nocturia due to nocturnal polyuria, with at least 2 nocturnal voids per night. The mean age of women treated with NOCDURNA 27.7 mcg was 59 years and 42% of women were aged 65 and older. The mean age of men treated with NOCDURNA 55.3 mcg was 62 years and 50% of men were aged 65 and older. Caucasians comprised 81%, Blacks 17%, and Asians 1% of the nocturia due to nocturnal polyuria population, and 12% were Hispanic. Concomitant use of anti-muscarinic medications, alpha-blockers, and alpha-reductase inhibitors was permitted for patients on a stable dose prior to study entry. Serious adverse reactions included 2 reports of hyponatremia in men treated with NOCDURNA 55.3 mcg. These 2 reports occurred in a trial in which all cases of serum sodium ≤125 mmol/L were reported as serious adverse reactions. Adverse Reactions Leading to Discontinuation Among women with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 3% for those treated with NOCDURNA 27.7 mcg and 2% for those in the placebo group. Among men with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 4% for those treated with NOCDURNA 55.3 mcg and 3% in the placebo group. 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 (Studies 1, 2 and 3) Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4 Women Men Adverse Reactions Placebo (N=173) NOCDURNA 27.7 mcg (N=196) Placebo (N=213) NOCDURNA 55.3 mcg (N=195) Hyponatremia or blood sodium decreased 1 (<1%) 1 (<1%) 0 4 (2.1%) Most Common Adverse Reactions Table 2 displays the most common adverse reactions in patients with nocturia due to nocturnal polyuria in Studies 1, 2, and 3. The most common adverse reactions reported with both the 27.7 mcg/day and 55.3 mcg/day dosages included dry mouth, hyponatremia or blood sodium decreased, and dizziness. The high incidence of dry mouth may have been affected by specific query about dry mouth in Study 3 (CS29). In Studies 1 and 2 where the adverse reaction was spontaneously reported, the incidence was ≤4%. Table 2: Common Adverse Reactions (Reported by >2% of NOCDURNA-Treated Patients and at a Higher Incidence With Either Dose Than With Placebo) in Patients With Nocturia Due to Nocturnal Polyuria (Studies 1, 2 and 3) Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4 Women Men Adverse Reactions Placebo (N=173) NOCDURNA 27.7 mcg (N=196) Placebo (N=213) NOCDURNA 55.3 mcg (N=195) Dry mouth 19 (11%) 23 (12%) 27 (13%) 27 (14%) Hyponatremia or blood sodium decreased 3 (2%) 6 (3%) 1 (<1%) 8 (4%) Headache 5 (3%) 4 (2%) 3 (1%) 7 (4%) Dizziness 0 3 (2%) 1 (<1%) 5 (3%) Hyponatremia Serum sodium was measured during screening, at baseline, and on all study visits during treatment including day 4, week 1, week 2 (males only), week 4 and then every month of the studies. Tables 3 and Table 4 show the incidence of serum sodium concentrations below the normal range based on the pooled analysis of three phase 3 studies. Table 3: Incidence of Hyponatremia by Sex in Patients with Nocturia due to Nocturnal Polyuria (Studies 1, 2, and 3) Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4 Women Men Serum Sodium (mmol/L) Placebo (N=171) NOCDURNA 27.7 mcg/day (N=191) Placebo (N=207) NOCDURNA 55.3 mcg/day (N=192) Some subjects received different doses over the course of Study 3 and are in more than one dose-group. n is number observed post baseline 130-134 7 (4%) 13 (7%) 6 (3%) 33 (17%) 126-129 0 (0%) 7 (4%) 0 (0%) 1 (<1%) ≤125 1 (<1%) 0 (0%) 0 (0%) 3 (2%) Table 4: Incidence of Hyponatremia by Sex and Age in Patients with Nocturia due to Nocturnal Polyuria (Studies 1, 2 and 3) Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4 Serum Sodium (mmol/L) Women <65 years Women ≥ 65 years Men < 65 years Men ≥ 65 years Placebo (N=95) NOCDURNA 27.7 mcg/day (N=113) Placebo (N=76) NOCDURNA 27.7 mcg/day (N=78) Placebo (N=95) NOCDURNA 55.3 mcg/day (N=98) Placebo (n=112) NOCDURNA 55.3 mcg/day (N=94) Some subjects received different doses over the course of study 3 and are in more than one dose-group. n is number observed post baseline 130-134 2 (2%) 4 (4%) 5 (7%) 9 (12%) 5 (5%) 11 (11%) 1 (<1%) 22 (23%) 126-129 0 (0%) 2 (2%) 0 (0%) 5 (6%) 0 (0%) 0 (0%) 0 (0%) 1 (1%) ≤125 0 (0%) 0 (0%) 1 (1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (3%)

Overdosage of desmopressin leads to an increased risk of prolonged fluid retention and hyponatremia. Signs of overdosage may include nausea, headache, drowsiness, confusion, and rapid weight gain due to fluid retention [See Warnings and Precautions (5.1) ] . In case of overdosage, NOCDURNA must be discontinued, serum sodium assessed, and hyponatremia treated appropriately.