WARNING: HYPONATREMIA NOCDURNA can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death [see Warnings and Precautions (5.1) ]. NOCDURNA 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 [see Contraindications (4) and Warnings and Precautions (5.1) ]. Ensure the serum sodium concentration is normal before starting or resuming NOCDURNA. Measure serum sodium within 7 days and approximately 1 month after initiating therapy, 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. [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ]. If hyponatremia occurs, NOCDURNA may need to be temporarily or permanently discontinued [see Warnings and Precautions (5.1) ]. WARNING: HYPONATREMIA See full prescribing information for complete boxed warning. NOCDURNA can cause hyponatremia, which may be life-threatening if severe ( 5.1 ) NOCDURNA 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. ( 4 , 5.1 ) Ensure serum sodium concentration is normal before starting or resuming NOCDURNA. Measure serum sodium within 1 week and approximately 1 month after initiating therapy 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 ( 2.2 , 5.1 ) If hyponatremia occurs, NOCDURNA may need to be temporarily or permanently discontinued ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Limit fluid intake to a minimum from 1 hour before until 8 hours after administration. Treatment without concomitant reduction of fluid intake may lead to fluid retention and hyponatremia ( 5.1 ) Fluid retention: Not recommended in patients at risk of increased intracranial pressure or history of urinary retention. ( 5.2 ) 5.1 Hyponatremia NOCDURNA can cause hyponatremia [see Boxed Warning and Adverse Reactions (6.1) ]. Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest, or death. NOCDURNA 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 Contraindications (4) , and Drug Interactions (7.1) ]. Prior to starting or resuming NOCDURNA, ensure that the serum sodium concentration is normal . Limit fluid intake to a minimum from 1 hour before administration until 8 hours after administration. Use of NOCDURNA without concomitant reduction of fluid intake may lead to fluid retention and hyponatremia. Advise patients to avoid drinks containing caffeine or alcohol before bedtime. Monitor the serum sodium concentration within 1 week and approximately 1 month of initiating NOCDURNA, and periodically thereafter. The frequency of serum sodium monitoring should be based on the patient's risk for hyponatremia. The incidence of hyponatremia was higher in patients 65 years of age or older compared to younger patients. 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, opiate analgesics, carbamazepine, lamotrigine, thiazide diuretics and chlorpropamide [see Drug Interactions (7.1) ]. If hyponatremia occurs, 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. Women are more sensitive to the effects of NOCDURNA compared to men [see Clinical Pharmacology (12.2) ]. The recommended dose for women is lower than for men because women had a higher risk of hyponatremia with the 55.3 mcg dose in clinical trials. 5.2 Fluid Retention NOCDURNA can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Therefore, NOCDURNA is contraindicated in patients with heart failure or uncontrolled hypertension [see Contraindications (4) ] . In addition, NOCDURNA is not recommended in patients at risk for increased intracranial pressure or those with a history of urinary retention.
6 ADVERSE REACTIONS 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%)
adverse reactions table
<table width="75%"><caption>Table 1: Most Common Adverse Reactions (≥2 Incidences) Leading to Discontinuation in Patients With Nocturia Due to Nocturnal Polyuria (Studies 1, 2 and 3)<footnote ID="K1130">Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4</footnote></caption><col width="45%" align="left" valign="top"/><col width="10%" align="center" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th colspan="2" styleCode="Botrule Rrule">Women</th><th colspan="2" styleCode="Botrule Rrule">Men</th></tr><tr><th styleCode="Lrule Rrule">Adverse Reactions</th><th align="center" styleCode="Rrule" valign="middle">Placebo (N=173)</th><th styleCode="Rrule">NOCDURNA 27.7 mcg (N=196)</th><th styleCode="Rrule">Placebo (N=213)</th><th styleCode="Rrule">NOCDURNA 55.3 mcg (N=195)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyponatremia or blood sodium decreased</td><td styleCode="Rrule">1 (<1%)</td><td styleCode="Rrule">1 (<1%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4 (2.1%)</td></tr></tbody></table>
adverse reactions table
<table width="75%"><caption>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)<footnote ID="K1235">Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4</footnote></caption><col width="45%" align="left" valign="top"/><col width="10%" align="center" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th colspan="2" styleCode="Botrule Rrule">Women</th><th colspan="2" styleCode="Botrule Rrule">Men</th></tr><tr><th styleCode="Lrule Rrule">Adverse Reactions</th><th align="center" styleCode="Rrule" valign="middle">Placebo (N=173)</th><th styleCode="Rrule">NOCDURNA 27.7 mcg (N=196)</th><th styleCode="Rrule">Placebo (N=213)</th><th styleCode="Rrule">NOCDURNA 55.3 mcg (N=195)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry mouth</td><td styleCode="Rrule">19 (11%)</td><td styleCode="Rrule">23 (12%)</td><td styleCode="Rrule">27 (13%)</td><td styleCode="Rrule">27 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyponatremia or blood sodium decreased</td><td styleCode="Rrule">3 (2%)</td><td styleCode="Rrule">6 (3%)</td><td styleCode="Rrule">1 (<1%)</td><td styleCode="Rrule">8 (4%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">5 (3%)</td><td styleCode="Rrule">4 (2%)</td><td styleCode="Rrule">3 (1%)</td><td styleCode="Rrule">7 (4%)</td></tr><tr><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 (2%)</td><td styleCode="Rrule">1 (<1%)</td><td styleCode="Rrule">5 (3%)</td></tr></tbody></table>
adverse reactions table
<table width="85%"><caption>Table 3: Incidence of Hyponatremia by Sex in Patients with Nocturia due to Nocturnal Polyuria (Studies 1, 2, and 3)<footnote ID="K1388">Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4</footnote></caption><col width="20%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th colspan="2" styleCode="Rrule Botrule">Women</th><th colspan="2" styleCode="Rrule Botrule">Men</th></tr><tr><th styleCode="Lrule Rrule">Serum Sodium (mmol/L)</th><th align="center" styleCode="Rrule" valign="top">Placebo (N=171)</th><th styleCode="Rrule" valign="top">NOCDURNA 27.7 mcg/day (N=191)</th><th styleCode="Rrule" valign="top">Placebo (N=207)</th><th styleCode="Rrule" valign="top">NOCDURNA 55.3 mcg/day (N=192)</th></tr></thead><tfoot><tr><td align="left" colspan="5">Some subjects received different doses over the course of Study 3 and are in more than one dose-group.</td></tr><tr><td align="left" colspan="5">n is number observed post baseline</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">130-134</td><td styleCode="Rrule">7 (4%)</td><td styleCode="Rrule">13 (7%)</td><td styleCode="Rrule">6 (3%)</td><td styleCode="Rrule">33 (17%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">126-129</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">7 (4%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">1 (<1%)</td></tr><tr><td styleCode="Lrule Rrule">≤125</td><td styleCode="Rrule">1 (<1%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">3 (2%)</td></tr></tbody></table>