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) ].

centration 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.

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) ].

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%)

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) ].

d 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 ). 8.2 lactation risk summary desmopressin is present in small amounts in human milk (see data ). there is no information on the effects of desmopressin on the breastfed infant or on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's need for nocdurna and any potential adverse effects on the breastfed child from nocdurna or from the underlying maternal condition. data human data the breast milk of lactating women was collected over 8 hours following desmopressin (300 mcg) administration using nasal spray. based on the measured concentrations of desmopressin, the amounts of desmopressin that may be transferred to a breastfed infant correspond to 0.0001-0.0005% of the dose administered. 8.4 pediatric use the safety and effectiveness of nocdurna have not been established in pediatric patients. 8.5 geriatric use 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) ] . 8.6 renal impairment no dose adjustment of nocdurna is required for patients with an egfr at or above 50 ml/min/1.73 m 2 . nocdurna is contraindicated in patients with an egfr below 50 ml/min/1.73 m 2 [see contraindications (4) ].

its 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 ).

see dosage and administration (2.1) ] . dose, sex, age and renal impairment affect the risk of developing hyponatremia [see warnings and precautions (5.1) ]. 12.3 pharmacokinetics the pharmacokinetics of desmopressin following sublingual administration of nocdurna has not been characterized. the pharmacokinetic information provided below is from studies following sublingual administration of higher doses or intravenous injection of desmopressin. absorption the overall mean absolute bioavailability of desmopressin administered sublingually (at doses of 200, 400 and 800 mcg, which represents 4, 8, and 16 times the maximum recommend dosage in men) was 0.25% (95% ci 0.21–0.31%). distribution the volume of distribution of desmopressin after intravenous administration of 2 mcg is 26.5 l. elimination the geometric mean terminal half-life is 2.8 hours. metabolism in vitro studies in human liver microsome preparations have shown that desmopressin is not a substrate for the human cyp450 system. excretion desmopressin is mainly excreted in the urine. after intravenous administration of 2 mcg, 52% of the dose was recovered in the urine within 24 hours as unchanged desmopressin. drug interaction studies in vitro studies in human liver microsome preparations have shown that desmopressin does not inhibit the human cyp450 system. no in vivo interaction studies have been performed with nocdurna. patients with renal impairment a pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) who received a single 2 mcg dose of desmopressin intravenous injection. the geometric mean terminal half-life was 2.8 hours in subjects with normal renal function, and 4, 6.6, and 8.7 hours in patients with mild, moderate, and severe renal impairment, respectively. in patients with mild, moderate and severe renal impairment, mean desmopressin area under the plasma drug concentration time curve (auc) was 1.5-fold, 2.4-fold and 3.7-fold higher, respectively, compared to that of subjects with normal renal function [see contraindications (4) , use in specific populations (8.6) ].

ours as unchanged desmopressin. drug interaction studies in vitro studies in human liver microsome preparations have shown that desmopressin does not inhibit the human cyp450 system. no in vivo interaction studies have been performed with nocdurna. patients with renal impairment a pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) who received a single 2 mcg dose of desmopressin intravenous injection. the geometric mean terminal half-life was 2.8 hours in subjects with normal renal function, and 4, 6.6, and 8.7 hours in patients with mild, moderate, and severe renal impairment, respectively. in patients with mild, moderate and severe renal impairment, mean desmopressin area under the plasma drug concentration time curve (auc) was 1.5-fold, 2.4-fold and 3.7-fold higher, respectively, compared to that of subjects with normal renal function [see contraindications (4) , use in specific populations (8.6) ].

121) or placebo (n=116) every night approximately 1 hour prior to bedtime for 3 months. in study 2, a total of 230 men with nocturia due to nocturnal polyuria were randomized to receive sublingual nocdurna 55.3 mcg (n=102) or placebo (n=128) every night approximately 1 hour prior to bedtime for 3 months. nocturnal polyuria was defined as nighttime urine production exceeding one-third of the 24-hour urine production confirmed with a 24-hour urine frequency/volume chart. the co-primary efficacy endpoints in each trial were 1) the change in number of nocturia episodes per night from baseline during the 3-month treatment period, and 2) 33% responder status during three months of treatment. a 33% responder was defined as a subject with a decrease of at least 33% in the mean number of nocturnal voids compared to baseline. many conditions can cause nocturia. the efficacy and safety of nocdurna have not been established for the treatment of all causes of nocturia. nocdurna is indicated only for patients who have nocturia due to nocturnal polyuria. the results for the co-primary efficacy endpoints among patients with nocturia due to nocturnal polyuria are shown in table 5. table 5. primary efficacy results in subjects with nocturia due to nocturnal polyuria in studies 1 and 2 (mitt population) women (study 1) men (study 2) placebo nocdurna 27.7 mcg once daily placebo nocdurna 55.3 mcg once daily n=114 n=118 n=128 n=102 mitt: modified intent-to-treat (including all randomized patients who received at least one dose of study drug) ci = confidence interval mean number of nocturnal voids baseline (mean) 2.9 2.9 3.0 3.0 change from baseline repeated measures ancova of change from baseline at week 1, month 1, month 2 and month 3, adjusted for age stratification factor (<65, ≥65 years), visit, and baseline nocturnal voids -1.2 -1.5 -0.9 -1.3 difference from placebo -0.3 -0.4 95% ci (-0.5, -0.1) (-0.6, -0.2) 33% responder status probability gee method for 33% responder status at week 1, month 1, month 2 and month 3, adjusted for age stratification factor (<65, ≥65 years), visit, and baseline nocturnal voids 0.62 0.78 0.50 0.67 odds ratio 2.15 2.02 95% ci (1.36, 3.41) (1.30, 3.14) to help interpret the clinical meaningfulness of the efficacy findings, results of the additional analyses for the percentage of nights during the 3-month treatment period with no nocturia and the percentage of nights during the 3-month treatment period with at most one nocturia episode, are displayed in table 6. table 6 summary of additional analysis results in subjects with nocturia due to nocturnal polyuria in studies 1 and 2 (mitt population) women (study 1) men (study 2) placebo nocdurna 27.7 mcg once daily placebo nocdurna 55.3 mcg once daily n=114 n=118 n=128 n=102 mitt: modified intent-to-treat (including all randomized patients who received at least one dose of study drug) ci: confidence interval percentage of nights with at most one nocturnal void baseline (mean) 0% 1% 1% 0% percentage ancova model adjusted for treatment, age stratification factor (<65, ≥65 years), and baseline nocturnal voids 45% 58% 32% 44% difference from placebo 13% 11% 95% ci (4%, 21%) (3%, 20%) percentage of nights with no nocturnal voids baseline (mean) 0% 0% 0% 0% percentage 15% 19% 7% 15% difference from placebo 4% 9% 95% ci (-3%, 11%) (4%, 14%)

s [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) ].