Nocdurna: Indications, Dosage, Precautions, Adverse Effects
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Nocdurna - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Nocturnal Polyuria, Nocturnal Enuresis (Enuresis), Urination - excessive volume (Nocturnal Polyuria)
Class: Antidiuretic hormones
Form: Tablets
Ingredients: Gelatin, Mannitol, Anhydrous Citric Acid, Desmopressin

Summary Product Information

Route of
Administration
Dosage Form/Strength Clinically Relevant Non medicinal
Ingredients
Sublingual Orally Disintegrating Tablets
Female: 25 μg
Male: 50 μg
Gelatin, Mannitol, Citric Acid

Indications and Clinical Use

NOCDURNA is indicated for treatment of nocturia in adults with four or less nocturnal voids. An insufficient number of adults with more than four nocturnal voids were studied to allow a conclusion on the efficacy of NOCDURNA in these subjects.1, 2, 3, 4, 5, 17, 24, 26, 27, 28, 29, 30, 31, 32, 44

Geriatrics

Clinical studies of desmopressin in the elderly at higher doses and with different dosage forms have shown an increased risk of hyponatremia with age and declining creatinine clearance. Desmopressin acetate is known to be excreted by the kidney, and the risk of adverse reactions to desmopressin may be greater in patients with impaired renal function. Desmopressin is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50 mL/min). 8 [See Clinical Pharmacology and Contraindications]

Use of NOCDURNA requires careful fluid restriction to prevent possible prolonged fluid retention and subsequent hyponatremia. Fluid restriction should be discussed with the patient. 35 [See Warnings and Precautions]

Pediatrics

Although the efficacy and safety of desmopressin acetate for use in pediatric Primary Nocturnal Enuresis (PNE) have been established with other formulations of desmopressin acetate, NOCDURNA doses of 25 μg and 50 μg have not been studied in this population.

Contraindications

Hypersensitivity

Hypersensitivity to desmopressin acetate or to any ingredient in the formulation or any component of NOCDURNA. For complete listing, see Dosage Forms, Composition and Packaging section of the Product Monograph.

Polydipsia

Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours).

Hyponatremia

NOCDURNA is contraindicated in patients with hyponatremia or a history of hyponatremia.

Renal impairment

NOCDURNA is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50 mL/min).8

Cardiac Insufficiency

A history of known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

NOCDURNA is contraindicated in patients with known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

Hematology

Because of the risk of platelet aggregation and thrombocytopenia, the drug should not be used in patients with type IIB or platelet-type (pseudo) von Willebrand's disease.

Sodium Losing Conditions

Existing medical conditions, which lead to sodium losing states such as nausea, bulimia, anorexia nervosa, chronic vomiting, diarrhea, adrenocortical insufficiency and salt losing nephropathies, are contraindicated for the use of desmopressin acetate.

Warnings and Precautions

General

Fluid Intake

Patients treated with diuretics for fluid retention should not be treated with desmopressin acetate.

Fluid Restriction

Fluid intake must be limited to a minimum from 1 hour before until 8 hours after administration. Treatment without concomitant reduction of fluid intake may lead to prolonged fluid retention and/or hyponatremia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, and in severe cases, convulsions). 6

Hyponatremia

NOCDURNA is a potent antidiuretic that may lead to prolonged fluid retention and/or hyponatremia, especially during the initial days of treatment, in elderly patients and patients with serum sodium levels in the low range. Unless properly diagnosed and treated, hyponatremia can be life-threatening. One of the phase III studies (CS29) indicated that during treatment with NOCDURNA, 3.1% and 4.2% of hyponatremia cases were observed in female and male subjects respectively. Therefore, serum sodium should be in the normal range before starting treatment and overall fluid restriction is warranted in all patients. 35Desmopressin treatment should be discontinued if serum sodium level falls below 125mmol/L.

Men aged 65 years and older on NOCDURNA 50 µg should have their serum sodium monitored within 4-8 days after initiation and at one month of treatment.35 [See Dosage and Administration]

Patients receiving NOCDURNA therapy may potentially develop symptomatic hyponatremia and experience the following signs or symptoms: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite, irritability, muscle weakness, muscle spasms or cramps, and abnormal mental status such as hallucinations, decreased consciousness, and confusion. Severe symptoms may include one or a combination of the following: seizure, coma and/or respiratory arrest. However, patients with serum sodium concentration below normal range can be asymptomatic. 35

Acute Illnesses

Treatment with desmopressin should be interrupted during acute intercurrent illnesses characterized by fluid and/or electrolyte imbalance (such as systemic infections, fever, and diarrhea).

Drugs that Potentiate Inappropriate Antidiuretic Hormone Secretion

Drugs that are known to induce syndrome of inappropriate antidiuretic hormone secretion may cause an additive antidiuretic effect leading to an increased risk of fluid retention/hyponatremia.

Cardiovascular

The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease because of possible tachycardia and changes in blood pressure.

Genitourinary

Bladder Dysfunction and Outlet Obstruction

Severe bladder dysfunction (i.e., neurological bladder dysfunction), outlet obstruction, low bladder capacity [such as overactive bladder (OAB) and benign prostate hyperplasia (BPH)], urological malignancies and gynecological abnormalities should be considered before starting treatment.

Renal

Desmopressin is mainly excreted in the urine. A pharmacokinetic study conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) receiving single-dose desmopressin acetate (2 µg) injection demonstrated a difference in desmopressin terminal half-life. Terminal half-life significantly increased from 3 hours in healthy volunteers to 9 hours in patients with severe renal impairment. 8

Desmopressin is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50 mL/min). 8 [See Contraindications]

Respiratory

Desmopressin acetate should be used with caution in patients with cystic fibrosis because these patients are prone to developing hyponatremia.

Other Conditions

Uncontrolled diabetes mellitus, uncontrolled hypertension, obstructive sleep apnea, hepatic and biliary disease.

Special Populations

Pregnant Women

No controlled studies in pregnant women have been carried out. However, as with all medication used during pregnancy, the physician should weigh possible therapeutic advantages against potential risks in each case.

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus 22 as well as data on exposed pregnancies in women with bleeding complications (n = 216) 38 indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus or newborn child.To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Nevertheless, caution should be exercised when prescribing to pregnant women. [See Toxicology]

Nursing Women

There have been no controlled studies in nursing mothers. Results from analysis of milk from nursing mothers receiving high doses of desmopressin (300 μg intranasal), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.44

Pediatrics

Although the efficacy and safety of desmopressin acetate in pediatrics Primary Nocturnal Enuresis (PNE) have been demonstrated with other desmopressin acetate formulations32 NOCDURNA doses of 25 µg and 50 µg have not been studied in this population.

Geriatrics

Clinical studies of desmopressin in the elderly at higher doses and with different dosage forms have shown an increased risk of hyponatremia with age and declining creatinine clearance. Desmopressin acetate is known to be excreted by the kidney, and the risk of adverse reactions to desmopressin may be greater in patients with impaired renal function. Desmopressin is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50 mL/min). 33 [See Clinical Pharmacology and Contraindications]

Monitoring and Laboratory Tests

Prior to treatment with NOCDURNA, all patients should have serum sodium within the normal range.

Men 65 years of age and older

For men 65 years and older, additional serum sodium monitoring is warranted within 4-8 days after initiation and at one month of treatment NOCDURNA should be discontinued if serum sodium falls below normal range. 3, 4, 5 [See Contraindications and Warnings and Precautions]

Adverse Reactions

Adverse Drug Reaction Overview

The safety analysis is derived from the following Phase 3 studies: CS29, CS31 and CS41.

Clinical trials CS29 and CS41 were placebo controlled, whereas CS31 and CS41 part II were open label extension trials of CS29 and CS41 part I respectively.

In CS29 (evaluating NOCDURNA 10, 25, 50, 100 µg and placebo in males and females), the most common ADR for NOCDURNA by MedDRA preferred term was dry mouth (26.7%). It should be noted that in this study subjects were specifically prompted about dry mouth; furthermore, the incidence of dry mouth was rather similar in the desmopressin NOCDURNA (24%) and placebo (25%) treatment groups. 3

In CS41 Part I (evaluating NOCDURNA 50, 75 µg and placebo in males), the most common ADR overall by MedDRA preferred term was dry mouth (3.1%),headache (2.9%) and hyponatremia (2.1%).5

Clinical Trial Adverse Drug Reactions

CS29 and CS31

CS29 was conducted in 2 parts. Part I was a double-blind, placebo-controlled, multi-center, randomized, parallel-group study investigating the efficacy and safety of 4 doses of NOCDURNA (10, 25, 50, and 100 µg). Subjects on active drug continued into CS29 Part II for 1 to 6 months and those on placebo were blindly randomized to an active dose. Subjects enrolled in CS29 Part II were eligible for study CS31, a long-term, open-label efficacy and safety extension. In CS31, subjects on the 10 µg dose were re-randomized to 25, 50 or 100 µg. 3, 4

A total of 778 subjects (639 CS29 Part 1; 139 re-randomized placebo) with nocturia were exposed to NOCDURNA in these Phase 3 clinical trials. A total of 367 subjects were treated for at least 1 year, of which 97 subjects were on the highest dose of 100 µg. 3

A summary of treatment-emergent adverse events reported by >1.0% of subjects in the NOCDURNA 25 or 50 µg during Part I of CS29 is presented by descending order of overall frequency in Table 1. 3

Table 1. Treatment-Emergent Adverse Events Considered Possibly or Probably Related to Study Drug Reported by at Least 1.0% of Subjects (CS29 Part I)
  Females Males
MedDRA Preferred Term Placebo
(N=67)
n (%)
NOCDURNA 25 μg
(N=96)
n (%)
Placebo
(N=93)
n (%)
NOCDURNA 50 μg
(N=118)
n (%)
Any ADR 21 (31.3%) 40 (42.6%) 26 (28.0%) 44 (37.3%)
Dry mouth 17 (25.4%) 23 (24.0%) 21 (22.6%) 28 (23.7%)
Headache 2 (3.0%) 1 (1.0%) 2 (2.2%) 6(5.1%)
Hyponatraemia 0 3 (3.1%) 1 (1.1%) 5 (4.2%)
Dizziness 0 2 (2.1%) 0 4 (3.4%)
Nausea 0 3 (3.1%) 0 2 (1.7%)
Blood sodium decreased 1 (1.5%) 2 (2.1%) 0 4 (3.4%)
Diarrhoea 0 1 (1.0%) 1 (1.1%) 3 (2.5%)
Fatigue 0 0 1 (1.1%) 2 (1.7%)
Micturation urgency 0 2 (2.1%) 1 (1.1%) 0
Muscle spasm 0 2 (2.1%) 0 0

ADR = (adverse drug reaction) AE assessed by the Investigator as possibly/probably related to study drug

As shown in Table 2, treatment-emergent adverse events reported by >5.0% of subjects in the NOCDURNA 25 and 50 µg groups were dry mouth, diarrhea and headache. It should be noted that subjects were specifically queried about dry mouth; therefore, it was not unexpected that the incidence of dry mouth was generally similar in the NOCDURNA (31.3-33.3%) and placebo (23.7-32.8.0%) treatment groups. In contrast, during CS31 open-label extension study and CS41, subjects were not queried about dry mouth, and the reported incidence of dry mouth was about 3%. 3, 4

Table 2: Summary of Common (>5.0% of Subjects in Any Treatment Group) Treatment-Emergent Adverse Events (CS29 Part I)
  Females Males
System Organ Class
MedDRA Preferred Term
Placebo
(N=67)
n (%)
NOCDURNA 25 μg
(N=67)
n (%)
Placebo
(N=93)
n (%)
NOCDURNA 50 μg
(N=78)
n (%)
Gastrointestinal Disorders
Dry mouth 22 (32.8%) 21 (31.3%) 22 (23.7%) 26 (33.3%)
Diarrhea 0 3 (4.5%) 2 (2.2%) 4 (5.1%)
Nervous System Disorders
Headache 4 (6.0%) 1 (1.5%) 5 (5.4%) 4 (5.1%)

CS41

The safety of NOCDURNA in males was further investigated in a multicenter Phase 3 trial (CS41) consisting of 2 parts. Part I was a double-blind, randomized, placebo-controlled, parallel-group 3-month period designed to evaluate the clinical effect and safety of two doses of NOCDURNA for treatment of nocturia in adult males. A total of 395 subjects were randomized to 1 of 3 treatment groups (NOCDURNA 75 µg, NOCDURNA 50 µg, or placebo). After the first 3 months of treatment, subjects were allowed to switch to desmopressin 100 µg for a period of 1 month for further evaluation of safety in an open-label extension phase (Part II).5

CS41 Part I

A summary of treatment-emergent adverse drug reactions reported by >1.0% of subjects in the NOCDURNA 50 µg during Part I of CS41 is presented in Table 3. 5

Table 3: Treatment-Emergent Adverse Drug Reactions Reported for at Least 1% of Subjects in Any Treatment Group (Safety Analysis Set) – CS41 Part I
System Organ Class
MedDRA Preferred Term
Placebo
(N=143)
n (%)
NOCDURNA 50 μg
(N=119)
n (%)
Gastrointestinal Disorders
Dry mouth 7 (5%) 4 (3%)
Injury, Poisoning and Procedural Complications
Medication error 1 (<1%) 2 (2%)
Metabolism and Nutrition Disorders
Hyponatremia 0 3 (3%)
Nervous System Disorders
Headache 2 (1%) 4 (3%)
Dizziness 1 (<1%) 2 (2%)
Psychiatric Disorders
Abnormal dreams 0 2 (2%)

ADR = adverse drug reaction; an AE assessed by the Investigator as possibly/probably related to study drug

CS41 Part II

In CS41 part II patients were treated, in an open-label, to a much higher dose of 100 µg for a month in order to collect safety data at a higher dose. 5 No safety concerns and unexpected adverse drug reaction were reported. In CS41 part II, 1% subjects experienced hyponatraemia and diarrhea.

Long Term Exposure Safety Data

In CS29 Part II and CS31 subjects were exposed for up to two years at doses ranging from 25 µg to 100 µg.3,4. No safety concerns and unexpected adverse drug reaction were reported even at high doses (upto 100 µg). Dry mouth with an incidence of 3% remained the most frequent reported adverse event in the CS31. The other AEs had an incidence of <1%.

The long-term studies CS29 Part II and CS31confirmed that the NOCDURNA is a safe and well tolerated drug. 3,4

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Values Over Time

Minor mean changes from baseline to the last visit were observed in hematology, clinical chemistry and urinalysis in all treatment groups. None of the mean changes or mean percentage changes was considered to be clinically meaningful. 3, 4, 5

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post approval use of desmopressin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Desmopressin has been marketed worldwide since 1972 in several formulations, including intranasal, intravenous, and oral formulations for the treatment of diabetes insipidus and primary nocturnal enuresis. The other oral formulations are available at much higher doses than NOCDURNA. The most frequent reported adverse reactions on alternate oral formulations are as follows:

Electrolytes

Hyponatremia/decreases serum sodium

Gastrointestinal Disorders

Abdominal pain, vomiting, nausea

Nervous System

Headache, convulsions

Skin

Rash/urticaria

Sensitivity/Resistance

Lack of effect

Drug Interactions

Drug-Drug Interactions

Drugs that potentiate inappropriate anti-diuretic hormone secretion

Drugs that are known to induce inappropriate antidiuretic hormone secretion may cause an additive antidiuretic effect leading to an increased risk of inappropriate fluid retention/hyponatremia.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs may induce additional fluid retention/hyponatremia.

Hepatic Metabolism

It is unlikely that NOCDURNA will interact with drugs affecting hepatic metabolism (i.e. CYP 450 system), since desmopressin has been shown not to undergo significant liver metabolism during in vitro studies with human microsomes. 33 However, formal in vivo interaction studies have not been performed with NOCDURNA.

Drug-Food Interactions

No food interaction study was conducted with the NODCURNA formulation. It has been previously shown that intake of a standardized meal with desmopressin tablets has no effect on pharmacodynamic parameters (urine production and osmolality) despite some pharmacokinetic influence. The fact that sublingually administered NOCDURNA is absorbed initially in the oral mucosa, pharynx and oesophagus implies that it is even less likely that food intake will influence its absorption. 34 Furthermore, the intended bedtime administration of desmopressin is not typically the time of meal. Therefore, it is very unlikely that any clinically significant drug-food interaction exists with sublingual administration of NOCDURNA.

Dosage and Administration

Dosing Considerations

Fluid Restriction

Patients should be instructed to limit fluid intake to a minimum from 1 hour before until 8 hours after administration. Overall fluid restriction should be observed. Treatment without concomitant reduction of fluid intake may lead to fluid retention and/or hyponatremia with or without accompanying warning signs and symptoms.

Serum Sodium Monitoring

All patients should receive a baseline serum sodium test to confirm serum sodium is in normal range before treatment initiation. Remind patients over age 65 of the importance of adhering to the recommended sodium monitoring schedule. NOCDURNA should be discontinued if serum sodium is below normal range. 3, 4, 5

Hyponatremia

Patients should be informed about the following signs and symptoms associated with hyponatremia: headache, nausea/vomiting, weight gain, restlessness, fatigue, tiredness, disorientation, muscle weakness, muscle spasms or cramps, and confusion. Desmopressin acetate treatment should be discontinued if serum sodium levels falls below 125mmol/L.

Acute Illness or Concomitant Medications

Patients should be informed that treatment should be stopped during acute intercurrent illnesses that can lead to fluid and/or electrolyte imbalance such as systemic infections (flu), fever, or chronic diarrhea. Caution patients about concomitant medications that can lead to hyponatremia.

Recommended Dose and Dosage Adjustment

Women 25 μg daily at bedtime administered sublingually
Men < 65 50 μg daily at bedtime administered sublingually
Men ≥ 65 50 μg daily at bedtime administered sublingually with additional serum sodium monitoring o within 4-8 days after initiation and at one month of treatment

Missed Dose

If the patient misses a dose, the patient should be advised not to take the missed dose.

Administration

NOCDURNA is an orally disintegrating tablet taken sublingually.

Restricted fluid intake is recommended a few hours before administration, especially one hour before, and until the next morning (at least 8 hours) after administration.

Overdosage

Recommended doses of NOCDURNA should not be exceeded. Overdose leads to a prolonged duration of action with an increased risk of prolonged fluid retention and hyponatremia. Signs of overdose may include nausea, headache, drowsiness, confusion, and rapid weight gain due to fluid retention. [See Warnings and Precautions]

In case of overdose, therapy should be discontinued. There is no known specific antidote for desmopressin. Symptomatic patients should be observed and cases of hyponatremia should be treated appropriately.

Action and Clinical Pharmacology

Mechanism of Action

The antidiuretic effects of desmopressin are mediated by stimulation of V2-receptors thereby increasing water re-absorption in the kidney, and hence reducing urine production. Stimulation of V2-receptors may also cause an increase in the levels of blood coagulation factors, factor VIII and von Willebrand factor, but this effect occurs at higher doses of desmopressin than those required for inducing antidiuresis. 42

Pharmacodynamics

NOCDURNA contains desmopressin, a structural analogue of the natural pituitary hormone arginine vasopressin. The difference lies in the desamination of cysteine and substitution of L-arginine by D-arginine. This results in a considerably longer duration of action and a complete lack of pressor effect in the dosages clinically used.

In study CS29, the weight-corrected NOCDURNA dose that induced 50% maximum achievable drug effect on nocturnal urine volume differed significantly between females and males. The estimated exposure for males was 2.7 fold (95% CI: 1.3-8.1) higher than the value for females to obtain an identical dynamic effect, corresponding to higher desmopressin sensitivity among females. 3

Gender and age appear to have a dose-dependent effect on hyponatremia. The incidences of hyponatremia rise with increasing dose and with increasing age.

Pharmacokinetics

Absorption

The overall mean absolute bioavailability of desmopressin orally disintegrating tablets administered sublingually from earlier dose-ranging studies of doses of 200, 400 and 800 is 0.25% with a 95% confidence interval of 0.21 – 0.31%. 9 Desmopressin exhibits a moderate-to-high variability in bioavailability, both within and between subjects. 10 Desmopressin orally disintegrating tablets show dose linearity regarding AUC and Cmax in the range of 60 to 240.7 However, the bioavailability of doses below 60 has not been evaluated.

Distribution

The distribution volume of desmopressin after intravenous administration is 33 L.

Metabolism

Desmopressin did not show any effect on any of the nine CYP 450 subtypes. In vivo drug-drug interactions based on activation or inhibition of CYP P450 are therefore very unlikely. -20

Excretion

Desmopressin is mainly excreted in the urine. After intravenous injection, 52% of the dose could be recovered in the urine within 24 hours as unchanged desmopressin. The geometric mean terminal half-life is 2.8 (CV = 24%) hours. 8

Terminal half-life significantly increases in patients with severe renal impairment (see Warnings and Precautions). 8

Special Populations and Conditions

Geriatric

The pharmacokinetics of desmopressin acetate in the nocturia population does not differ from those in healthy subjects. A pooled data analysis demonstrated no significant correlation between age and pharmacokinetics, and no gender-related difference in AUCinf could be found. In very elderly patients, a decrease in the renal elimination of desmopressin could be expected. 34

Use of NOCDURNA requires careful fluid restriction to prevent possible prolonged fluid retention and subsequent hyponatremia. Fluid restriction should be discussed with the patient [See Warnings and Precautions and Gender and Age Effects].

Gender and Age Effect

A two part study involving single oral dosage with 400 µg desmopressin (Part A) and a randomized, placebo-controlled, 2 way crossover evaluation involving treatment with 400 µg desmopressin or placebo for 3 consecutive nights with a 7-14 day washout period showed that the pharmacokinetic parameters in elderly (>65 years) nocturic subjects did not differ from those in healthy subjects.

A gender-related difference in the extent but not in the rate of absorption was observed. 11 A subsequent pooled data analysis of several clinical studies did not confirm this difference. The linear relationship between plasma desmopressin concentrations at 2-3 hours post-dose and AUCinf in these subjects suggests that plasma desmopressin concentrations at 2 (or 3) hours can be used as an accurate predictor of AUCinf in elderly subjects with nocturia.

The low level of absorption of desmopressin following oral administration means that a high level of variability may be expected. A study evaluating intra and inter individual variation in pharmacokinetics of desmopressin after three administration in an oral lyophilisate to healthy non-smoking volunteers showed no gender differences in intra and inter-subject variability in AUC-∞ AUC, or Cmax. After multiple (3) doses of desmopressin Melt at 200 µg, the PK parameters did not differ statistically significantly after each dose. 10

The large Phase 3 study with desmopressin Melt CS029 is the first to show a clear gender difference in the effect of desmopressin on nocturnal urine volume. A further analysis was performed on the data obtained from nocturia patients in this study, together with single-dose pharmacokinetic data from healthy subjects in a three-period crossover study comparing the exposure of oral lyophilisate containing 60, 120 and 240 µg desmopressin in 24 non-smoking subjects 6 and an open-labeled, randomized, two period crossover study investigating the relative bioavailability of two single doses of the currently marketed MINIRIN Tablets (2 x 200 µg ) and a single dose of desmopressin administered as a new orodispersible tablet (240 µg). 6

Mean desmopressin concentration profiles are shown by dose and gender in Figure 1. Age and gender were found not to be statistically significant while weight was significant with respect to log(Cmax) and borderline significant with respect to log(AUC). Gender differences in drug exposure were not statistically significant when adjusting for body weight.

The incidence of hyponatremia increased with increasing doses of NOCDURNA . In CS29 and CS31, hyponatremia referred to serum sodium below 130 mmol/L, and patients continued treatment unless serum sodium fell below 125 mmol/L. No female subject who received NOCDURNA 25 µg had serum sodium levels below 125 mmol/L and none of these subjects discontinued therapy due to hyponatremia. No males under 65 years of age had serum sodium levels below 125 mmol/L. During CS29, among males ≥65 years of age, 2 who received NOCDURNA 100 µg and 1 who received 50 µg NOCDURNA had serum sodium levels fall below 125 mmol/L; all 3 subjects were discontinued, 2 due to “hyponatremia” and 1 due to “blood sodium decreased”. Minimum post baseline serum sodium levels by age groups in females treated with NOCDURNA 25 µg and males treated with NOCDURNA 50 µg is presented by age group for CS29 and CS31 in Table 4. 3, 4

Table 4: Minimum Post-Baseline Serum Sodium Levels by Age Group in Females Treated with NOCDURNA 25 μg and Males treated with NOCDURNA 50 μg (Overall Safety population CS29+CS31)
Serum Sodium
(mmol/L)
NOCDURNA 25 μg
for Females
NOCDURNA 50 μg
for Males
<65 years
(N=59)
≥65 years
(N=37)
<65 years
(N= 53)
≥65 years
(N=65)
Observed N* 59 (100%) 37 (100%) 52 (98.1%) 65 (100%)
≥135 48 (81.4%) 27 (73.0%) 37 (69.8%) 33 (50.8%)
         
130-134 10 (16.9%) 6 (16.2%) 15 (28.3%) 21 (32.3%)
125-129 1 (1.7%) 4 (10.8%) 0 10 (15.4%)
<125 0 0 0 1( 1.5%)

* Number of subjects with data

CS41 Part I

During CS41 Part I, 4 males who received NOCDURNA 75 µg and 2 who received NOCDURNA 50 µg had serum sodium less than or equal to 125 mmol/L; all 6 subjects were discontinued, 5 due to “hyponatremia” and 1 due to “dizziness”. No males <65 years of age who received NOCDURNA 50 µg and one male who received NOCDURNA 75 µg had serum sodium ≤125 mmol/L. Minimum post baseline serum sodium levels in males who received NOCDURNA 50 µg is presented by age group for CS41 Part I in Table 5. 5

Table 5: Minimum Post-Baseline Serum Sodium Levels by Age Group in Males Treated with NOCDURNA 50 μg (CS41 Part I)
Serum Sodium (mmol/L) NOCDURNA 50 μg
(N=119)
Age <65
(N=62)
Age ≥65
(N=57)
≥ 135 60 (97%) 48 (84%)
130-134 2 (3%) 7 (12%)
126-129 0 0
≤ 125 0 2 (4%)

Due to the rare cases of serum sodium levels ≤125 mmol/L in males ≥65 years who received NOCDURNA 50 µg in the Phase 3 trials, serum monitoring is warranted in this group.3, 4, 5

Storage and Stability

Store at 25°C; excursions permitted to 15 – 30°C. Keep in original package to protect from moisture and light. Use immediately upon opening individual tablet blister.

Dosage Forms, Composition and Packaging

NOCDURNA is an orally disintegrating tablet containing desmopressin acetate equivalent to 25 or 50 µg of desmopressin as free base. The inactive ingredients are gelatin, mannitol, and anhydrous citric acid.

NOCDURNA 25 µg is a white, round, orally disintegrating tablet with “25” on one side.

NOCDURNA 50 µg is a white, round, orally disintegrating tablet with “50” on one side.

NOCDURNA Initiation Pack for Men ≥ 65 Years of Age is packaged as a unit dose blister (4 units per box).

NOCDURNA is packaged as a unit dose blister, 10 units per blister pack, 3 blister packs (30 unit doses) per box.

Special Handling Instructions

No special requirement.