NOCDURNA Orally disintegrating tablet Ref.[27533] Active ingredients: Desmopressin

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.³⁵ Desmopressin 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 insipidus²² 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 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):

ADR = (adverse drug reaction) AE assessed by the Investigator as possibly/probably related to study drug
Cross-reference: [Table 14.6.3.2 ] ISS

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):

Cross reference: [14.7.3.2] CS31 CTR

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:

Dry mouth 7 (5%) 4 (3%)

ADR = adverse drug reaction; an AE assessed by the Investigator as possibly/probably related to study drug
Cross-reference: [Table 7.1.10] CS 41 CTR

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-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.