DDAVP Melt for Primary Nocturnal Enuresis: Indications, Dosage, Precautions, Adverse Effects
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DDAVP Melt for Primary Nocturnal Enuresis - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Primary Nocturnal Enuresis
Class: Antidiuretic hormones
Form: Tablets
Ingredients: desmopressin, gelatin , mannitol, citric acid

Desmopressin Acetate Oral Disintegrating Tablets

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Sublingual Oral Disintegrating
Tablets
60 μg, 120 μg, 240 μg
Gelatin, Mannitol, Citric Acid
For a complete listing see Dosage Forms,
Composition and Packaging section.

Indications and Clinical Use

DDAVP MELT is indicated for

  • treatment of Central Diabetes Insipidus
  • treatment of Primary Nocturnal Enuresis

Central Diabetes Insipidus

DDAVP MELT (60 μg, 120 μg and 240 μg desmopressin) is indicated for the management of vasopressin sensitive central diabetes insipidus, and for the control of temporary polyuria and polydipsia following head trauma, hypophysectomy or surgery in the pituitary region.

Primary Nocturnal Enuresis

DDAVP MELT (60 μg, 120 μg and 240 μg desmopressin) is indicated in the management of nocturnal enuresis in patients 5 years of age and older who have normal ability to concentrate urine. DDAVP MELT should be used in conjunction with non-medicinal therapy, such as motivational counselling and bladder exercises.

Contraindications

  • Hypersensitivity to desmopressin or any of the tablet constituents.
  • Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia
  • Any condition associated with impaired water excretion, such as:
    • Hyponatremia
    • Severe liver disease
    • Nephrosis
    • Cardiac insufficiency
    • Chronic renal insufficiency
    • Congestive heart failure
    • Habitual or psychogenic polydypsia
  • Any medical conditions which lead to sodium losing states such as:
    • Vomiting
    • Diarrhoea
    • Bulimia
    • Anorexia nervosa
    • Adrenocortical insufficiency
    • Salt losing nephropathies

Warnings and Precautions

General

In general, by adequate treatment with DDAVP MELT, thirst is automatically reduced. However, there is potential risk of water intoxication if, during treatment, excessive liquid is consumed. Fluid intake should be adjusted to reduce the possibility of water intoxication and hyponatremia especially in the very young and elderly patients (See DOSAGE AND ADMINISTRATION). Particular attention should be paid to the risk of extreme decrease in plasma osmolality and resulting seizures in young children.

Treatment with desmopressin should be interrupted during acute inter-current illnesses characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, and gastroenteritis).

In patients with Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) or with high intra-cranial pressure, it is necessary that extra care be exercised with liquid intake.

Desmopressin should not be administered to dehydrated patients until water balance has been adequately restored.

Desmopressin is not effective in controlling polyuria caused by renal disease, nephrogenic diabetes insipidus, psychogenic diabetes insipidus, hypokalemia or hypercalcemia.

Cardiovascular

Desmopressin acetate can occasionally produce a slight elevation of blood pressure, which disappears with a reduction in dosage. 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

Severe bladder dysfunction and outlet obstruction should be considered before starting treatment.

Respiratory

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

Special Populations

Pregnant Women

No controlled studies in pregnant women have been carried out. 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 indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus or newborn child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

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.

Paediatrics

Use of desmopressin in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water retention due to over ingestion of fluids.

Geriatric

Geriatric patients should be closely observed for possible hyponatremia and water retention due to over ingestion of fluids.

Monitoring and Laboratory Tests

Central Diabetes Insipidus

Continued response to desmopressin acetate is monitored by urine volume and osmolality.

Adverse Reactions

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Five pharmacokinetic and pharmacodynamic (PK/PD) studies were conducted. Four studies enrolled healthy volunteers and one study was conducted in children with primary nocturnal enuresis (PNE). Comparison of the methodologies of the five studies is presented in Table 1.

Table 1 Study Design of the Pharmacokinetic and Pharmacodynamic Studies
Study No. Type of Study Formulation Dosage Number, Age Sex of
Patients
Study 1 Single-center, open-label,
randomized, balanced, 4-way
cross-over study
DDAVP MELT
200, 400, 800 μg sublingually
Desmopressin 2 μg IV
24 healthy male volunteers
(18-55 years)
Study 2 Open-label, randomized, 2-
period cross-over study
DDAVP MELT
240 μg sublingually
DDAVP Tablets
2x 200 μg orally
14 male and 14 female
healthy volunteers (18–55
years)
Study 3 Single-center, open- label,
randomized, balanced, 6-
sequence, 3-period cross-over
study
DDAVP MELT
60, 120, 240 μg sublingually
15 male and 10 female
healthy volunteers (18–55
years)
Study 4 Single-center, open-label,
replicated, randomized, 2-
sequence, 4-period, , crossover
study
DDAVP MELT
240 μg sublingually
DDAVP tablets
2x 200 μg orally
32 male and 33 female
healthy volunteers (18- 55
years)
Study 5 Double-blind, randomized,
placebo-controlled, parallel
group study
DDAVP MELT
30, 60, 120, 240, 360, 480 μg
sublingually
Placebo sublingually
64 males and 20 females
with PNE (6-12 years)

72 DDAVP MELT
12 Placebo

A total of 214 subjects were treated with DDAVP MELT in the PK/PD studies. Of these, 172 were also administered DDAVP tablets: 28 in Study 2, 65 in Study 4 and 79 patients in the open-label part of Study 5. Twenty-four (24) subjects were also administered desmopressin intravenously. One hundred and forty two subjects were healthy volunteers and 72 were PNE children.

Sixty-one subjects (29%) of the 214 subjects exposed to desmopressin from DDAVP MELT reported 96 adverse events, all of which were mild to moderate in intensity.

Sixty-five subjects (38%) of the 172 subjects exposed to desmopressin from DDAVP Tablets reported 82 adverse events, all of which were mild to moderate in intensity.

The most frequently reported adverse events (>3%) in subjects in the PK/PD studies are presented by body system in Table 2 for the Safety Population (received at least one dose of study medication) of each study.

Table 2: Number of Subjects Reporting AEs in the PK/PD Studies
(Frequency >3%).
Adverse Event DDAVP MELT DDAVP Tablets
  No. % No. %
No. subjects exposed 214 172
No. subjects with adverse events 61 29 65 38
No. adverse events 96 82
Nervous System        
    Headache 26 12.1 27 15.7
Gastrointestinal        
    Nausea 7 3.3 5 2.9

The most commonly reported adverse events in the PK/PD studies were headache and nausea. Overall, numbers of adverse events reported were low, and were generally reported with similar frequency between the DDAVP MELT and DDAVP Tablets, desmopressin i.v. and/or placebo.

Headache, nausea and vomiting are known adverse drug reactions to desmopressin, and may be signs and symptoms of water retention and hyponatremia which are recognized sequelae of unrestricted fluid intake during desmopressin administration.

Treatment without concomitant reduction of fluid intake may lead to water retention/ hyponatremia with or without accompanying warning signs or symptoms (headache, nausea/ vomiting, weight gain and in severe cases convulsions).

Serum SGOT levels were elevated in 4/16 patients, 6 months after commencing oral desmopressin acetate therapy (200 to 600 µg/day). Two of these patients had exhibited baseline levels of SGOT that were above the normal range and all four patients had normal SGOT levels on repeat test at 9 months, even though desmopressin acetate administration continued. The possibility that desmopressin acetate has an adverse effect on serum enzymes is therefore remote.

Primary nocturnal enuresis diabetes insipidus

Common (>1/100) General: headache
Gastrointestinal: Abdominal pain, nausea
Very rare (< 1/10,000) Hyponatremia

Post Marketing Experience (DDAVP Tablet):

Very rare cases of emotional disturbances in children have been reported.

Isolated cases of allergic skin reactions and more severe general allergic reactions have been reported.

Drug Interactions

Drug-Drug Interactions

It is unlikely that desmopressin will interact with drugs affecting hepatic metabolism, since desmopressin has been shown not to undergo significant liver metabolism in in vitro studies with human microsomes.

Potential Drug-Drug Interactions
Proper name Clinical comment
Clofibrate
Chlorpropamide
Carbamazapine
May potentiate the antidiuretic activity of
desmopressin
Demeclocycline
Lithium
Norepinephrine
May decrease the antidiuretic activity of
desopressin
Other Pressor agents Although the pressor activity of desmopressin acetate is very low compared with the antidiuretic activity, use of large doses of desmopressin with other pressor agents should be done only with careful patient monitoring.
Drugs known to induce SIADH, e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine and carbamazepine May cause an additive antidiuretic effect leading to an increased risk of water intoxication.
Non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors May induce water retention and hyponatremia
Proper name Clinical comment
Opiates, such as loperamide May result in a 3-fold increase of plasma desmopressin concentrations, which may lead to water retention and hyponatremia. Although not investigated, other drugs slowing intestinal transport might have the same effect

Drug-Food Interactions

It has been previously shown that intake of a standardized meal with DDAVP MELT has no effect on pharmacodynamic parameters (urine production and osmolality) despite some pharmacokinetic influence.

Dosage and Administration

Dosing Considerations

Central Diabetes Insipidus

To institute desmopressin therapy, patients should be withdrawn from previous medication and allowed to establish a baseline polyuria and polydipsia. The stable polyuria is used as a baseline to determine the magnitude and duration of the response to medication.

Primary Nocturnal Enuresis

A restricted fluid intake is recommended a few hours before administration, especially one hour before bedtime. In the event that the child wakes up during the night, liquid intake should be restricted.

Recommended Dose and Dosage Adjustment

Central Diabetes Insipidus

The recommended initial dose in adults and children is 60 μg three times daily administered sublingually. This dosage regimen should then be adjusted in accordance with the patient’s response. The recommended daily dose range is 120- 720 µg divided equally into 2 or 3 doses a day.

The lowest effective dose should be used and the effective dosage, as determined by urine volume and osmolality and in some cases, plasma osmolality, should be assessed periodically.

In children, the evening dose is usually 2x higher than the morning and midday dose to ensure sufficient antidiuresis during sleep. This is generally not a requirement for adult patients, presumably because adults sleep for shorter periods of time.

Primary Nocturnal Enuresis

The dosage of DDAVP MELT must be determined for each individual patient and adjusted according to response as follows:

  • The recommended initial dose is 120 μg 1 hour before bedtime.
  • If the patient experiences a wet night after three days on an initial dose of 120 μg increase the dose by 120 μg.
  • The dose may be titrated up to 360 μg to achieve the desired response.

The physician should be consulted if enuresis persists at the maximal dose of 360 µg.
DDAVP MELT is intended for treatment periods of up to three months. The need for continued treatment should be reassessed by means of period of at least one week without DDAVP MELT. If the patient is still wetting the bed, then reintroduce DDAVP MELT at the same dosage prior to discontinuing treatment for another three months and reassess.

Missed Dose

Central Diabetes Insipidus

If the patient misses a dose, the patient should be advised to take the missed dose as soon as possible. However if it is almost time for the next dose, the patient should be advised to skip the missed dose, to return to the regular dosing schedule and to not double dose.

Primary Nocturnal Enuresis

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

Overdosage

Overdosage will increase the risk of fluid retention and symptoms which include headaches, abdominal cramps, nausea, and facial flushing. Dosage and frequency of administration should be reduced, or the drug withdrawn, according to severity of the condition.

If hyponatremia occurs following medication or excessive fluid intake, treatment should be discontinued and fluid intake restricted until serum sodium is normalized. In most cases this is sufficient. In cases with severe symptoms, (e.g., those associated with the central nervous system (CNS) such as unconsciousness), admission to hospital and a slow normalization of serum sodium is required to avoid additional complications.

For management of a suspected drug overdose, contact your regional Poison Control Centre

Action and Clinical Pharmacology

Mechanism of Action

Desmopressin is a synthetic structural analogue of the antidiuretic hormone, arginine vasopressin, which alters the permeability of the renal tubule to increase resorption of water. The increase in the permeability of both the distal tubules and collecting ducts appears to be mediated by a stimulation of the adenylcyclase activity in the renal tubules.

The synthetic analogue exhibits a greater antidiuretic potency, as well as a longer half-life and duration of action, as compared to vasopressin.

Pharmacodynamics

Clinical studies have demonstrated that perioral administration of desmopressin is active in eliciting an antidiuretic effect in humans, be they normal subjects, or adults and children suffering from central diabetes insipidus (CDI) of various etiologies, or from nocturnal enuresis.

The only recognized pharmacodynamic actions detected after orally administered desmopressin are reduction in urine flow and increase in urine osmolality. A number of studies have examined dose, and concentration-effect relationships of desmopressin with respect to its antidiuretic effects. Some studies show clear dose- and concentration-effect relationships, while others do not.

Pharmacokinetics

Human pharmacokinetic studies have been conducted on desmopressin using the oral and intravenous formulations.

Absorption:

Due to the rapid disintegration of DDAVP MELT, desmopressin is immediately available for absorption via the membranes of the mouth, followed by the pharynx, the oesophagus and the stomach.

Pharmacokinetic Parameter (1x240 μg DDAVP MELT)
1 x 240 μg DDAVP MELT
Parameter Test*
DDAVP MELT
AUCT
(pg.h/mL)
73.2
85.7 (61.9 %)
AUCI
(pg.h/mL)
79.0
91.5 (59.0%)
Cmax
(pg/mL)
18.0
21.1 (59.5%)
§Tmax (h) 1.5
(0.5-4.0)
§T1/2(h) 3.19
(1.51-5.25)

* DDAVP MELT Tablets (Ferring Inc, Canada)
Expressed as the median and (range)

It is known that the efficacy of desmopressin is not influenced by Cmax, but by total exposure over time, i.e. AUC.

Distribution

The distribution of desmopressin has not been fully characterized. It is not known if desmopressin crosses the placenta, but small quantities have been shown to be distributed into milk.

Metabolism

The metabolic fate of desmopressin is unknown. Unlike vasopressin, desmopressin apparently is more resistant to metabolism by aminopeptidases or other peptidases.

In vitro human liver microsome metabolism of desmopressin has shown that no significant amount is metabolised in the liver, and thus human liver metabolism in vivo is not likely to occur. Furthermore, no in vitro inhibition on any of the nine human Cytochrome P450 enzyme subtypes could be demonstrated.

Excretion

Urinary clearance in 6 hydrated volunteers administered DDAVP oral tablets was calculated to be 0.514 mL/min/kg body weight and the amount of peptide excreted in the urine during the 6-

hour observation period constituted 16.4% of the amount absorbed from the intestine over the same period of time.

Special Populations

Pediatrics

The pharmacokinetic parameters (AUC and Cmax) obtained in children were comparable to those obtained in adults. However, for children with PNE, little is known about the actual plasma levels of desmopressin required to obtain a maximal antidiuretic effect for a relevant time period.

Storage and Stability

DDAVP MELT should be stored in the original package in a dry place at a temperature between 15º C to 25º C.

DDAVP MELT is stable for 48 months.

Dosage Forms, Composition and Packaging

Dosage Forms

DDAVP MELT

  • 60 μg is a white, round tablet marked with a drop shape figure on one side.
  • 120 μg is a white, round tablet marked with two drop shape figures on one side.
  • 240 μg is a white, round tablet marked with three drop shape figures on one side.

Composition

Medicinal ingredients: 60 μg, 120 μg or 240 μg desmopressin

Non medicinal ingredients: gelatin, mannitol and citric acid

Packaging

DDAVP MELT is packaged in a blister pack. Each blister pack contains 10 tablets in boxes of 10 and 30.