It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.

Ferring Ireland Limited

Ferring Ireland Limited

Summary of Product Characteristics last updated on medicines.ie: 26/5/2015

Desmotabs Melt 240 micrograms oral lyophilisate

1. NAME OF THE MEDICINAL PRODUCT

Desmotabs Melt 240 micrograms oral lyophilisate

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each unit contains 240 micrograms desmopressin (free base), present as desmopressin acetate.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral lyophilisate

White, round, oral lyophilisate marked with three drop shaped figures on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

1. For the diagnosis and treatment of cranial diabetes insipidus including post- hypophysectomy polyuria/polydipsia and for the treatment of primary nocturnal enuresis in patients (from 5 to 65 years of age) with normal ability to concentrate urine.

2. Desmotabs Melt is indicated for the symptomatic treatment of nocturia in adults up to 65 years only, associated with nocturnal polyuria, i.e. nocturnal urine production exceeding bladder capacity.

4.2 Posology and method of administration

General

Method of administration: Desmotabs Melt is placed under the tongue where it dissolves without the need for water.

Effect of food: Food intake may reduce the intensity and duration of the antidiuretic effect at low doses of desmopressin (see section 4.5).

In the event of signs or symptoms of water retention and /or hyponatraemia (headache, nausea/vomiting, weight gain, and, in severe cases, convulsions) treatment should be interrupted until the patient has fully recovered. When restarting treatment strict fluid restriction should be enforced (see section 4.4).

If adequate clinical effect is not achieved within 4 weeks following appropriate dose titration the medication should be discontinued.

Indication specific

Central Diabetes Insipidus:

Dosage is individual in diabetes insipidus but the total daily sublingual dose normally lies in the range of 120 micrograms to 720 micrograms. A suitable starting dose in adults and children is 60 micrograms three times daily administered sublingually. This dosage regimen should then be adjusted in accordance with the patient's response. For the majority of patients, the maintenance dose is 60 micrograms to 120 micrograms sublingually three times daily.

Primary Nocturnal Enuresis:

The recommended initial dose is 120 micrograms at bedtime, administered sublingually.

If this dose is not sufficiently effective, the dose may be increased up to 240 micrograms sublingually. Fluid restriction should be observed. Desmotabs Melt is intended for treatment periods of up to 3 months. The need for continued treatment should be reassessed by means of a period of at least one week without Desmotabs Melt.

Nocturia:

The recommended initial dose is 60 micrograms at bedtime, administered sublingually. If this dose is not sufficiently effective after one week, the dose may be increased up to 120 micrograms sublingually and subsequently 240 micrograms sublingually by weekly dose escalations. Fluid restriction should be observed.

In nocturia patients, a frequency/volume chart should be used to diagnose nocturnal polyuria for at least 2 days before starting treatment. A night-time urine production exceeding the functional bladder capacity or exceeding 1/3 of the 24 hour urine production is regarded as nocturnal polyuria.

Special Populations

Elderly:

The initiation of treatment in the elderly (patients over 65 years) is contraindicated in patients being treated for nocturia and primary nocturnal enuresis.

Dosage recommendation for elderly suffering from central diabetes insipidus is the same as for other age groups.

In the event of signs or symptoms of water retention and/or hyponatraemia (headache, nausea/vomiting, weight gain, and, in severe cases, convulsions) treatment should be interrupted until the patient has fully recovered. When restarting treatment strict fluid restriction should be enforced (see 4.4). If adequate clinical effect is not achieved within 4 weeks following appropriate dose titration the medication should be discontinued.

Renal Impairment

Desmotabs Melt is contraindicated in case of moderate and severe renal insufficiency (creatinine clearance below 50 ml/min) (see section 4.3).

Hepatic Impairment

In vitro human liver microsome metabolism studies of desmopressin have shown that no significant amount is metabolized in the liver by the cytochrome P450 system. Thus human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur. The effect of desmopressin on the pharmacokinetics of other drugs is likely to be minimal due to its lack of inhibition of the cytochrome P450 drug metabolizing system (see section 4.5).

Paediatric Population

Desmotabs Melt is indicated in Central Diabetes Insipidus and Primary Nocturnal Enuresis (see section 4.1 and indication specific information in 4.2 above). Dose recommendations are the same as in adults.

4.3 Contraindications

Desmotabs Melt is contraindicated in cases of:

- Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40ml/kg/24 hours);

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

- Moderate and severe renal insufficiency (creatinine clearance below 50 ml/min);

- Known hyponatraemia;

- Syndrome of inappropriate ADH secretion;

- Hypersensitivity to desmopressin or to any of the excipients of Desmotabs Melt.

- Patients over the age of 65 for the treatment of primary nocturnal enuresis.

- Patients over the age of 65 for the treatment of nocturia.

Before prescribing Desmotabs Melt the diagnoses of psychogenic polydipsia and alcohol abuse should be excluded.

4.4 Special warnings and precautions for use

Special warnings:

When used for primary nocturnal enuresis or nocturia indications, the 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 water retention and/or hyponatraemia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, and, in severe cases, convulsions). All patients and, when applicable, their guardians should be carefully instructed to adhere to the fluid restrictions.

Use of the product should be under specialist supervision with appropriate facilities available for monitoring and interpretation of response.

All patients on desmopressin therapy should be observed for the signs of symptoms associated with hyponatraemia (headache, nausea/vomiting, weight increased and, in severe cases, convulsions).

Care should be taken with patients who have reduced renal function and/or cardiovascular disease or cystic fibrosis.

Patients being treated for primary nocturnal enuresis or nocturia should discontinue Desmotabs Melt during an episode of vomiting and/or diarrhoea until their fluid balance is once again normal.

Precautions:

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

- Elderly patients and patients with low serum sodium levels may have an increased risk of hyponatraemia therefore Desmotabs Melt is contraindicated in patients being treated for primary nocturnal enuresis and nocturia.

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

- Precautions must be taken in patients at risk for increased intracranial pressure.

- Desmopressin should be used with caution in patients with conditions characterized by fluid and/or electrolyte imbalance

- Precautions to avoid hyponatraemia including careful attention to fluid restriction and more frequent monitoring of serum sodium must be taken in case of concomitant treatment with drugs, which are known to induce Syndrome of Inappropriate Antidiuretic Hormone (SIADH), e.g. tricyclic antidepressants, selective serotonine reuptake inhibitors, chlorpromazine and carbamazepine, case of concomitant treatment with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

4.5 Interaction with other medicinal products and other forms of interaction

Substances, which are known to induce SIADH, e.g. tricyclic antidepressants, selective serotonine reuptake inhibitors, chlorpromazine and carbamazepine, as well as some antidiabetics of the sulfonylurea group particularly Chlorpropamide may cause an additive antidiuretic effect leading to an increased risk of water retention/hyponatraemia (see section 4.4).

NSAIDs may induce water retention/hyponatraemia (see section 4.4).

Concomitant treatment with loperamide may result in a 3-fold increase of desmopressin plasma concentrations, which may lead to an increased risk of water retention/hyponatraemia.

Although not investigated, other drugs slowing intestinal transport might have the same effect.

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. However, formal in vivo interaction studies have not been performed.

A standardized 27% fat meal significantly decreased absorption (rate and extent) of Desmopressin tablets. No significant effect was observed with respect to pharmacodynamics (urine production or osmolality).

Food intake may reduce the intensity and duration of the antidiuretic effect at low oral doses of desmopressin tablets.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus as well as data on a limited number (n=54) of exposed pregnancies in women with von Willebrand disease indicate no adverse effects of desmopressin on pregnancy or on the health of the foetus/ 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/ foetal development, parturition or postnatal development. There have been rare reports of malformations in children born to mothers treated for diabetes insipidus during pregnancy.

Caution should be exercised when prescribing Desmotabs Melt to pregnant women.

Fertility studies have not been done. In vitro analysis of human cotyledon models have shown that there is no transplacental transport of desmopressin when administered at therapeutic concentrations corresponding to recommended dose.

Lactation:

Results from analyses of milk from nursing mothers receiving high dose desmopressin (300 micrograms intranasal), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.

4.7 Effects on ability to drive and use machines

Desmotabs Melt has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most serious adverse reaction with desmopressin is hyponatraemia, which may cause headache, abdominal pain, nausea, vomiting, weight increase, dizziness, confusion, malaise, memory impairment, vertigo, falls and in severe cases convulsions and coma. The majority of adults treated for nocturia who develop hyponatraemia have developed low serum sodium after three days of dosing. In adults the risk of hyponatraemia increases with increasing dose of desmopressin and the risk has been found to be more prominent in women.

In adults the most commonly reported adverse reaction during treatment was headache (12%). Other common adverse reactions were hyponatraemia (6%), dizziness (3%), hypertension (2%), and gastrointestinal disorders (nausea (4%), vomiting (1%), abdominal pain (3%), diarrhoea (2%) and constipation (1%)). Less common is an influence of the sleep pattern/consciousness level presenting itself as e.g. insomnia (0.96%), somnolence (0.4%) or asthenia (0.06%). Anaphylactic reactions have not been seen in clinical trials but spontaneous reports have been received.

In children the most commonly reported adverse reaction during treatment was headache (1%), less common were psychiatric disorders (affect lability (0.1%), aggression (0.1%), anxiety (0.05%), mood swings (0.05%), nightmare (0.05%)) which generally abated after treatment discontinuation and gastrointestinal disorders (abdominal pain (0.65%), nausea (0.35%), vomiting (0.2%) and diarrhoea (0.15%)). Anaphylactic reactions have not been seen in clinical trials but spontaneous reports have been received.

Tabulated summary of adverse reactions

Adults:

Based on the frequency of adverse drug reactions reported in clinical trials with oral desmopressin conducted in adults for treatment of Nocturia (N=1557) combined with the post marketing experience for all adult indications (incl Central Diabetes Insipidus). Reactions only seen in post marketing have been added in the 'Not known'-frequency column.

MedDRA Organ Class

Very common

(>10%)

Common

(1-10%)

Uncommon

(0.1-1%)

Rare

(0.1-0.01%)

Not known

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hyponatraemia*

Dehydration**, Hypernatraemia**

Psychiatric disorders

Insomnia

Confusional state*

Nervous system disorders

Headache*

Dizziness*

Somnolence, paraesthesia

Convulsions*, Asthenia**, Coma*

Eye disorders

Visual impairment

Ear and labyrinth disorders

Vertigo*

Cardiac disorders

Palpitations

Vascular disorders

Hypertension

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Nausea*, Abdominal pain*, Diarrhoea, Constipation, Vomiting*

Dyspepsia, Flatulence, bloating and distension

Skin and subcutaneous tissue disorders

Sweating, Pruritus, Rash, Urticaria

Dermatitis allergic

Musculoskeletal and connective tissue disorders

Muscle spasms, Myalgia

Renal and urinary disorders

Bladder and urethral symptoms

General disorders and administration site conditions

Oedema, Fatigue

Malaise*, Chest pain, Influeza like illness

Investigations

Weight increased*, Hepatic enzyme increased, Hypokalaemia

* Hyponatraemia may cause headache, abdominal pain, nausea, vomiting, weight increase, dizziness, confusion, malaise, memory impairment, vertigo, falls and in severe cases convulsions and coma

** Only seen in the CDI indication

Children and Adolescents:

Based on the frequency of adverse drug reactions reported in clinical trials conducted in children and adolescents with oral desmopressin for treatment of Primary Nocturnal Enuresis (N = 1923). Reactions only seen in post marketing have been added in the 'Not known'-frequency column.

MedDRA Organ Class

Very common

(>10%)

Common

(1-10%)

Uncommon

(0.1-1%)

Rare

(0.1-0.01%)

Not known

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hyponatraemia*

Psychiatric disorders

Affect lability**, Aggression***

Anxiety symptoms, Nightmare****, Mood swings****

Abnormal behaviour, Emotional disorder, Depression, Hallucination, Insomnia

Nervous system disorders

Headache*

Somnolence

Disturbance in attention, Psychomotor hyperactivity, Convulsions*

Vascular disorders

Hypertension

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Abdominal pain*, Nausea*, Vomiting*, Diarrhoea

Skin and subcutaneous tissue disorders

Dermatitis allergic, Rash, Sweating, Urticaria

Renal and urinary disorders

Bladder and urethral symptoms

General disorders and administration site conditions

Oedema peripheral, Fatigue

Irritability

* Hyponatraemia may cause headache, abdominal pain, nausea, vomiting, weight increase, dizziness, confusion, malaise, memory impairment, vertigo, falls and in severe cases convulsions and coma

** Post marketing reported equally in children and adolescents (<18 years)

*** Post marketing almost exclusively reported in children and adolescents (<18 years)

****Post marketing reported primarily in children (<12 years)

Other special populations:

Elderly patients and patients with serum sodium levels in the lower range of normal may have an increased risk of developing hyponatraemia (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2. Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Overdose of Desmotabs Melt leads to a prolonged duration of action with an increased risk of water retention and hyponatraemia.

Treatment

Although the treatment of hyponatraemia should be individualised, the following general recommendations can be given - discontinue the desmopressin treatment, fluid restriction, and symptomatic treatment if needed.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vasopressin and analogues.

ATC code: H01B A02.

Desmotabs Melt 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.

Clinical trials with desmopressin tablets in the treatment of nocturia showed the following:

• A reduction of at least 50 % in the mean number of nocturnal voids was obtained in 39 % of patients with desmopressin compared to 5 % of patients with placebo (p<0.0001).

• The mean number of voids per night decreased by 44 % with desmopressin compared to 15 % with placebo (p<0.0001).

• The median duration of first undisturbed sleep period increased by 64% with desmopressin compared to 20 % with placebo (p<0.0001).

• The mean duration of first undisturbed sleep period increased by 2 hours with desmopressin compared to 31 minutes with placebo (p<0.0001).

Effect of treatment with individual oral dose of desmopressin tablets between 0.1 and 0.4 mg during 3 weeks, compared with placebo (pooled data).

Desmopressin

Placebo

Statistical significance vs. placebo

Variable

Mean baseline value

Mean value during 3 weeks of treatment

Mean baseline value

Mean value during 3 weeks of treatment

Number of nocturnal voids

2.97 (0.84)

1.68 (0.86)

3.03 (1.10)

2.54 (1.05)

(p<0.0001)

Nocturnal diuresis rate (ml/min)

1.51 (0.55)

0.87 (0.34)

1.55 (0.57)

1.44 (0.57)

(p<0.0001)

Duration of first undisturbed sleep period (min)

152 (51)

270 (95)

147 (54)

178 (70)

(p<0.0001)

Eight percent of the patients interrupted in the desmopressin dose titration phase due to adverse effects, and 2 % in the subsequent double-blind phase (0.63 % on desmopressin and 1.45 % on placebo).

5.2 Pharmacokinetic properties

Absorption:

The overall mean absolute bioavailability of desmopressin administered sublingually as Desmotabs Melt at doeses of 200,400 and 800 micrograms is 0.25% with a 95% confidence interval of 0.21 – 0.31%. The Cmax was 14, 30 and 65 pg/mL after administration of 200,400 and 800 micrograms respectively. Tmax was observed at 0.5 – 2.0 hours after dosing. The geometric mean terminal half-life is 2.8 (CV=24%) hours.

Correlation table between Desmopressin Tablet and Desmotabs Melt:

Desmopressin Tablets

Desmopressin Tablets

Desmotabs Melt

Desmotabs Melt

Desmopressin acetate

Desmopressin free base

Desmopressin free base

Desmopressin acetate.

0.1mg

89 micrograms

60 micrograms

Approx 67 micrograms*

0.2mg

178 micrograms

120 micrograms

Approx 135 micrograms*

0.4mg

356 micrograms

240 micrograms

Approx 270 micrograms*

(*) calculated for comparative purposes

Distribution:

The distribution of desmopressin is best described by a two-compartment distribution model with a volume of distribution during the elimination phase of 0.3-0.5 L/kg.

Biotransformation:

The in vivo metabolism of desmopressin has not been studies. In vitro human liver microsome metabolism studies of desmopressin have shown that no significant amount is metabolized in the liver by the cytochrome P450 system. Thus human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur. The effect of desmopressin on the PK of other drugs is likely to be minimal due to its lack of inhibition of the cytochrome P450 drug metabolizing system.

Elimination:

The total clearance of desmopressin has been calculated to 7.6 L/hr. The terminal half-life of desmopressin is estimated to be 2.8 hours. In healthy subjects the fraction excreted unchanged was 52% (44%-60%).

Linearity/non-linearity:

There are no indications of non-linearities in any of the pharmacokinetic parameters of desmopressin.

Characteristics in specific groups of patients:

Renal Impairment:

Depending on the degree of renal impairment the AUC and half-life increased with the severity of the renal impairment. In patients with moderate and severe renal impairment (creatinine clearance below 50ml/min) desmopressin is contraindicated.

Hepatic Impairment:

No studies performed.

Children:

The population pharmacokinetics of desmopressin tablets has been studies in children with PNE and no significant difference from adults were detected.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Carcinogenicity studies have not been performed with desmopressin, because it is very closely related to the naturally-occurring peptide hormone.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gelatin

Mannitol (E421)

Citric Acid, anhydrous

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container

Aluminium/aluminium blisters of 10 oral lyophilisates in pack sizes of 10, 30, 90 or 100 oral lyophilisates.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Ferring Ireland Limited

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

8. MARKETING AUTHORISATION NUMBER(S)

PA 1009/7/4

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 September 2005

Date of last renewal: 30 September 2010

10. DATE OF REVISION OF THE TEXT

May 2015

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.