SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

ADIURETIN® 0.1mg/ml Nasal Spray Desmopressin 0.1mg/ml Nasal Spray

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

10 micrograms desmopressin acetate per actuation For excipients, see 6.1

3. PHARMACEUTICAL FORM

Nasal spray, solution Clear, colourless solution

4. CLINICAL PARTICULARS

4.1.    Therapeutic indications

ADIURETIN Nasal Spray is indicated for:

i)    The treatment of nocturia associated with multiple sclerosis where other treatments have failed.

ii)    The diagnosis and treatment of vasopressin-sensitive cranial diabetes insipidus.

iii)    Establishing renal concentration capacity.

4.2.    Posology and method of administration

For nasal use only

Each actuation contains 10 micrograms of desmopressin acetate.

The spray bottle should be held upright and the protective cap removed from the spray nozzle. The spray should be primed when using it for the first time. This is done by spraying several actuations in the air until a consistent, fine spray is seen. If the spray has not been used within 7 days of the previous dose, it should be re-primed by spraying at least one actuation in the air before use.

The dose is administered by tilting the head slightly back and placing the nozzle just inside the nostril ensuring that the dip-tube is in the liquid. One actuation is administered whilst holding the breath (without sniffing) and the procedure repeated alternating the nostrils until the prescribed dose has been administered. The protective cap is replaced after use.

Treatment of Nocturia:

When Desmopressin Nasal Spray is used for the treatment of nocturia associated with multiple sclerosis, fluid intake must be limited to a minimum from 1 hour before using the spray at bedtime until the next morning and in any case for a minimum of 8 hours after administration.

For multiple sclerosis patients up to 65 years of age with normal renal function suffering from nocturia the dose is one or two sprays intranasally (10 to 20 micrograms) at bedtime. Not more than one dose should be used in any 24 hour period. If a dose of two sprays is required, this should be as one spray into each nostril.

Treatment of Diabetes Insipidus:

Dosage is individual but clinical experience has shown that the average maintenance dose in adults and children is one or two sprays (10 to 20 micrograms) once or twice daily. If a dose of two sprays is required, this should be as one spray into each nostril.

Diagnosis of Diabetes Insipidus:

The diagnostic dose in adults and children is two sprays (20 micrograms). Failure to elaborate a concentrated urine after water deprivation, followed by the ability to do so after the administration of ADIURETIN Nasal Spray confirms the diagnosis of cranial diabetes insipidus. Failure to concentrate after the administration suggests nephrogenic diabetes insipidus.

Renal Function Testing:

Recommended doses for the renal concentration capacity test:

Adults: Two sprays into each nostril (a total of 40 micrograms)

Children: (1-15 years): One spray into each nostril (a total of 20 micrograms). Infants (to 1 year): One spray (10 micrograms).

Adults and children with normal renal function can be expected to achieve concentrations above 700mOsm/kg in the period of 5-9 hours following administration of ADIURETIN Nasal Spray. It is recommended that the bladder should be emptied at the time of administration.

In normal infants a urine concentration of 600mOsm/kg should be achieved in the 5 hour period following the administration of ADIURETIN Nasal Spray. The fluid intake at the two meals following the administration should be restricted to 50% of the ordinary intake in order to avoid water overload.

4.3. Contraindications

ADIURETIN Nasal Spray is contraindicated in cases of: syndrome of inappropriate ADH secretion (SIADH) known hyponatraemia

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

moderate and severe renal insufficiency (creatinine clearance below 50ml/min)

hypersensitivity to desmopressin or to any of the excipients of Desmopressin Nasal Spray.

Before prescribing ADIURETIN Nasal Spray, the diagnoses of habitual or psychogenic polydipsia (resulting in a urine production exceeding 40mg/kg/24 hours) and alcohol abuse should be excluded.

When used to control nocturia in patients with multiple sclerosis, desmopressin should not be used in patients with hypertension or cardiovascular disease.

Desmopressin should not be prescribed to patients over the age of 65 for the treatment of nocturia associated with multiple sclerosis.

4.4 Special warnings and precautions for use

ADIURETIN should only be used in patients where orally administered formulations are not suitable.

When ADIURETIN is prescribed, it is recommended:

-    to start at the lowest dose

-    to ensure compliance with fluid restriction instructions

-    to increase dosage progressively, with caution

-    to ensure that in children, administration is under adult supervision in order to control the dose intake.

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

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

When ADIURETIN is used for the treatment of nocturia associated with multiple sclerosis, periodic assessments should be made of blood pressure and weight to monitor the possibility of fluid overload. Treatment with ADIURETIN should be interrupted during acute intercurrent illness characterised by fluid and/or electrolyte imbalance (such as vomiting, diarrhoea, systemic infections, fever, gastroenteritis).

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.

Elderly patients and patients with low serum sodium levels may have an increased risk of hyponatraemia.

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 SIADH e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, carbamazepine and NSAIDs.

When used for diagnostic purposes, fluid intake must be limited and not exceed 0.5 litres from 1 hour before until 8 hours after administration.

Following diagnostic testing for diabetes insipidus or renal concentration capacity, care should be taken to prevent fluid overload. Fluid should not be forced, orally or parenterally, and patients should only take as much fluid as they require to satisfy thirst.

There is some evidence from post-marketing data for the occurrence of severe hyponatraemia in association with the nasal spray formulation of ADIURETIN, when it is used in the treatment of cranial diabetes insipidus.

Precautions to prevent fluid overload must be taken in:

-    conditions characterised by fluid and/or electrolyte imbalance

-    patients at risk for increased intracranial pressure

Renal concentration capacity testing in children below the age of 1 year should only be performed under carefully supervised conditions in hospital.

4.5 Interaction with other medicinal products and other forms of interaction

Substances which are known to induce SIADH e.g. tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine and carbamazepine, may cause an additive antidiuretic effect leading to an increased risk of water retention and/or hyponatraemia (see 4.4).

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

4.6. Pregnancy and lactation

Pregnancy:

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus indicate rare cases of malformations in children treated during pregnancy. 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.

Caution should be exercised when prescribing to pregnant women. Blood pressure monitoring is recommended due to the increased risk of preeclampsia.

Lactation:

Results from analyses of milk from nursing mothers receiving high dose desmopressin (300 micrograms intranasally) 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

None

4.8    Undesirable effects

Side-effects include headache, stomach pain, nausea, nasal congestion, rhinitis and epistaxis. Isolated cases of allergic skin reactions and more severe general allergic reactions have been reported. Very rare cases of emotional disorders including aggression in children have been reported. Treatment without concomitant reduction of fluid intake may lead to water retention/hyponatraemia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, decreased serum sodium and in severe cases, convulsions).

4.9    Overdose

An overdose of Desmopressin Nasal Spray leads to a prolonged duration of action with an increased risk of water retention and/or hyponatraemia.

Treatment:

Although the treatment of hyponatraemia should be individualised, the following general recommendations can be given. Hyponatraemia is treated by discontinuing the desmopressin treatment, fluid restriction and symptomatic treatment if needed.

5.    PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Desmopressin is a structural analogue of vasopressin, with two chemical changes, namely desamination of the N-terminal and replacement of the 8-L-Arginine by D-8-Arginine. These changes have increased the antidiuretic activity and prolonged the duration of action. The pressor activity is reduced to less than 0.01% of the natural peptide as a result of which side-effects are rarely seen.

5.2. Pharmacokinetic properties

Following intranasal administration, the bioavailability of desmopressin is of the order of 10%.

Pharmacokinetic parameters following intravenous administration have been reported as follows:

Total clearance: 2.6ml/ min/kg body wt.

T/ 55 mins

Plasma kinetics of DDAVP in man

H. Vilhardt, S. Lundin, J. Falch

Acta Pharmacol et Toxicol, 1986, 58, 379-381

In vitro, in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised in the liver and thus human liver metabolism in vivo is not likely to occur.

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.

5.3. Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium Chloride Citric Acid Monohydrate Disodium Phosphate Dihydrate Benzalkonium Chloride Solution 50% Purified Water

Incompatibilities

None known.

Shelf life

3 years.

Special precautions for storage

Do not store above 25°C. Keep the bottle in the outer carton.

Nature and contents of container

Multidose container, Type I brown glass bottle with a pre-compression pump set comprising of a spray pump with a metering valve, nasal applicator and protection cap.

Pack size: 60 actuations (sprays) - 6ml

Instructions for use and handling

None.

MARKETING AUTHORISATION HOLDER

Ferring Pharmaceuticals Ltd

Drayton Hall

Church Road

West Drayton

UB7 7PS

UK

MARKETING AUTHORISATION NUMBER

PL 3194/0090

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 7^th October 2004

DATE OF REVISION OF THE TEXT

04/11/2015