Minirin

Desmopressin acetate.

Tablet: MINIRIN 0.1 mg: Each tablet contains desmopressin acetate 0.1 mg equivalent to desmopressin (free base) 0.089 mg.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
Oral lyophilisate: Each melt oral lyophilisate contains desmopressin (free base) 60 mcg and 120 mcg added as desmopressin acetate, respectively.
Injection: 1 ml MINIRIN solution for injection contains 4 microgram desmopressin acetate equivalent to 3.56 microgram desmopressin.
Excipients with known effect: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free.
Nasal spray: Each mL of solution for nasal spray contains desmopressin acetate 0.1 mg equivalent to 89 μg desmopressin and, benzalkonium chloride 0.1 mg.
Minirin nasal spray is supplied in bottles provided with precompression spray pumps designed to deliver 10 mcg per spray dose.
Excipients/Inactive Ingredients: Tablet: lactose monohydrate, potato starch, povidone and magnesium stearate.
Oral lyophilisate: Gelatin, mannitol (E421) and anhydrous citric acid.
Injection: Sodium chloride, hydrochloric acid and water for injection.
Nasal spray: Benzalkonium chloride (solution), sodium chloride, citric acid monohydrate (E 330), disodium phosphate dihydrate, and purified water.

Pharmacotherapeutic group: vasopressin and analogues. ATC code: H01B A02.
Pharmacology: Pharmacodynamics: MINIRIN contain 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.
Tablet: Desmopressin is a potent compound with an EC₅₀ value of 1.6 pg/mL, for the antidiuretic effect. After oral administration, an effect lasting from 6 to 14 hours or more, can be expected.
Injection: Desmopressin at high dosage, 0.3 μg/kg body weight intravenously, leads to a two- to fourfold increase in plasma of factor VIII coagulant activity (VIII:C). Also the content of von Willebrand factor-antigen (vWF:Ag) increases, but to a lesser extent. At the same time there is a release of the plasminogen activator (t-PA).
Administration of desmopressin at a high dosage has also been shown to lead to a shortening or normalisation of the bleeding time in patients with prolonged bleeding time as in uremia, liver cirrhosis, congenital or drug-induced thrombocyte dysfunction and in patients with prolonged bleeding time of unknown etiology.
By administration of desmopressin instead of factor VIII concentrates, the risk of transmission of HIV-infection and hepatitis virus is avoided.
Pharmacokinetics: Absorption: Tablet & Oral lyophilisate: The absolute bioavailability of MINIRIN tablets is 0.16% with an SD of 0.17%. Mean maximum plasma concentration is reached within 2 hours.
Concomitant use of food decreases the rate and extent of absorption by 40%.
Correlation table between MINIRIN tablet and MINIRIN oral lyophilisate: (See Table 1.)

Click on icon to see table/diagram/image

Oral lyophilisate: The overall mean absolute bioavailability of desmopressin administered sublingually as Minirin oral lyophilisate at doses of 200, 400 and 800 mcg is 0.25% with a 95% confidence interval of 0.21-0.31%. The C_max was 14, 30 and 65 pg/mL after administration of 200, 400 and 800 mcg, respectively. T_max was observed at 0.5-2 hrs after dosing.
Injection: The bioavailability following subcutaneous injection compared with intravenous administration is about 85%. Maximal plasma concentration after 0.3 μg/kg given as a subcutaneous injection is achieved after approximately 60 minutes and it amounts to 600 pg/ml in average.
Nasal spray: Bioavailability is approx. 3-5%. The maximum plasma concentration is reached after approx. one hour and does not increase in proportion to the administered dose. One intranasal dose of 10-20 μg produces an antidiuretic effect for 8-12 hours.
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.
Nasal spray: The distribution volume during the elimination phase is 38 L. Desmopressin does not cross the blood-brain barrier.
Biotransformation: The in-vivo metabolism of desmopressin has not been studied. In vitro human liver microsome metabolism studies of desmopressin have shown that no significant amount is metabolized in the liver by 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-lives of desmopressin is estimated to 2.8 hours. In healthy subjects the fraction excreted unchanged was 52% (44%-60%).
Injection: The duration of the haemostatic effect depends of the half-life for VIII:C which is about 8-12 hours.
Linearity/Nonlinearity: Oral lyophilisate: Linearity (dose-proportional pharmacokinetics) was established for Minirin oral lyophilisate for dose levels from 60-240 mcg.
Characteristics in specific group of patients: Renal Impairment: Depending on the degree of renal impairment the AUC and half-live increased with the severity of the renal impairment in patients with moderate and severe renal impairment (creatinine clearance below 50 ml/min) desmopressin is contraindicated.
Hepatic Impairment: No studies performed.
Children: Tablet & Oral lyophilisate: The population pharmacokinetics of MINIRIN tablets has been studied in children with PNE and no significant difference from adults were detected.
Nasal spray: Metabolism: In vitro studies with human liver microsomes have shown that an insignificant amount of desmopressin is metabolised in the liver microsomes. It is therefore unlikely that desmopressin is metabolised in the liver in humans. Desmopressin does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in vitro and thus should desmopressin not affect the pharmacokinetics of other drugs metabolized by CYP enzymes.
Elimination: The total clearance of desmopressin has been calculated to 7.6 L/h. The half-life for desmopressin in the elimination phase is 2.8 hours in average. In healthy subjects the fraction excreted unchanged in urine is 52%.
Toxicology: PRECLINICAL SAFETY DATA: Tablet: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction; and development (injection).
Tablet: Carcinogenicity studies have not been performed with desmopressin, because it is very closely related to the naturally-occurring peptide hormone.
Injection: No studies of the carcinogenic potential have been performed.

Tablet: MINIRIN tablets are indicated for the treatment of central diabetes insipidus. The use of MINIRIN in patients with an established diagnosis will result in a reduction in urinary output with concomitant increase in urine osmolality and decrease in plasma osmolality. This will result in decreased urinary frequency and decreased nocturia.
MINIRIN tablets are indicated for the treatment of primary nocturnal enuresis in children aged 5 years or more.
Oral lyophilisate: MINIRIN oral lyophilisate is indicated for the treatment of central diabetes insipidus.
MINIRIN oral lyophilisate is indicated for the treatment of primary nocturnal enuresis in patients (from 5 years of age) with normal ability to concentrate urine.
Injection & Nasal spray: Central Diabetes Insipidus: The use of Minirin in patients with an established diagnosis will result in a reduction in urinary output with concomitant increase in urine osmolality and decrease in plasma osmolality. This will result in decreased urinary frequency and decreased nocturia.
Renal concentrating capacity test: Minirin can be used to test the capacity of the kidneys to concentrate urine; as a diagnostic aid in the examination of the kidney function. This is especially useful in the differential diagnosis between level of urinary tract infections. Cystitis will opposite to pyelonephritis not cause a subnormal ability to concentrate urine.
Injection: Hemophilia A and von Willebrand's disease: For the therapeutic control of bleeding and bleeding prophylaxis in connection with minor surgical procedures in patients with mild haemophilia A and von Willebrand's disease who respond positively to the test dose. In exceptional cases, even moderate forms of the disease can be treated. MINIRIN must not be used in patients with von Willebrand's disease type II B.

Tablet: General: Optimal dose of MINIRIN tablets is individually adjusted.
Effect of food: Food intake may reduce the intensity and duration of the antidiuretic effect at low doses of desmopressin (see Interactions).
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 Precautions).
If adequate clinical effect is not achieved within 4 weeks following appropriate dose titration the medication should be discontinued.
Indication Specific: Central diabetes insipidus: A suitable initial dose for children and adults is 0.1 mg three times daily. The dose is then adjusted according to the response of the patient. According to clinical experience gained so far, the daily dose lies in the range of 0.2 mg and 1.2 mg. For most patients, 0.1-0.2 mg three times daily is the optimal dose regimen.
In the event of signs of water retention/hyponatremia treatment should be interrupted and the dose should be adjusted.
Primary nocturnal enuresis: A suitable initial dose is 0.2 mg at bedtime. The dose may be increased up to 0.4 mg if the lower dose is not sufficiently effective. The need for continued treatment should be reassessed after 3 months by means of a period of at least 1 week without MINIRIN treatment. Fluid restriction should be observed.
Tablet & Oral lyophilisate: Special Populations: Elderly: The initiation of treatment in patients >65 years is not recommended. Should physicians decide to initiate desmopressin treatment in these patients then serum sodium should be measured before beginning the treatment and 3 days after initiation or increase in dosage and at other times during treatment as deemed necessary by the treating physician.
Paediatric Population: MINIRIN is indicated in Central Diabetes Insipidus and Primary Nocturnal Enuresis (see Pharmacology: Pharmacodynamics under Actions and Indication Specific information as previously mentioned). Dose recommendations are the same as in adults.
Tablet, Oral lyophilisate & Nasal spray: Renal Impairment: see Contraindications.
Hepatic Impairment: see Interactions.
Nasal spray: 1 dose of the spray provides 0.1 ml, which corresponds to 10 μg desmopressin acetate.
MINIRIN nasal formulations should be used only when treatment with oral formulations is inappropriate and always start at the lowest dose (see Precautions).
Fluid restriction should be observed (see Indication Specific instructions in Precautions).
If signs of water retention and/or hyponatraemia (headache, nausea/vomiting, weight gain and in serious cases convulsions) develop, treatment should be discontinued until the patient has recovered completely. Fluid intake should be strictly limited when treatment is reinstated (see Precautions).
Elderly: See Precautions.
Paediatric Population: MINIRIN is indicated in children with central diabetes insipidus and for testing of renal concentration capacity, see Precautions & Adverse Reactions.
Central diabetes insipidus: Oral lyophilisate: Dosage is individual in diabetes insipidus but the total daily sublingual dose normally lies in the range of 120-720 mcg.
Adults and Children: Starting dose: 60 mcg 3 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 60-120 mcg 3 times daily.
Injection: The injection may be used when the intranasal or oral administration is considered unsuitable. Individual dosage is determined after testing of the effect on urine osmolality and diuresis at different dose levels. In the event of signs of water retention/hyponatraemia treatment should be interrupted and the dose should be adjusted.
Normal dosage, intravenous injection: Adults: 1-4 μg (0.25-1 ml) 1-2 times daily.
Children above the age of 1 year: 0.4-1 μg (0.1-0.25 ml) 1-2 times daily.
Children below the age of 1 year: 0.2-0.4 μg (0.05-0.1 ml) 1-2 times daily.
For patients who have been controlled on intranasal MINIRIN and who must be switched to the injection form, either because of poor intranasal absorption or because of the need for surgery, the comparable antidiuretic dose of the injection is about 10% of the intranasal dose.
Nasal spray: Dosage is individual but clinical experience has shown that the normal daily dose for adults is 10-20 μg 1-2 times daily and for children 5-10 μg, 1-2 times daily.
Primary Nocturnal Enuresis: Oral lyophilisate: Recommended Initial Dose: 120 mcg at bedtime, administered sublingually.
If this dose is not sufficiently effective, the dose may be increased up to 240 mcg sublingually. Fluid restriction should be observed. Minirin oral lyophilisate is intended for treatment periods of up to 3 months. The need for continued treatment should be reassessed by means of a period at least 1 week without Minirin oral lyophilisate.
Renal concentrating capacity test: Injection: Normal adult dose by intramuscular or subcutaneous injection is 4 μg (1 ml).
For children above the age of 1 year the dose is 1 to 2 μg (0.25 to 0.5 ml).
For children below the age of 1 year is 0.4 μg (0.1 ml).
For children it is recommended to use primarily the intranasal presentation.
After administration of MINIRIN injection, any urine collected within 1 hour is discarded. During the next 8 hours 2 portions of urine are collected for measurement of osmolality. Fluid restriction should be observed, see Precautions.
The reference level for normal urine osmolality after MINIRIN administration is 800 mOsm/kg for most patients. With values under this level, the test should be repeated. A repeated low result indicates an impaired ability to concentrate urine and the patient should be referred for further examination into the underlying cause of the malfunction.
Nasal spray: Normal Dose: Adults: 40 μg. Children >12 months: 20 μg; <12 months: 10 μg. After administration of Minirin dDAVP, possible urine within 1 hour is discarded. During the next 8 hours, 2 portions of urine are collected for urine osmolality testing. Fluid restriction should be observed, (see Precautions).
The reference level for normal urine osmolality after MINIRIN administration is 800 mOsm/kg for most patients. With values under this level, the test should be repeated. A similar low result indicates an impaired ability to concentrate urine and the patient should be referred for further examination into the underlying cause of the malfunction.
Haemophilia A and von Willebrand's Disease: Injection: MINIRIN injection is administered as an intravenous infusion at a dose of 0.3 μg/kg bodyweight diluted in sterile physiological saline and infused slowly over 15-30 minutes. In adults and children weighing 10 kg or more, 50 ml of diluent is used; in children weighing 10 kg or less, 10 ml of diluent is used.
If a positive effect is obtained, the initial MINIRIN dose may be repeated 1-2 times with intervals of 6-12 hours. Further repetition of the dose may result in a reduced effect.
In patients with haemophilia, the desired increase of VIII:C is appraised by the same criterion as in the treatment with factor VIII-concentrate. The VIII:C-concentration must be followed up regularly since in a few cases the effect has been seen to decrease with repeated doses. If the MINIRIN-infusion does not lead to the desired increase of the VIII:C-concentration in plasma, the treatment may be complemented with a supply of factor VIII-concentrate. The treatment of patients with haemophilia should be conducted in consultation with each patient's coagulation laboratory.
Determination of the coagulation factor and bleeding time before MINIRIN-treatment: Plasma levels of VIII:C and vWF:Ag increase substantially after desmopressin administration. However, it has not been possible to establish any correlation between the plasma concentration of these factors and the bleeding time, either before or after desmopressin. The effect of desmopressin on the bleeding time should therefore, if possible, be tested in the individual patient.
The bleeding time test should be as standardized as possible, e.g. with the use of Simplate II. Determination of bleeding time and plasma levels of the coagulation factors should be conducted in cooperation or consultation with a coagulation laboratory.
Injection: Posology for special populations: Renal impairment: MINIRIN injection should be used with caution in patients with moderate and severe renal insufficiency (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No studies have been performed in this population.
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.
Method of administration: Oral lyophilisate: Minirin oral lyophilisate is placed under the tongue where it dissolves without the need for water.
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 Precautions).
If adequate clinical effect is not achieved within 4 weeks following appropriate dose titration the medication should be discontinued.
Injection: The injection is normally administered intravenously but may, if needed, also be given intramuscularly or subcutaneously, depending on the indications.

Overdose of MINIRIN leads to prolonged duration of action with an increased risk of water retention and hyponatraemia.
Nasal spray: Even normal doses may cause water intoxication in association with a high fluid intake. Doses exceeding 0.3 μg/kg i.v. and 2.4 μg/kg intranasally have together with fluid intake caused hyponatraemia and convulsions in children and adults.
Symptoms: The same symptoms as for water intoxication. Headache, nausea. Fluid retention, hyponatraemia, hypoosmolality, oliguria, CNS depression, convulsions, pulmonary oedema. See Adverse Reactions.
Treatment: Tablet: Although the treatment of hyponatremia should be individualized, the following general recommendations can be given. Asymptomatic hyponatremia is treated with discontinuing the desmopressin treatment and fluid restriction. Infusion of isotonic or hypertonic sodium chloride may be added in cases with symptoms. When the water retention is severe (convulsions and unconsciousness) treatment with furosemide should be added.
Nasal spray: The treatment of hyponatraemia must be tailored to the individual, but the following general recommendations may be given.
Hyponatraemia is treated by discontinuing the desmopressin treatment and restricting fluids. If the patient has symptoms, an infusion of isotonic or hypertonic sodium chloride may be given. When the fluid retention is serious (convulsions and loss of consciousness), treat with furosemide.

MINIRIN are contraindicated in cases of: Hypersensitivity to the active substances or to any of the excipients.
Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40 ml/kg/24 hours).
A history of unstable angina and/or known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics.
Known hyponatraemia.
Syndrome of inappropriate ADH secretion (SIADH).
Tablet: Moderate and severe renal insufficiency (creatinine clearance below 50 ml/min).
Injection: von Willebrand's disease type IIB.

Tablet & Oral lyophilisate: When used for primary nocturnal enuresis indication, the fluid intake must be limited to a minimum from 1 hour before, until the next morning (at least 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.
Tablet: This product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Injection: When MINIRIN injection is prescribed, it is recommended to maintain fluid and electrolyte balance. Treatment without concomitant reduction of fluid intake may lead to fluid retention and/or hyponatremia with or without accompanying warning signs and symptoms, see Adverse Reactions.
In addition for renal concentration capacity testing: When used for diagnostic purposes the fluid intake must be limited to a maximum of 0.5 L to quench thirst from 1 hour before until 8 hours after administration. Renal concentration capacity testing in children below the age of 1 year should only be performed in hospital and under careful supervision.
In addition for haemostatic use: The benefits of desmopressin versus other hemostatic therapies should be carefully assessed in situations where prolonged haemostasis is required including active postoperative bleeding and variceal bleeding in patients with cirrhosis.
Measures to prevent fluid overload must be taken in patients requiring treatment with diuretic agents.
Special attention must be paid to the risk of fluid retention/hyponatraemia (see Adverse Reactions). The fluid intake should be restricted to the least possible and the body weight should be checked regularly. If there is a gradual increase of the body weight, decrease of serum sodium to below 130 mmol/L or plasma osmolality to below 270 mOsm/kg body weight, the fluid intake must be reduced drastically and the administration of MINIRIN interrupted.
MINIRIN does not reduce prolonged bleeding time in thrombocytopenia.

Tablet & Oral lyophilisate: Severe bladder dysfunction and outlet obstruction should be considered before starting treatment for central diabetes insipidus.
Elderly patients and patients with serum sodium levels in the lower range of normal may have an increased risk of hyponatraemia.
Treatment with desmopressin should be interrupted during acute intercurrent illnesses characterised 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 SIADH, e.g. tricyclic antidepressants, selective serotonine reuptake inhibitors, chlorpromazine and carbamazepine, case of concomitant treatment with NSAIDs.
Injection: Severe bladder dysfunction and outlet obstruction should be considered before starting treatment for central diabetes insipidus.
Precautions must be taken in patients at risk for increased intracranial pressure.
Infants, elderly and patients with serum sodium levels in the lower range of normal may have an increased risk of hyponatraemia.
Treatment with MINIRIN injection should be interrupted or carefully adjusted during acute intercurrent illnesses characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, gastroenteritis) as well as in excessive bleeding, and the fluid and electrolyte balance should be carefully monitored.
Special attention should be given when desmopressin is co-administered with other drugs affecting water and/or sodium homeostasis (see Interactions). In patients with chronic therapy with drug(s) affecting water and/or sodium homeostasis, MINIRIN injection should be administered after confirmation of normal baseline sodium.
Precautions must be taken in patients with moderate and severe renal insufficiency (creatinine clearance below 50 ml/min).
MINIRIN injection should not be used in patients with hypersensitivity to desmopressin or to any of the excipients in the product (see Adverse Reactions).
Due to post-marketing reports with MINIRIN injections of deep vein thrombosis, cerebrovascular accident and disorder (stroke), cerebral thrombosis, myocardial infarction, angina pectoris and chest pain, considerations should be taken before using MINIRIN injection in elderly patients and in patients with risk factors and history of thrombosis, thrombophilia and known cardiovascular disease.
Nasal spray: MINIRIN nasal formulations should be used only when treatment with oral formulations is inappropriate.
When MINIRIN is prescribed it is recommended to: start with the lowest dose; ensure compliance with fluid restriction instructions; increase dose progressively, with caution; ensure that children administration is under adult supervision in order to control the dose intake.
MINIRIN should be used with caution to prevent fluid overload in: the treatment of small children and elderly patients; patients with fluid and/or electrolyte imbalance; patients with risk of increased intracranial pressure.
Without simultaneous reduction in fluid intake, treatment can lead to water retention and/or hyponatraemia (headache, nausea/vomiting, weight gain and in serious cases convulsions).
Elderly patients, patients with low plasma sodium levels and patients with high 24-hour urine volumes (above 2.8 to 3 litres) have an increased risk of developing hyponatraemia.
In patients with urgency/urge incontinence, organic causes for increased micturition frequency or nocturia (e.g. benign prostatic hyperplasia, urinary tract infection, bladder stones/tumours), polydipsia or poorly controlled diabetes mellitus, the specific cause of the symptoms should be dealt with primarily.
To prevent hyponatraemia, caution must be exercised and particular attention should be paid to fluid retention and frequent checks made of sodium plasma levels in the following circumstances: concomitant treatment with drugs that are known to induce inappropriate ADH secretion syndrome (SIADH), e.g. tricyclic antidepressants, SSRIs, chloropromazine and carbamazepine as well as some antidiabetics of the sulfonylurea group such as chlorpropamide; concomitant treatment with NSAID preparations.
Treatment with desmopressin should be carefully adjusted during acute illness characterized by fluid and/or electrolyte imbalance such as systemic infections, fever and gastroenteritis.
Experience from clinical use indicates a risk of severe hyponatraemia in association with the nasal formulation of desmopressin, when it is used in the treatment of central diabetes insipidus.
MINIRIN 0.1mg/ml nasal spray may cause bronchospasm due to the presence of benzalkonium chloride in this product.
At testing of renal concentration capacity: When used diagnostically, fluid intake should be restricted to a maximum of 0.5 L to satisfy thirst for 1 hour before administration until 8 hours after administration. Renal concentration capacity testing in children below 1 year of age should only be performed in hospital and under careful supervision.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: MINIRIN tablets has no or negligible influence on the ability to drive and use machines.

Pregnancy: Tablet & Oral lyophilisate: 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 bleeding complications 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, embryonic/foetal development, parturition or postnatal development.
Caution should be exercised when prescribing 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 concentration corresponding to recommended dose.
Nasal spray: 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 doses.
Injection & Nasal spray: Published data on a limited number of exposed pregnancies in women with diabetes insipidus (n=53) as well as data on exposed pregnancies in women with bleeding complications (n=216) 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, embryonic/foetal development, parturition or postnatal development.
Caution should be exercised when prescribing MINIRIN to pregnant women.
Injection: Animal reproduction studies have shown no clinically relevant effects on parents and offspring. In vitro analysis of human cotyledon models have shown that there is no transplacental transport of desmopressin when administered at therapeutic concentration corresponding to recommended dose.
Lactation: Results from analyses of milk from nursing mothers receiving a high dose desmopressin acetate (300 microgram intranasally), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.
Nasal spray: Whether desmopressin will accumulate in breast milk upon repeated doses has not been studied.
Fertility: Injection: Studies with desmopressin in animals have shown no impairment of fertility in male and female rats.
Nasal spray: Fertility studies have not been carried out.

Tablet: 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 post marketing have been added in the 'Not known'-frequency column. (See Table 2.)

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Children and adolescents: Based on the frequency of adverse drug reactions reported in clinical trials with oral desmopressin conducted in children and adolescents for treatment of Primary Nocturnal Enuresis (N=1923). Events only seen in post marketing have been added in the 'Not known' frequency column. (See Table 3.)

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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 Precautions).
Oral lyophilisate: 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 (including 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: Not Known: Anaphylactic reaction.
Metabolism and Nutrition Disorders: Common: Hyponatraemia^*. Not Known: Dehydration^**, hypernatraemia^**.
Psychiatric Disorders: Uncommon: Insomnia. Rare: Confusional state^*.
Nervous System Disorders: Very Common: Headache^*. Common: Dizziness*. Uncommon: Somnolence, paraesthesia. Not Known: Convulsions^*, asthenia^**, coma^*.
Eye Disorders: Uncommon: Visual impairment.
Ear and Labyrinth Disorders: Uncommon: Vertigo^*.
Cardiac Disorders: Uncommon: Palpitations.
Vascular Disorders: Common: Hypertension. Uncommon: Orthostatic hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea.
Gastrointestinal Disorders: Common: Nausea^*, abdominal pain^*, diarrhoea, constipation, vomiting*. Uncommon: Dyspepsia, (HLT) flatulence, bloating, distention.
Skin and Subcutaneous Tissue Disorders: Uncommon: Sweating, pruritus, rash, urticaria. Rare: Allergic dermatitis.
Musculoskeletal and Connective Tissue Disorders: Common: Myalgia. Uncommon: Muscle spasms.
Renal and Urinary Disorders: (HLT) Bladder and urethral symptoms.
General Disorders and Administration Site Conditions: Common: (HLT) Oedema, fatigue. Uncommon: Malaise*, chest pain, influenza-like illness.
Investigations: Uncommon: Increased weight, increased hepatic enzyme, hypokalaemia.
^*Hyponatraemia may cause headache, abdominal pain, nausea, vomiting, increased weight, dizziness, confusion, malaise, memory impairment, vertigo, falls and in severe cases, convulsions and coma.
^**Only seen in the CDI indication.
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: Not Known: Anaphylactic reaction.
Metabolism and Nutrition Disorders: Not Known: Hyponatraemia^*.
Psychiatric Disorders: Uncommon: Affect lability^**, aggression^***. Rare: (HLT) Anxiety symptoms, nightmare^*, mood swings^****. Not Known: Abnormal behaviour, emotional disorder, depression, hallucination, insomnia.
Nervous System Disorders: Common: Headache^*. Rare: Somnolence. Not Known: Attention disturbance, psychomotor hyperactivity, convulsions^*.
Vascular Disorders: Rare: Hypertension.
Respiratory, Thoracic and Mediastinal Disorders: Not Known: Epistaxis.
Gastrointestinal Disorders: Uncommon: Abdominal pain^*, nausea^*, vomiting^*, diarrhoea.
Skin and Subcutaneous Tissue Disorders: Not Known: Allergic dermatitis, rash, sweating, urticaria.
Renal and Urinary Disorders: (HLT) Bladder and urethral symptoms.
General Disorders and Administration Site Conditions: Uncommon: Peripheral oedema, fatigue. Rare: Irritability.
^*Hyponatraemia may cause headache, abdominal pain, nausea, vomiting, increased weight, 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).
Injection: Summary of the safety profile: The most frequently reported adverse reaction with MINIRIN injection during post marketing is hyponatraemia. Hyponatraemia may cause headache, nausea, vomiting, water intoxication, weight increase, malaise, abdominal pain, muscle cramps, dizziness, confusion, decreased consciousness, generalized or local oedemas (peripheral, face), and in severe cases brain oedema, hyponatraemic encephalopathy, convulsions, and coma (see Precautions).
Rare cases of serious hypersensitivity reactions including anaphylactoid shock and reaction have been reported in association with MINIRIN injection (see Precautions).
Tabulated list of adverse reactions: The table as follows is based on the frequency of adverse drug reactions reported in clinical trials with MINIRIN injection conducted in adults for treatment of central diabetes insipidus and haematological indications (N=53) and OCTOSTIM injections (n=76), combined with the post marketing experience for MINIRIN/OCTOSTIM injections. Reactions only seen in post marketing or in other desmopressin formulations have been added in the 'Not known' frequency column. The table as follows shows the frequencies of adverse reactions reported. Adverse reactions are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000) and Not known (cannot be estimated from the available data). (See Table 4.)

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Description of selected adverse reactions: During post-marketing the most frequently reported adverse reaction with MINIRIN/OCTOSTIM injection is hyponatraemia. Hyponatraemia may cause headache, nausea, vomiting, water intoxication, weight increase, malaise, abdominal pain, muscle cramps, dizziness, confusional state, decreased consciousness, generalized or local oedemas (peripheral, face), and in severe cases brain oedema, hyponatraemic encephalopathy, convulsions, and coma. Nausea, vomiting, headache and dizziness have been reported without registered hyponatraemia. The hyponatraemia is a result of the antidiuretic effect, arising from increased water reabsorption by the renal tubules and osmotic dilution of plasma. Special attention should be paid to the precautions addressed in Warnings and Precautions.
Hyponatraemia is reversible. Treatment should be individualised and rapid overcorrection should be avoided to reduce the risk of further complications (see Dosage & Administration and Precautions).
Post-marketing hypersensitivity reactions including local allergic reactions such as dyspnoea, erythema, generalized or local oedemas (peripheral, face), pruritus, rash, rash macular, rash maculopapular, rash erythematous, skin plaque and urticaria, have been reported in association with MINIRIN/OCTOSTIM injection. More serious hypersensitivity reactions including anaphylactic shock and reaction, and anaphylactoid shock and reaction have also been reported in association with MINIRIN/OCTOSTIM injection. Allergic reactions usually occur rapidly after drug administration and may occur during first time usage or after repeated exposure of MINIRIN/OCTOSTIM injection.
Rare post-marketing cases of deep vein thrombosis, cerebrovascular accident/disorder (stroke), cerebral thrombosis, pulmonary embolism, myocardial infarction, angina pectoris and chest pain have been reported in patients treated with desmopressin. Due to confounding factors and/or missing information, a causal relationship with MINIRIN/OCTOSTIM injection has not been established/confirmed.
Paediatric population: Adverse reaction data from clinical trials in children is very limited.
Other special populations: Elderly and patients with serum sodium levels in the lower range of normal may have an increased risk of developing hyponatraemia (see Precautions).
Nasal Spray: Summary of the safety profile: The most serious adverse reaction with desmopressin is hyponatraemia, see "Description of selected adverse reactions".
The most commonly reported adverse reactions during treatment were nasal congestion (27%), high body temperature (15%) and rhinitis (12%). Other common adverse reactions were headache (9%), upper respiratory tract infection (9%), gastroenteritis (7%), abdominal pain (5%). Anaphylactic reactions have not been seen in clinical trials but spontaneous reports have been received.
Tabulated summary of adverse reactions: The following table is based on the frequency of adverse drug reactions reported in clinical trials with nasal MINIRIN conducted in children and adults for treatment of central diabetes insipidus, primary nocturnal enuresis and at testing of renal concentration capacity (N=745) combined with the post marketing experience for all indications. Reactions only reported post-marketing or for other desmopressin formulations have been added in the "Not known" frequency column. (See Table 5.)

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Description of selected adverse reactions: The most serious adverse reaction with desmopressin is hyponatraemia, which may give symptoms like headache, nausea, vomiting, weight increase, malaise, abdominal pain, muscle spasms, dizziness, confusion, decreased consciousness and in serious cases convulsions and coma. The cause of the potential hyponatraemia is the anticipated antidiuretic effect.
Paediatric population: Hyponatraemia is reversible and in children it is often seen to occur in relation to changes in daily routines affecting fluid intake and/or perspiration.
Special precautions should be observed in children, see Precautions.
Special populations: Elderly patients and patients with low serum sodium levels may have an increased risk of developing hyponatraemia (see Precautions).

Substances, which are known to induce SIADH, e.g. opioids (injection only), 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/hyponatremia (see Precautions).
Indomethacin increases the urine concentrating effect of desmopressin without influencing the duration. The effect is probably without any clinical significance.
NSAIDs may induce water retention/hyponatraemia (see Precautions).
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.
Tablet & Oral lyophilisate: 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.
Tablet: The concomitant use of food decreases the rate and extent of absorption of MINIRIN tablets by 40%. 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 MINIRIN tablets.

INCOMPATIBILITIES: Tablet: Not applicable.
Injection: This medicinal products must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING: Tablet: No special requirements.
Injection: For intravenous infusion the dose (0.3 μg/kg body weight) should be diluted in 0.9% sodium chloride for injection (physiological saline) and given over 15-30 minutes.
Nasal spray: Before MINIRIN nasal spray is used for the first time, the pump should be primed by pressing it downwards 4 times, or until an even spray is obtained. If the spray has not been used during the previous week, the pump must be primed again by pressing once or until an even spray is obtained.
Important: The lower end of the tube must always be submerged in the liquid when using the spray.
At the least hesitation whether correct dose is administered, no further spray dose should be given until the next time for administration. In small children the administration should be monitored by an adult to ensure correct dosing.
Instructions for Use: Nasal spray: 1. Remove the protective cap.
2. Hold the bottle.
3. Tilt the head slightly backwards. Insert the nasal applicator into one nostril. Hold breath and spray once.
4. If the patient was prescribed more than one dose, repeat the administration in the other nostril. For every further dose, change nostrils and repeat according to instructions.
5. Replace the protective cap. Always store the bottle upright.

SHELF LIFE: Tablet: 36 months.
Oral lyophilisate: 36 months.
Injection: 48 months.
Nasal spray: 3 years.
Minirin tablets: Do not store above 25°C.
Keep the container tight closed and do not remove the desiccant capsule from the cap.
Minirin oral lyophilisate should not be stored above 30°C. Store in the original package in order from moisture and light.
MINIRIN injection should be stored at 2-8°C.
Minirin nasal spray should not be stored above 25°C at room temperature.

Antidiuretics / Haemostatics

H01BA02 - desmopressin ; Belongs to the class of vasopressin and analogues. Used in posterior pituitary lobe hormone preparations.

POM