Minirin

Minirin

desmopressin

Manufacturer:

Ferring

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Desmopressin acetate.
Description
Each mL of solution for nasal spray contains desmopressin acetate 0.1 mg, benzalkonium chloride (preservative) 0.1 mg, constituents and purified water to 1 mL. Minirin (dDAVP) nasal spray is supplied in bottles provided with precompression spray pumps designed to deliver 100 microliter solution (=10 mcg) per actuation. Each mL of intranasal rhinyle contains desmopressin acetate 0.1 mg, chlorobutanol (preservative) 5 mg, sodium chloride, hydrochloric acid (to adjust pH to 4) and purified water to 1 mL. Minirin (dDAVP) intranasal rhinyle is supplied in a bottle with 2 rhinyle tubes marked with volumes from 0.025-0.2 mL. Each ampoule for injection contains desmopressin acetate 4 mcg, sodium chloride 9 mg, hydrochloric acid (to adjust pH to 4) and water for injection.
Action
Desmopressin is a structural analogue of the natural hormone arginine vasopressin. Two chemical changes have been made to the natural hormone eg, desamination of 1-cysteine and substitution of 8-L-arginine by 8-D-arginine. These structural changes result in a compound with significantly increased antidiuretic potency, very little activity on smooth muscle, hence the avoidance of undesirable pressor side effects. The duration of the antidiuretic effect is about 8-12 hrs. Minirin (dDAVP) in a high dosage, 0.3 mcg/kg body weight IV or SC, leads to a 2- to 4-fold 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). Maximum plasma concentration following a dose of 0.3 mcg/kg body weight is reached after approximately 60 min and amounts to an average of 600 pg/mL. Plasma half-life ranges between 3 and 4 hrs. The duration of the haemostatic effect depends on the plasma half-life for VIII:C which is about 8-12 hrs. Administration of desmopressin has also been shown to lead to a shortening or normalization 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. The risk of transmission of HIV infection and hepatitis virus as seen for factor VIII concentrates is avoided by administration of desmopressin. The pH of the solution is about 4.
Indications/Uses
Central Diabetes Insipidus: The use of Minirin (dDAVP) 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 also indicated in the symptomatic treatment of nocturia in adults associated with nocturnal polyuria ie, nocturnal urine production exceeding bladder capacity.
Primary Nocturnal Enuresis: Minirin (dDAVP) tablet is indicated for the treatment of primary nocturnal enuresis in patients ≥5 years who have normal ability to concentrate urine.
Nocturia: Minirin (dDAVP) tablet and injection is indicated for the symptomatic treatment of nocturia in adults associated with nocturnal polyuria ie, nocturnal urine production exceeding bladder capacity.
Renal Concentrating Capacity Test: Minirin (dDAVP) nasal spray, intranasal rhinyle and injection 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, opposite to pyelonephritis, will not cause a subnormal ability to concentrate urine.
Hemophilia A and von Willebrand's Disease: Minirin (dDAVP) injection is indicated for the therapeutic control of bleeding and bleeding prophylaxis in connection with minor surgical procedures in patients with mild Hemophilia 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.
Other Bleeding Disorders: Minirin (dDAVP) injection is also indicated in shortening or normalization of prolonged bleeding time prior to an invasive therapeutic or diagnostic operation, or for therapeutic control of bleeding in patients with prolonged bleeding time as a consequence of congenital or drug-induced thrombocyte dysfunction, uremia, cirrhosis of the liver or in patients with prolonged bleeding time of unknown etiology.
Dosage/Direction for Use
One metered dose of nasal spray administers 0.1 mL which corresponds to 10 mcg desmopressin acetate.
One mark of the rhinyle tube (0.05 mL) corresponds to 5 mcg desmopressin acetate.
Central Diabetes Insipidus: Tablet: Adults and Children: Initial Dose: 0.1 mg 3 times daily. The dose is then adjusted according to the response of the patient. According to the clinical experience gained so far, the daily dose varies between 0.2 and 1.2 mg. For most patients, 0.1-0.2 mg 3 times daily is the optimal dose regimen.
Nasal Spray and Intranasal Rhinyle: Dosage is individual but clinical experience has shown that the normal daily dose for adults is 10-20 mcg 1-2 times daily and for children 5-10 mcg 1-2 times daily.
Injection: The injection may be used when the intranasal administration is considered unsuitable. The dosage is determined for each patient and adjusted according to urine volume and serum sodium. Normal dosage, IV injection: Adults: 1-4 mcg (0.25-1 mL) 1-2 times daily. Children >1 year: 0.4-1 mcg (0.1-0.25 mL) 1-2 times daily; <1 year: 0.2-0.4 mcg (0.05-0.1 mL) 1-2 times daily. For patients who have been controlled on intranasal Minirin (dDAVP) 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.
Primary Nocturnal Enuresis: Tablet: Initial Dose: 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 re-assessed after 3 months by means of a period of at least 1 week without Minirin (dDAVP) treatment. A restricted water intake must be observed.
Nocturia: Tablet: Initial Dose: 0.1 mg at bedtime. If dose is not sufficiently effective after 1 week, it can be increased to 0.2 mg and then to 0.4 mg by means of weekly increases. Fluid restriction is to be enforced.
In nocturic patients, a frequency/volume chart should be used to diagnose nocturnal polyuria for at least 2 days and nights before starting treatment. A night-time urine production exceeding functional bladder capacity or exceeding 1/3 of the 24-hr urine production is regarded as nocturnal polyuria.
Renal Concentrating Capacity Test: The reference level for normal urine osmolality after Minirin (dDAVP) administration is 800 mOsmol/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.
Nasal Spray and Intranasal Rhinyle: Adults: Normal Dose: 40 mcg. Children >12 months: 20 mcg. <12 months: 10 mcg. After administration of Minirin (dDAVP), any urine collected within 1 hr is discarded. During the next 8 hrs, 2 portions of urine are collected for osmolality testing. Fluid restriction should be observed (see also Precautions).
Injection: Adults: 4 mcg (1 mL) IM or SC. Children >12 months: 0.4-1 mcg (0.1-0.25 mL) 1-2 times daily. <12 months: 0.2-0.4 mcg (0.05-0.1 mL) 1-2 times daily. For children, it is recommended to use primarily the intranasal presentation. After administration of Minirin (dDAVP), possible urine collected within 1 hr is discarded. During the next 8 hrs, 2 portions of urine are collected for measurement of osmolality. Special attention must be paid to the risk of water retention. The fluid intake should be restricted to least possible and the body weight should be checked regularly.
The fluid intake should be restricted to least possible and the body weight should be checked regularly. The fluid intake must be limited and not exceed 0.5 L from 1 hr before until 8 hrs after administration.
Hemophilia A and von Willebrand's Disease: Injection: Therapeutic Control of Bleeding or Bleeding Prophylaxis Prior to an Invasive Operation: 0.3 mcg/kg body weight diluted in physiological saline to 50-100 mL and given as an IV infusion over 15-30 min.
If a positive effect is obtained, the initial Minirin (dDAVP) dose may be repeated 1-2 times with intervals of 6-12 hrs. Further repetition of the dose may result in a reduced effect.
In patients with hemophilia, 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 (dDAVP) 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 hemophilia should be conducted in consultation with each patient's coagulation laboratory.
Determination of the Coagulation Factor and Bleeding Time Before 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 eg, 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.
Administration: Before using Minirin (dDAVP) nasal spray for the first time, prime the pump by pressing it downwards 4 times, or until an even spray is obtained. If the nasal spray has not been used during the last week, it is necessary to prime it again by pressing it downwards once, or until an even spray appears. Note: The end of the tube inside the bottle must always be submerged in the liquid when spraying.
Instructions for Use: Nasal Spray: Remove the productive cap from the applicator. Hold the bottle in upright position. Tilt head backwards slightly. Insert the nasal applicator into one nostril. Hold the breath as the dose is administered. If >1 dose is prescribed, repeat administration in the other nostril. Use alternative nostrils for each additional dose. Replace the protective cap. Always store the bottle upright.
Intranasal Rhinyle: Pull plastic tag on neck of bottle.
Break security seal and remove plastic cap.
Twist-off the small knurled seal from the dropper. Use the same seal (reversed) to prevent subsequent leakage, especially if the bottle is not stored upright.
Take the calibrated part of the plastic tube (rhinyle) in one hand and place the fingers of the other hand around the cylindrical part of the dropper. Insert the top of the dropper in a downward position into the end of the rhinyle marked with an arrow and squeeze the dropper until the solution has reached the desired mark. The un-numbered mark between the end and the 0.05 mark is approximately the 0.025 mL position. If difficulty is experienced in filling the rhinyle, a diabetic or tuberculin syringe may be used to draw up the dose and load the rhinyle tube.
Hold the rhinyle with the fingers approximately 3/4 inch from the end and insert it into a nostril until the tips of the fingers reach the nostril.
Put the other end of the rhinyle into the mouth. Hold the breath, tilt back the head and then blow with a short strong puff through the rhinyle so that the solution reaches the right place in the nasal cavity. Through this procedure, the medication is limited to the nasal cavity and the preparation does not pass down into the back of the throat.
After use, close the bottle with the plastic cap, wash the rhinyle in water and shake thoroughly, until no more water is left. The rhinyle can then be used for the next application.
Overdosage
Overdosage increases the risk of fluid retention and hyponatremia. Although the treatment of hyponatremia should be individualized, the following general recommendations can be given: Asymptomatic hyponatremia is treated with discontinuation of desmopressin treatment and fluid restriction. Infusion of isotonic or hypertonic sodium chloride may be added in cases with symptoms. When the fluid retention is severe (convulsions and unconsciousness), treatment with furosemide should be added.
Contraindications
Hypersensitivity to desmopressin or to any constituents of Minirin (dDAVP). Minirin (dDAVP) must not be used in cases of habitual and psychogenic polydipsia urine production exceeding 40 mL/kg/24 hrs), syndrome of inappropriate antidiuretic hormone secretion (SIADH), known hyponatremia, moderate to severe renal insufficiency (creatinine clearance <50 mL/min).
For Renal Concentration Capacity Testing: History of known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics.
For Hemostatic Use: Unstable angina pectoris, decompensated cardiac insufficiency and von Willebrand's disease type IIB.
Warnings
In the treatment of primary nocturnal enuresis and nocturia, fluid intake shall be limited to the least possible during the period of 1 hr before and 8 hrs after administration. Treatment without concomitant reduction in fluid intake can lead to water retention and/or hyponatremia (headache, nausea/vomiting, weight gain and in serious cases, convulsions).
In patients with urgency/urge incontinence, organic causes for increased micturition frequency or nocturia [eg, benign prostatic hyperplasia (BPH), urinary tract infection, bladder stones/tumors], polydipsia and poorly adjusted diabetes mellitus, the specific cause should be treated.
In clinical trials, higher occurrence of hyponatremia was found in patients >65 years. Therefore, initiation of treatment in the elderly is not recommended, especially not in those patients suffering from other conditions that may increase the likelihood of fluid or electrolyte imbalance.
Elderly patients, patients with low serum sodium levels and patients with a high 24-hr urine volume (>2.8-3 L) may have an increased risk for hyponatremia.
In connection with the infusion of Minirin (dDAVP) for hemostatic use, the patient's blood pressure must be monitored continuously. Minirin (dDAVP) does not reduce prolonged bleeding time in thrombocytopenia.
Special Precautions
General: Particular precautions to prevent fluid overload must be taken in very young and elderly patients, conditions characterized by fluid and/or electrolyte imbalance and patients at risk for increased intracranial pressure. To prevent hyponatremia, 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 SIADH eg, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), chlorpromazine and carbamazepine. Concomitant treatment with NSAID preparations. Treatment with desmopressin should be carefully adjusted during acute illness characterized by fluid and/or electrolyte imbalance eg, systemic infections, fever and gastroenteritis. For Renal Concentrating Capacity Testing: Testing in children <1 year should only be performed in hospital and under careful supervision. When used for diagnostic purposes, the fluid intake must be limited to a maximum of 0.5 L to quench thirst from 1 hr before until 8 hrs after administration.
For Hemostatic Use: Measures to prevent fluid overload must be taken in patients with conditions requiring treatment with diuretic agents. Nasal Spray: Minirin (dDAVP) nasal spray should only be used when oral formulations are unsuitable. Recommendations when Minirin (dDAVP) is Prescribed: Administration to children should be supervised by an adult to ensure that the correct dose is given. Minirin (dDAVP) nasal spray may cause bronchospasm due to the presence of benzalkonium chloride. There is some evidence from post-marketing data for the occurrence of severe hyponatremia in association with the nasal spray formulation of desmopressin, when it is used in the treatment of cranial diabetes insipidus.
Use in pregnancy: Data on a limited number (n=53) of pregnant women who were treated for diabetes insipidus indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus/newborn. No other relevant epidemiological data are available. Animal studies do not indicate direct to indirect adverse effects with respect to pregnancy, development of the embryo/fetus, childbirth or postnatal development. Caution should be exercised when prescribing to pregnant women.
Use in lactation: Results from analyses of milk from nursing mothers receiving high-dose desmopressin (300 mcg intranasally), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis. Whether desmopressin will accumulate in breast milk upon repeated doses has not been studied.
Use In Pregnancy & Lactation
Use in pregnancy: Data on a limited number (n=53) of pregnant women who were treated for diabetes insipidus indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus/newborn. No other relevant epidemiological data are available. Animal studies do not indicate direct to indirect adverse effects with respect to pregnancy, development of the embryo/fetus, childbirth or postnatal development. Caution should be exercised when prescribing to pregnant women.
Use in lactation: Results from analyses of milk from nursing mothers receiving high-dose desmopressin (300 mcg intranasally), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis. Whether desmopressin will accumulate in breast milk upon repeated doses has not been studied.
Adverse Reactions
Treatment without concomitant reduction of fluid intake may lead to fluid retention/hyponatremia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, decreased serum sodium, weight gain and in severe cases, convulsions). Primary Nocturnal Enuresis and Diabetes Insipidus: Common (>1/100): General: Headache. At high doses: Fatigue. Circulation: At high doses: Transient fall in blood pressure with a reflex tachycardia and facial flushing at the time of administration. Gastrointestinal: Abdominal pain, nausea. Upper Respiratory Tract: Nasal congestion/rhinitis, epistaxis. Rare (<1/1000): General: At high doses: Dizziness. Very Rare (<1/10,000): Metabolism: Hyponatremia. Treatment without concomitant restriction of water intake may lead to water retention with accompanying signs and symptoms (reduced serum sodium, weight gain and in serious cases, convulsions). Post-Marketing Experience: Isolated cases of emotional disturbances in children, allergic skin reactions and more severe general allergic reactions have been reported. Nocturia: Common: Hyponatremia (low serum sodium levels), headache, dizziness, peripheral edema, more frequent need of urinating during daytime, stomach pain, nausea, dry mouth and weight gain.
Drug Interactions
Substances which are known to release antidiuretic hormone eg, tricyclic antidepressants, SSRIs, chlorpromazine and carbamazepine may cause an additive antidiuretic effect leading to an increased risk of water retention/hyponatremia. Medicines that slow down intestinal passage and some pain-reliever and anti-inflammatory (NSAIDs) may reinforce the effect of Minirin (dDAVP), with an increased risk of water retention/hyponatremia (see Precautions). Concomitant treatment with dimeticone may result in a decreased absorption of Minirin (dDAVP).
Storage
Tablet: Store at room temperature (maximum 25°C) and in a dry place (maximum 60% relative humidity). Nasal Spray: Store at room temperature (maximum 25°C). Intranasal Rhinyle: Store in a refrigerator at 2-8°C. When travelling at room temperature (maximum 25°C), closed bottles will maintain stability for 4 weeks. Injection: Store at 2-8°C. Stable for 3 years.
ATC Classification
H01BA02 - desmopressin ; Belongs to the class of vasopressin and analogues. Used in posterior pituitary lobe hormone preparations.
Presentation/Packing
Tab 0.1 mg x 30's. 0.2 mg x 30's. Nasal spray 0.1 mg/mL x 2.5 mL. Intranasal rhinyle 0.1 mg/mL x 2.5 mL. Inj 4 mcg/mL x 1 mL x 10's.
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