Octostim (Desmopressin Acetate)

OCTOSTIM®

Ferring

Desmopressin Acetate

Antihemorrhagic

Action And Clinical Pharmacology: Desmopressin is a synthetic structural analogue of the natural human hormone, arginine vasopressin.

Desmopressin administration causes a transient increase in all components of the Factor VIII complex (Factor VIII coagulant activity, Factor VIII related antigen, and ristocetin cofactor) and in plasminogen activator. Either directly or indirectly, desmopressin causes these factors to be released very rapidly from their endothelial cell storage sites. In addition, desmopressin may have a direct effect on the vessel wall, with increased platelet spreading and adhesion at injury sites.

A second dose given before endothelial cell stores are replenished will not have as great an effect as the initial dose. Responses as great as the initial one usually are seen if 48 hours or more have elapsed between doses.

The pharmacokinetic and pharmacodynamic profiles after s.c. or i.v. administration to healthy volunteers are equivalent. The plasma half-life ranges from 3.2 to 3.6 hours.

Indications And Clinical Uses: For prevention of bleeding in patients with mild hemophilia A and mild von Willebrand’s disease Type I, and for the prevention or treatment of bleeding in patients with uremia.

Hemophilia A: For patients with hemophilia A with Factor VIII levels greater than 5%.

Desmopressin will often maintain hemostasis in patients with hemophilia A during surgical procedures and postoperatively, when administered 30 minutes prior to the scheduled procedure.

Desmopressin will also stop bleeding in hemophilia A patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, i.m. hematomas or mucosal bleeding.

In certain clinical situations, it may be justified to try desmopressin in patients with Factor VIII levels between 2 to 5%; however, these patients should be carefully monitored.

von Willebrand’s Disease (Type I): For patients with mild to moderate classic von Willebrand’s disease (Type I) with Factor VIII levels greater than 5%. Desmopressin will often maintain hemostasis in surgical procedures and postoperatively when administered 30 minutes prior to the scheduled procedure.

Desmopressin will usually stop bleeding in mild to moderate von Willebrand’s patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, i.m. hematomas or mucosal bleeding.

Those von Willebrand’s disease patients who are least likely to respond are those with severe homozygous von Willebrand’s disease with Factor VIII antigen and von Willebrand’s Factor (ristocetin cofactor) activities less than 1%. Other patients may respond in a variable fashion depending on the type of molecular defect they have. Bleeding time and Factor VIII coagulant activity, Factor VIII antigen and von Willebrand’s Factor activities should be checked during administration of desmopressin to ensure that adequate levels are being achieved.

Desmopressin is not indicated for the treatment of severe classic Type I von Willebrand’s disease and Type IIb and when there is evidence of an abnormal molecular form of Factor VIII antigen (see Contraindications).

Other Hemostatic Disorders: For the treatment of prolonged bleeding time in patients with uremia. It will assist in the maintenance of hemostasis in such patients during surgical procedures and post-operatively when administered prior to the procedure.

Therapeutic efficacy (i.e. normalization of bleeding time) should be established in individual patients at the time of diagnosis of the bleeding disorder, or at least 72 hours prior to an elective treatment, by administration of a test dose of desmopressin (see Precautions, Laboratory Tests).

Contra-Indications: Hypersensitivity to desmopressin.

Because of the risk of platelet aggregation and thrombocytopenia, desmopressin should not be used in patients with Type IIb or platelet-type (pseudo) von Willebrand’s disease.

Manufacturers’ Warnings In Clinical States: Patients who do not have a need of antidiuretic hormone for its antidiuretic effect, in particular those who are young or elderly, should be cautioned to ingest only enough fluid to satisfy thirst, in order to decrease potential occurrence of water intoxication and hyponatremia. Patients receiving i.v. therapy must have fluid input and output monitored closely to prevent hyponatremia and water intoxication.

Desmopressin must be used with caution in patients prone to vascular headaches, patients with coronary insufficiency and hypertensive cardiovascular diseases, because of possible changes in blood pressure and tachycardia.

Desmopressin has no therapeutic effect in Glazmann’s thrombasthenia.

Tachyphylaxis may develop with repeated use.

Lack of therapeutic effect has been noted in patients who have been febrile or otherwise stressed for several days. Whenever possible, therapeutic efficacy (i.e. Factor VIII response in hemophilia and bleeding time correction in other disorders) should be established in individual patients prior to use and followed throughout the course of treatment. The coincident use of antifibrinolytic agents to counteract desmopressin-induced plasminogen activator release has been recommended; however, benefit has not been clearly established.

Precautions: General: The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease, because of possible tachycardia, and changes in blood pressure.

Desmopressin should not be used in patients with hemophilia B because it has no effect on Factor IX levels.

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

Desmopressin has an antidiuretic effect. Patients receiving this drug should be cautioned to reduce their ingestion of fluids for at least 6 hours after receiving the drug. Patients receiving i.v. fluids must be placed on fluid input/output monitoring.

Desmopressin should be used with caution in patients with cystic fibrosis because these patients are prone to hyponatremia. Children and geriatric patients should be closely observed for possible water retention due to over ingestion of fluids.

Children: Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication.

No controlled trials have been conducted in children with renal insufficiency. No controlled trials have been conducted in infants under 3 months of age with von Willebrand’s disease or hemophilia A. The physician should weigh possible therapeutic advantages against potential risks in each case.

Pregnancy: Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to desmopressin. The use of desmopressin in pregnant women with no harm to the fetus has been reported; however, no controlled studies have been carried out. Unlike preparations containing the natural hormones, desmopressin in antidiuretic doses has no uterotonic action, but the physician should weigh possible therapeutic advantages against potential risks in each case.

Lactation: There have been no controlled studies in nursing mothers. A single study on a post-partum woman demonstrated a marked change in plasma desmopressin level following an intranasal dose of 10 g, but little drug was detectable in breast milk.

Drug Interactions: Clofibrate, chlorpropamide and carbamazepine may potentiate the antidiuretic activity of desmopressin while demeclocycline, lithium and norepinephrine may decrease in activity.

Although the pressor activity of desmopressin is very low compared with the antidiuretic activity, use of doses of desmopressin as large as 0.3 g/kg with other pressor agents, should be done only with careful patient monitoring.

Laboratory Tests: Hemophilia A: Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII antigen and Factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial thromboplastin time. Factor VIII coagulant activity should be determined before giving desmopressin for hemostasis. If Factor VIII coagulant activity is present at less than 5% of normal, desmopressin should not be relied upon alone.

von Willebrand’s Disease: Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII antigen and Factor VIII ristocetin cofactor (von Willebrand factor). The skin bleeding time may be helpful in following these patients and should always be assessed preoperatively.

Uremia: A test dose of desmopressin should be administered at the time of diagnosis of the bleeding disorder, or at least 72 hours prior to an elective treatment. The skin bleeding times should be measured before and 1 hour after desmopressin administration.

Adverse Reactions: Infrequently, desmopressin has produced transient headache, mild abdominal cramps and vulvar pain. Facial flushing, tachycardia, mild hypotension and oliguria have also been reported.

Side effects following i.v. administration to 297 patients included transient facial flushing (approximately 18%), fatigue (3%), headache (2%), and oliguria (1%). Other effects reported at a frequency of less than 1% included nausea, dizziness, syncope and abdominal cramping.

Side effect following s.c. administration to 190 subjects included transient facial flushing (7%). Other effects reported at a frequency of less than 1% included hypotension, transient headache, abdominal tension, nausea, tachycardia and discomfort at the injection site.

See Warnings for the possibility of water intoxication and hyponatremia. Very occasionally, i.v. injection of desmopressin has produced local erythema, swelling or burning pain along the course of the vein.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Excessive doses may cause headaches, abdominal cramps, nausea and facial flushing. In such cases, the dosage should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition.

There is no known antidote for desmopressin. Water intoxication responds rapidly to diuretic therapy (e.g. furosemide) and appropriate replacement fluid support, without interference with hemostatic effects.

Dosage And Administration: Hemophilia A and von Willebrand’s Disease Type I and Other Hemostatic Disorders: The injection is administered by s.c. injection or as an i.v. infusion over 20 to 30 minutes.

If desmopressin injection is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure. The peak effect is obtained 1 hour after administration. Response is immediate for bleeding time reduction.

S.C. Injection: 0.3 g/kg.

Note: The necessity for repeat administration of desmopressin or use of any blood products for hemostasis should be determined by laboratory response as well as the clinical condition of the patient. The tendency toward tachyphylaxis (lessening of response) with repeated administration, given more frequently than every 48 hours should be considered in treating each patient.

I.V. Infusion: Children: 0.3 g/kg; adults: 0.3 g/kg (maximum dose 20 g).

Dilution for Infusion: Dilute in sterile physiological saline and infuse slowly over 20 to 30 minutes. In adults and children weighing more than 10 kg, 50 mL of diluent is used; in children weighing 10 kg or less, 10 mL of diluent is used.

Side effects may be decreased by slow infusion. Blood pressure and pulse rate should be monitored during infusion.

Availability And Storage: Each mL contains: desmopressin acetate 15 g with sodium chloride and hydrochloric acid to adjust the pH to 3.5, in water for injection. Ampuls of 1 mL, cartons of 5. Unopened ampuls should be kept in the refrigerator at 2 to 8°C (do not freeze). It is recommended that the storage of the diluted solutions at room temperature does not exceed 24 hours.

OCTOSTIM® Ferring Desmopressin Acetate Antihemorrhagic

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