Antidiuretic Hormone Analogue
Action And Clinical Pharmacology: Desmopressin is a synthetic structural analogue of the natural human hormone, arginine vasopressin. As such, it exerts its action on the reabsorption of water in the renal tubule.
It also causes a transient increase in all components of the Factor VIII complex and plasminogen activator. These are released very rapidly from their endothelial cell storage sites. Moreover, it may have a direct effect on the vessel wall, with increased platelet spreading and adhesion at injury sites. The duration of action is from 8 to 12 hours. 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.
Indications And Clinical Uses: Antidiuretic hormone replacement therapy in the treatment of central diabetes insipidus, primary and secondary.
For patients with hemophilia A with Factor VIII levels greater than 5%. It will often maintain hemostasis in patients with hemophilia A during surgical procedures and postoperatively, when administered 45 minutes prior to scheduled procedure. It 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 and 5%, however, these patients should be carefully monitored.
Desmopressin is not indicated for the treatment of hemophilia B because it has no effect on Factor IX levels.
Desmopressin should not be given to patients with Factor VIII antibodies.
Von Willebrand’s Disease (Type 1): For patients with mild to moderate classic von Willebrand’s disease (Type 1) with Factor VIII levels greater than 5%. Desmopressin will often maintain hemostasis in patients with mild to moderate von Willebrand’s disease during surgical procedures and postoperatively when administered 45 minutes prior to the scheduled procedure.
Desmopressin will usually stop bleeding in mild to moderate von Willebrand’s disease 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 coagulant activity, 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 1 von Willebrand’s Disease and Type II B and when there is evidence of an abnormal molecular form of Factor VIII antigen (see Warnings).
Contra-Indications: Hypersensitivity to desmopressin.
Manufacturers’ Warnings In Clinical States: When used for bleeding disorders, desmopressin is for i.v. use only, by infusion. Patients who do not have 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.
Desmopressin should not be used to treat patients with Type II B von Willebrand’s Disease, since severe thrombocytopenia may be induced.
Desmopressin must be used with caution in patients prone to vascular headaches, patients with coronary insufficiency and hypertensive cardiovascular diseases, because of possible change in blood pressure and tachycardia. Very occasionally, injection of desmopressin has produced local erythema, swelling or burning pain, along course of vein.
Desmopressin has no therapeutic effect in Glanzmann’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 anti-fibrinolytic agents to counteract desmopressin-induced plasminogen activator release has been recommended; however, benefit has not been clearly established.
Desmopressin has no therapeutic effect in renal diabetes insipidus.
Precautions: Use desmopressin with caution in patients with coronary arterial insufficiency and/or hypertensive cardiovascular disease because of possible tachycardia, and changes in blood pressure. Severe allergic reactions have not been reported with desmopressin. It is not known whether antibodies to desmopressin acetate are produced after repeated injections.
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.
Hemophilia B: Desmopressin should not be used for these patients, because it has no effect on Factor IX levels.
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 pre-operatively.
Diabetes Insipidus: In the control of diabetes insipidus, use the lowest effective dose and assess dosage periodically.
Do not administer desmopressin to dehydrated patients until water balance has been adequately restored.
Laboratory tests for monitoring the patient include urine volume and osmolality. In some cases, plasma osmolality may be required.
Pregnancy: Reproduction studies performed in rats and rabbits with s.c. doses up to 12.5 times the human dose when used for Factor VIII stimulation and 125 times the human dose when used in diabetes insipidus have revealed no evidence of harm to the fetus due to desmopressin. There are several publications of management of diabetes insipidus in pregnant women with no harm to the fetus reported; however, there are no adequate and well controlled studies in pregnant women. Published reports stress that, as opposed to preparations containing the natural hormones, desmopressin in antidiuretic doses has no uterotonic action, but the physician will have to weigh possible therapeutic advantages against possible danger in each case.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when desmopressin is administered to a nursing woman.
Children: Observe children closely for possible hyponatremia and water intoxication due to overingestion of fluids.
Desmopressin should not be used in infants younger than 3 months in the treatment of hemophilia A or von Willebrand’s disease.
Adverse Reactions: Infrequently, desmopressin has produced transient headache, nausea, mild abdominal cramps and vulvar pain. These symptoms disappear with reduction in dosage. Facial flushing, tachycardia (20 to 40%), mild hypotension (fall in systolic and diastolic blood pressure by approximately 15 torr) have also been reported, and decreased urine output for 6 to 8 hours commonly observed. See Warnings for the possibility of water intoxication and hyponatremia.
Very occasionally, injection of desmopressin has produced local erythema, swelling or burning pain, along course of vein.
Drug Interactions: Although the pressor activity of desmopressin is very low compared with the antidiuretic activity, the use of desmopressin doses as large as 0.3 Âµg/kg with other pressor agents, should be done only with careful patient monitoring.
The coincident use of antifibrinolytic agents to counteract desmopressin-induced plasminogen activator release, has been recommended. Desmopressin has been used with epsilon aminocaproic acid or used with tranexamic acid without adverse effects. However, benefit has not been clearly demonstrated.
Symptoms And Treatment Of Overdose: Symptoms: Headaches, abdominal cramps and nausea (see Adverse Effects).
Treatment: No specific antidote. Reduce dosage and frequency of administration or withdraw the drug according to severity of the condition.
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: Desmopressin is administered as an i.v. infusion. Children: 0.3 Âµg/kg. Adults: 10.0 Âµg/m(maximum dose 20 µg).
Dilution for infusion: Diluted in sterile physiological saline and infused 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. (If desmopressin is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure.) The peak effect is obtained in 1 hour after administration. Response is immediate for bleeding time reduction.
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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Diabetes Insipidus: Diagnosis of Central Diabetes Insipidus: Central diabetes insipidus may be demonstrated by the inability to produce urine osmolality above 175 mOsm/kg with dehydration severe enough to cause a loss of greater than 2% of body weight. The patient responding to 5 units of arginine vasopressin given s.c. after dehydration confirms the diagnosis of central diabetes insipidus.
Parenteral application: Desmopressin may be administered s.c., i.m. or i.v. In the majority of adults 1 to 4 Âµg once daily will provide satisfactory control of the diabetes insipidus. In children a dose of 0.4 µg once a day may be used. The dose should be drawn up from the ampul at a fraction of a mL, using an insulin syringe and not prepared by dilution.
Desmopressin dosage must be determined for each patient and adjusted according to the pattern of response. Response should be estimated by 2 parameters: adequate duration of sleep and adequate, not excessive, water turnover.
To institute desmopressin therapy, patients should be withdrawn from previous medication and allowed to establish a baseline polyuria and polydipsia. The stable polyuria is used as a baseline to determine the magnitude and duration of the response to medication. In less severe cases, prior water loading may be desirable to establish a vigorous flow of urine. When the urine osmolality reaches a plateau at the low level (in most cases, less than 100 mOsm/kg), the first dose of desmopressin is administered intranasally or parenterally. A urine sample is obtained after 2 hours and hourly thereafter following desmopressin administration. Samples are measured for volume and osmolality. When the patient has reached the previous baseline urine osmolality and urine flow, the drug effect has ceased and the next desmopressin dose is administered. The cycle is then repeated until the patient has reached a stable condition.
I.V., I.M. or S.C.: Children: 0.1 mL (0.4 Âµg) once daily. Adults: 0.25 to 1 mL (1 to 4 µg) once daily.
One mL (4 µg) of desmopressin solution has an antidiuretic activity of about 16 IU.; 1 µg of desmopressin is equivalent to 4 IU.
For patients who have been controlled on intranasal desmopressin 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 explained below.
Intranasal administration requires a higher dosage than i.v. administration since only 10% of intranasally administered drug will be absorbed. The intransal dosage that is required is therefore 10 times larger than the i.v. dose, thus an approximate parenteral dosage of 1/10 that of the intranasal, is required and should be adjusted for each patient individually, to obtain an adequate diurnal rhythm of water turnover.
Availability And Storage: Each ampul contains: desmopressin acetate 4 µg (equivalent to 3.6 µg free base) in 1 mL of an isotonic sterile and pyrogen-free water solution, for i.v., i.m. or s.c. administration. Ampuls of 1 mL, cartons of 10. Store at about 4°C in a refrigerator. Do not freeze. Store away from light.
DDAVP® INJECTION Ferring Desmopressin Acetate Antidiuretic Hormone Analogue
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