Desmopressin Acetate
Indications: Diabetes insipidus; Enuresis, primary nocturnal; Hemophilia A; Von Willebrand's disease
DESCRIPTION:
Desmopressin acetate--nasal spray, rhinal tube, and injection) is an antidiuretic hormone affecting renal water conservation and a synthetic analogue of 8-arginine vasopressin. It is chemically defined as follows:
Empirical formula:C48H74N14O17S2
SCH2CH2CO-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2Β·C2H4O2Β·3H2O 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
Molecular Weight is 1183.2
Nasal Spray/Rhinal Tube
Desmopressin is provided as a sterile, aqueous solution for intranasal use. Each ml contains:
Desmopressin acetate - 0.1 mg
Chlorobutanol - 5.0 mg
Sodium Chloride - 9.0 mg
Hydrochloric acid to adjust pH to approximately 4.0
The desmopressin nasal spray compression pump delivers 0.1 ml (10 mcg) of desmopressin per spray.
Injection
Desmopressin is provided as a sterile, aqueous solution for injection. Each ml contains:
Desmopressin acetate - 4.0 mug
Sodium Chloride - 9.0 mg
Hydrochloric acid to adjust pH to 4.0
The 10 ml vial contains chlorobutanol as a preservative (5.0 mg/ml).
CLINICAL PHARMACOLOGY:
Desmopressin contains as active substance 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin, which is a synthetic analogue of the natural hormone arginine vasopressin. One ml (0.1 mg) of desmopressin has an antidiuretic activity of about 400 IU; 10 mug of desmopressin acetate is equivalent to 40 IU.
The biphasic half-lives for desmopressin were 7.8 and 75.5 minutes for the fast and slow phases, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the hormone used in this condition. As a result, desmopressin provides a prompt onset of antidiuretic action with a long duration after each administration. 2. The change in structure of arginine vasopressin to desmopressin has resulted in a decreased vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced antidiuretic activity, so that clinically effective antidiuretic doses are usually below threshold levels for effects on vascular or visceral smooth muscle. 3. Desmopressin administered intranasally has an antidiuretic effect about one-tenth that of an equivalent dose administered by injection.
Injection Only
One ml (4 mcg) of desmopressin acetate solution has an antidiuretic activity of about 16 IU; 1 mug of desmopressin is equivalent to 4 IU.
Desmopressin has been shown to be more potent than arginine vasopressin in increasing plasma levels of factor VIII activity in patients with hemophilia and von Willebrand's disease Type I.
Dose-response studies were performed in healthy persons, using doses of 0.1-0.4 mug/kg body weight, infused over a 10-minute period. Maximal dose response occurred at 0.3-0.4 mug/kg. The response to desmopressin of factor VIII activity and plasminogen activator is dose-related, with maximal plasma levels of 300-400% of initial concentrations obtained after infusion of 0.4 mug/kg body weight. The increase is rapid and evident within 30 minutes, reaching a maximum at a point ranging from 90 minutes to two hours. The factor VII related antigen and ristocetin cofactor activity were also increased to a smaller degree, but still are dose-dependent.
The bioavailability of the subcutaneous route of administration was determined qualitatively using urine output data. The extract fraction of drug absorbed by that route of administration has not been quantitatively determined.
The percentage increase of factor VIII levels in patients with mild hemophilia A and von Willebrand's disease was not significantly different from that observed in normal healthy individuals when treated with 0.3 mug/kg of desmopressin infused over 10 minutes.
Plasminogen activator activity increases rapidly after desmopressin infusion, but there has been no clinically significant fibrinolysis in patient treated with desmopressin.
The effect of repeated desmopressin administration when doses were given every 12 to 24 hours has generally shown a gradual diminution of the factor VIII activity increase noted with a single dose. The initial response is reproducible in any particular patient if there are 2 or 3 days between administrations.
INDICATIONS AND USAGE:
Nasal Spray/Rhinal Tube
Primary Nocturnal Enuresis
Nasal Spray/Rhinal Tube: Desmopressin is indicated for the management of primary nocturnal enuresis. It may be used alone or adjunctive to behavioral conditioning or other non-pharmacological intervention. It has been shown to be effective in some cases that are refractory to conventional therapies.
Central Cranial Diabetes Insipidus
Nasal Spray/Rhinal Tube/Injection: Desmopressin is indicated as antidiuretic replacement therapy in the management of central cranial diabetes insipidus and for management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. It is ineffective for the treatment of nephrogenic diabetes insipidus.
The use of desmopressin in patients with an established diagnosis will result in a reduction in urinary output with increase in urine osmolality and a decrease in plasma osmolality. This will allow the resumption of a more normal life-style with a decrease in urinary frequency and nocturia.
There are reports of an occasional change in response with time, usually greater than 6 months. Some patients may show a decreased responsiveness, others a shortened duration of effect. There is no evidence this effect is due to the development of binding antibodies but may be due to a local inactivation of the peptide.
Patients are selected for therapy by establishing the diagnosis by means of the water deprivation test, the hypertonic saline infusion test, and/or the response to antidiuretic hormone. Continued response to desmopressin can be monitored by urine volume and osmolality.
Desmopressin is also available as a solution for injection when the intranasal route may be compromised. These situations include nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may also be inappropriate where there is an impaired level of consciousness. In addition, cranial surgical procedures, such as transsphenoidal hypophysectomy create situations where an alternative route of administration is needed as in cases of nasal packing or recovery from surgery.
Hemophilia A
Injection: Desmopressin injection is indicated for patients with hemophilia A with factor VIII coagulant activity 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 scheduled procedure.
Desmopressin will also stop bleeding in hemophilia A patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematoses or mucosal bleeding.
Desmopressin is not indicated for the treatment of hemophilia A with factor VII coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in patients who should have factor VIII antibodies.
In certain clinical situations, it may be justified to try desmopressin in patients with factor VIII levels between 2%-5%; however, these patients should be carefully monitored.
von Willebrand's Disease (Type I)
Injection: Desmopressin injection is indicated 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 patients with mild to moderate von Willebrand's disease during surgical procedure 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, intramuscular hematosesa 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 and factor VIII von Willebrand's factor antigen levels 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, ristocetin cofactor activity, and von Willebrand's factor antigen 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 von Willebrand's disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen. (See WARNINGS.)
Diabetes Insipidus
Injection: Desmopressin injection is indicated as antidiuretic replacement therapy in the management of central (cranial) diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. Desmopressin is ineffective for the treatment of nephrogenic diabetes insipidus.
Desmopressin is also available as an intranasal preparation. However, this means of delivery can be compromised by a variety of factors that can make nasal insufflation ineffective or inappropriate. These include poor intranasal absorption, nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may be inappropriate where there is an impaired level of consciousness. In addition, cranial surgical procedures, such as transsphenoidal hypophysectomy, create situations where an alternative route of administration is needed as in cases of nasal packing or recovery from surgery.
CONTRAINDICATIONS:
Known hypersensitivity to desmopressin.
WARNINGS:
Nasal Spray/Rhinal Tube
1. For intranasal use only.
2. In very young and elderly patients in particular, fluid intake should be adjusted in order to decrease the potential occurrence of water intoxication and hyponatremia. Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in seizures which could lead to coma.
Injection
Patients who do not have need of antidiuretic hormone and for its diuretic effect, in particularly those who are young or elderly, should be cautioned to ingest only enough fluid to satisfy thirst, in order to decrease the potential occurrence of water intoxication and hyponatremia.
Fluid intake should be adjusted, particularly in very young and elderly patients, in order to decrease the potential occurrence of water intoxication and hyponatremia. Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma molality that may result in seizures which could lead to coma.
Desmopressin should not be used to treat patients with type IIB von Willebrand's disease since platelet aggregation may be induced.
PRECAUTIONS:
General
Nasal Spray/Rhinal Tube
Desmopressin at high dosage has infrequently produced a slight elevation of blood pressure, which disappeared with a reduction in dosage. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease because of possible rise in blood pressure.
Desmopressin should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, because these patients are prone to hyponatremia.
Central Cranial Diabetes Insipidus: Since desmopressin is used intranasally, changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in which case desmopressin should not be used. For such situations, desmopressin injection should be considered.
Primary Nocturnal Enuresis: If changes in the nasal mucosa have occurred, unreliable absorption may result. Desmopressin should be discontinued until the nasal problems resolve.
Injection
For injection use only.
Desmopressin Injection (desmopressin acetate) has infrequently produced changes in blood pressure causing either a slight elevation in blood pressure or a transient fall in blood pressure and a compensatory increase in heart rate. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease.
Desmopressin Injection should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, because these patients are prone to hyponatremia.
There have been rare reports of thrombotic events following desmopressin Injection in patients predisposed to thrombus formation. No causality has been determined, however, the drug should be used with caution in these patients.
Severe allergic reactions have been reported rarely. Fatal anaphylaxis has been reported in one patient who received intravenous desmopressin. It is not known whether antibodies to desmopressin injection 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 agulant 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.
von Willebrand's Disease: Laboratory tests doe assessing patient status include levels of factor VIII coagulant activity, factor VIII ristocetin cofactor activity, and factor VIII von Willebrand factor antigen. The skin bleeding time may be helpful in following these patients.
Diabetes Insipidus: Laboratory tests for monitoring the patient include urine volume and osmolality. In some cases, plasma osmolality may be required.
Information for the Patient
Nasal Spray/Rhinal Tube: Patients should be informed that the bottle accurately delivers 50 doses of 10 mug each. Any solution remaining after 50 doses should be discarded since the amount delivered thereafter may be substantially less than 10 mug of drug. No attempt should be made to transfer remaining solution to another bottle. Patients should be instructed to read accompanying directions on use of the spray pump carefully before use.