Desmopressin, a synthetic polypeptide structurally related to arginine vasopressin (antidiuretic hormone), the natural human posterior pituitary hormone, elicits a greater antidiuretic response, on a weight basis, than does arginine vasopressin, and, among other pharmacologic effects, causes a dose-dependent increase in plasma factor VIII (antihemophilic factor) activity.
Desmopressin is used intranasally, orally, or parenterally to prevent or control polydipsia, polyuria, and dehydration in patients with diabetes insipidus caused by a deficiency of endogenous posterior pituitary vasopressin (antidiuretic hormone) (neurohypophyseal diabetes insipidus) and to manage temporary polyuria and polydipsia associated with trauma or surgery in the pituitary region. Because of its relatively long duration of action and relative lack of adverse effects, many experts consider intranasal desmopressin the drug of choice for chronic treatment in patients with mild to severe neurohypophyseal diabetes insipidus. In children, intranasal desmopressin is preferred to vasopressin injection and to oral antidiuretic agents such as chlorpropamide because of the frequency of adverse effects of these agents in pediatric patients. Although intranasal administration of the drug is preferred for chronic therapy, parenteral administration of the drug may be useful when factors that can make nasal insufflation ineffective or inappropriate are present; these include poor intranasal absorption, nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. In addition, parenteral administration of the drug may be preferred when the patient has an impaired level of consciousness. Parenteral administration of the drug also may be necessary during recovery from surgery or when nasal packing is present in patients who have undergone cranial surgical procedures such as transsphenoidal hypophysectomy.
Desmopressin is not effective in controlling polyuria caused by renal disease, nephrogenic diabetes insipidus, hypokalemia, or hypercalcemia. In uncontrolled studies, desmopressin had variable effectiveness in controlling polyuria secondary to administration of lithium.
Desmopressin is used orally for the management of primary nocturnal enuresis.103, 105, 106, 107 It may be used alone or as an adjunct to behavioral therapy and/or other nondrug measures, and has been shown to be effective in some cases refractory to standard therapies (e.g., imipramine, enuresis alarms).105, 107
Some desmopressin intranasal preparations (i.e., nasal solutions containing 0.1 mg of desmopressin acetate per mL) initially received approval from the US Food and Drug Administration (FDA) for the treatment of primary nocturnal enuresis.101, 115, 117 However in late 2007, FDA withdrew its prior approval for the treatment of primary nocturnal enuresis due to the risk of serious hyponatremia that may result in seizures and death, particularly in children, following a review of 61 postmarketing cases of hyponatremia-related seizures associated with the use of desmopressin.115 FDA requested that prescribing information for desmopressin be revised to include information about the risk of severe hyponatremia and seizures and the safe use of desmopressin, and to state that these desmopressin intranasal preparations are no longer indicated for the treatment of primary nocturnal enuresis.101, 115, 117 FDA states that the status of all other approved indications for the individual desmopressin intranasal preparations has not changed.115 (See Cautions: Adverse Effects and Precautions and Contraindications.)
The etiology of nocturnal enuresis is not precisely known, but appears to be related to delayed maturation of the cortical mechanisms that allow voluntary control of the micturition reflex.104 The condition is characterized by nocturnal incontinence without overt daytime voiding symptoms and is usually 3 times more common in boys than in girls.104, 106 Primary nocturnal enuresis is diagnosed when a child never has experienced a period of consistent nighttime continence; the condition is considered secondary when nocturnal enuresis occurs in a formerly “dry” child, and usually is associated with an emotionally disruptive event.104, 106 Treatment is not usually indicated until a child reaches the age of 6; the condition will then spontaneously remit in 15% of patients every year thereafter.103, 104, 105, 106 The frequency of this condition in adults is less than 1%.103, 104 Other possible etiologies for nocturnal enuresis (e.g., neurologic and/or spinal abnormalities, diabetes insipidus or diabetes mellitus, chronic renal failure, bacteriuria [especially in girls]) should be ruled out before initiation of drug therapy.104, 106
Controlled studies of oral desmopressin in doses of 0.2-0.6 mg daily for 2 weeks in patients 5-17 years of age with primary nocturnal enuresis indicated that patients experienced about 27-40% fewer nights of incontinence while receiving the drug versus placebo; a greater response was observed with increasing dosages up to 0.6 mg daily.112, 123 In an open-label extension study of 6 months' duration in patients completing the placebo-controlled studies, 11% of patients receiving desmopressin achieved a complete or near complete response (no more than 2 nights of incontinence/2 weeks) and did not require titration to the 0. 6-mg daily dose.112 The majority of patients (86%) were titrated to the 0. 6-mg daily dose.112 When all dosage arms were combined (0.2-0.6 mg daily), 56% of patients receiving desmopressin experienced at least a 50% reduction in the number of nights of incontinence/2 weeks, while 38% of patients achieved a complete or near complete response.112 Although limited data demonstrate that desmopressin is effective for the control of primary nocturnal enuresis,112, 121, 122, 123 the relapse rate after cessation of desmopressin therapy is high103, 104, 105, 106, 121, 122 (with rates of nocturnal incontinence sometimes approaching incontinence rates before treatment);105 enuresis alarms have been observed to be the most effective treatment for nocturnal enuresis.124
Desmopressin acetate is used intranasally or parenterally for the management of spontaneous or trauma-induced bleeding episodes such as hemarthrosis, intramuscular hematoma, or mucosal bleeding in patients with mild hemophilia A.100, 108, 111, 114 The drug is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition. Desmopressin acetate also is used parenterally or intranasally to maintain hemostasis during surgical procedures and postoperatively in patients with hemophilia A.100, 108, 111, 113, 114 The drug is not indicated for patients with hemophilia B or those with factor VIII antibodies. Desmopressin acetate generally is indicated in patients with hemophilia A whose plasma factor VIII activity is greater than 5%.100, 111, 114 Although use of desmopressin may be justified in certain clinical situations in patients with hemophilia A whose factor VIII activity is between 2-5%, these patients should be carefully monitored if the drug is used. Desmopressin is ineffective in patients with severe hemophilia A.
The National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) currently recommends that parenteral or intranasal desmopressin be used whenever possible for the treatment of mild hemophilia A.108 When desmopressin does not provide adequate treatment, patients should be treated with antihemophilic factor (recombinant) or antihemophilic factor (human).108 MASAC states that cryoprecipitate is not recommended as a treatment alternative for the management of hemophilia A.108 Despite the fact the donor units used to prepare cryoprecipitate are screened for antibody to HIV-1, HIV-2, hepatitis C virus, and hepatitis B surface antigen (HBsAg), cryoprecipitate may still be infectious for several reasons, including the several months' delay in seroconversion after HIV or hepatitis C infection.108
Desmopressin acetate is used intranasally or parenterally for the management of spontaneous or trauma-induced bleeding episodes in patients with mild to moderate type 1 von Willebrand disease.100, 108, 109, 110, 114 The drug is designated an orphan drug by the FDA for use in this condition. The drug also is used parenterally to maintain hemostasis during surgical procedures and postoperatively in these patients. MASAC and other experts state that desmopressin acetate is the treatment of choice for the management of mild to moderate type 1 von Willebrand disease,108, 109, 110 especially those whose plasma factor VIII activity is greater than 5%.100, 111, 114 Patients least likely to respond to the drug are those with severe homozygous von Willebrand disease whose factor VIII and factor VIII/von Willebrand factor activities are less than 1%; the response of other patients may be variable depending on the type of molecular defect associated with their disease. Desmopressin acetate is not indicated for patients with severe type 1 von Willebrand disease or when there is evidence of an abnormal molecular form of factor VIII antigen. Bleeding time, factor VIII and ristocetin cofactor activities, and von Willebrand factor antigen should be monitored during desmopressin therapy to ensure that an adequate response is being achieved. If individuals with type 1 disease become transiently unresponsive to desmopressin acetate, many experts recommend use of antihemophilic factor (human) preparations rich in von Willebrand factor (i.e., Alphanate®, Humate-P®, Koate®-DVI).108, 109, 110
Desmopressin acetate may be effective for the management of bleeding in some, but not all, individuals with type 2A, 2M, or 2N von Willebrand disease†.108, 109, 110, 118, 119, 120 Although desmopressin acetate reportedly has been used effectively in some patients with type 2B von Willebrand disease,110, 119 the drug usually is not used in these individuals because of an increased risk of thromboembolic events.100, 110, 111, 114, 118, 119, 120 Desmopressin acetate is ineffective for the management of bleeding in individuals with type 3 von Willebrand disease.110, 118, 119, 120 Experts generally recommend use of antihemophilic factor (human) preparations rich in von Willebrand factor if prevention or control of bleeding is necessary in individuals with type 2A, 2M, or 2N von Willebrand disease who do not respond to desmopressin acetate or when prevention or control of bleeding is considered necessary in those with type 2B or type 3 von Willebrand disease (e.g., in surgical situations).108, 109, 110 These antihemophilic factor (human) preparations are particularly useful for the management of von Willebrand disease in pediatric patients who are too young to receive desmopressin acetate.108 (See Cautions: Pediatric Precautions.) Cryoprecipitate should not be used in the management of von Willebrand disease except in emergency, life- or limb-threatening situations when desmopressin acetate or appropriate preparations of antihemophilic factor (human) are not available.108, 109
Intranasal desmopressin has been used in adults and children to evaluate the ability of the kidneys to concentrate urine†. Use of the drug for this purpose is easier and more rapid but may be less accurate than the Mosenthal concentrating test.
Intranasal desmopressin has been used in a small number of patients with sickle cell anemia to induce hyponatremia for the prevention and treatment of sickle cell crisis†; however, further studies are needed to establish the safety and efficacy of the drug for this condition. In a few patients, chronic hyponatremia induced by desmopressin reduced the frequency of painful crises, and acutely induced hyponatremia shortened the duration of crises; however, successful therapy requires strict dietary regulation and patient supervision. Because of the need for further studies and the potential complications of hyponatremia (e.g., seizures), use of intranasal desmopressin for the management of patients with sickle cell disease should be limited to severely afflicted patients who can be treated and evaluated in a strictly supervised setting.
In one randomized, placebo-controlled study in uremic patients† with prolonged bleeding times and hemorrhagic tendencies, IV desmopressin increased factor VIII activity and reduced bleeding time; in some additional uremic patients who received IV desmopressin before surgery or renal biopsy, bleeding time was reduced and associated with normal hemostasis.
Desmopressin acetate is administered intranasally, orally, by subcutaneous injection, direct IV injection, or slow IV infusion.100, 101, 102, 111, 112, 114, 116, 117
Desmopressin acetate intranasal preparations should be administered in children under adult supervision in order to monitor the dose and fluid intake.101, 115, 117
Desmopressin acetate nasal solutions containing 0.1 mg of the drug per mL are used for the treatment of diabetes insipidus;101, 102 desmopressin acetate nasal solution containing 1.5 mg of the drug per mL is used for the treatment of hemophilia A or von Willebrand disease.114 Desmopressin acetate nasal solutions containing 0.1 or 1.5 mg/mL are administered using the spray pump supplied by the manufacturers;101, 114 alternatively, desmopressin acetate nasal solutions containing 0.1 mg/mL can be administered using a calibrated nasal tube supplied by the manufacturers.101, 102
The intranasal spray pump provided by the manufacturers delivers 0.1 mL of solution per actuation.101, 114 When the nasal solution containing 0.1 mg/mL is administered using the spray pump, each 0.1-mL spray delivers a dose of 10 mcg of desmopressin acetate; if a dose other than a multiple of 10 mcg is required, the solution should be administered using a nasal tube.101 The nasal tube has 4 graduation markings that measure 0.05, 0.1, 0.15, or 0.2 mL and can be used to administer 5, 10, 15, or 20 mcg, respectively.102 When the nasal solution containing 1.5 mg/mL is administered using the spray pump, each 0.1-mL spray delivers a dose of 150 mcg of desmopressin acetate; if a dose other than a multiple of 150 mcg is required, parenteral desmopressin acetate therapy should be used.114
Desmopressin acetate nasal solution should be administered intranasally according to the manufacturer's instructions to ensure that the drug is deposited high in the nasal cavity and does not pass down the throat. The patient must be carefully instructed in the proper use of the nasal tube or spray pump in order to obtain optimum results. Desmopressin generally should not be administered intranasally when changes in the nasal mucosa such as scarring, edema, or other condition may cause erratic, unreliable absorption of the drug. The drug should not be administered intranasally when nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, or severe atrophic rhinitis is present.101, 114 Intranasal therapy also may be inappropriate when the patient has impaired consciousness.114 In addition, cranial surgical procedures, such as transphenoidal hypophysectomy, create situations in which an alternative route of administration is needed as in cases of nasal packing or recovery from surgery.101
For IV infusion, the appropriate dose of desmopressin acetate should be diluted in 10 or 50 mL of 0.9% sodium chloride injection for administration in children weighing 10 kg or less or in adults and children weighing more than 10 kg, respectively; the solution is then infused IV slowly over 15-30 minutes. Blood pressure and pulse should be monitored during infusion of the drug.
The intranasal, oral, or parenteral dose of desmopressin acetate required for antidiuresis is variable and must be adjusted according to the patient's requirements and response. Morning and evening doses must be adjusted separately for an adequate diurnal rhythm of water turnover. Response is generally estimated by duration of sleep and adequate, not excessive, turnover of water.
For the management of neurohypophyseal diabetes insipidus, the usual adult maintenance dosage of desmopressin acetate recommended by the manufacturer is 10-40 mcg (0.1-0.4 mL or 1-4 sprays from the spray pump of a solution containing 0.1 mg/mL) given intranasally in 1-3 divided doses daily. Some clinicians have recommended an adult desmopressin acetate maintenance dosage of 5-40 mcg (0.05-0.4 mL of a solution containing 0.1 mg/mL). Most adults require 20 mcg daily administered in 2 divided doses in the morning and the evening. In children 3 months to 12 years of age, the initial dose of desmopressin acetate is 5 mcg or less (0.05 mL of a solution containing 0.1 mg/mL) administered intranasally in the evening.101, 102, 117 In children 3 months to 12 years of age, the usual intranasal dosage is 5-30 mcg (0.05-0.3 mL of a solution containing 0.1 mg/mL) daily in a single evening dose or divided in 2 doses. About 25-33% of adults and children can be controlled with a single daily dose. The lowest effective dosage should be used. Fluid intake should be restricted.101, 117 (See Cautions: Precautions and Contraindications.)
If the drug is administered by subcutaneous or direct IV injection in adults or children 12 years of age or older for the management of diabetes insipidus, the usual maintenance dosage is 2-4 mcg daily given in 2 divided doses. The parenteral dosage for the management of diabetes insipidus in children younger than 12 years of age has not been established. Patients with diabetes insipidus being switched from intranasal to subcutaneous or IV administration of the drug should generally receive one-tenth their maintenance intranasal dosage parenterally. The lowest effective parenteral dosage should be given. During long-term use, patients rarely may develop tolerance to the drug and require cautious increase in dosage to achieve an adequate therapeutic response. Fluid intake should be restricted.116 .)
If oral desmopressin acetate is used for the management of diabetes insipidus in patients who previously received the drug intranasally, oral therapy should be initiated 12 hours after the last intranasal dose.112 The usual initial oral dosage of desmopressin acetate for adults and pediatric patients is 0.05 mg twice daily, and subsequent dosage should be adjusted according to response.112 In clinical studies, the optimal dosage range for most patients was 0.1-0.8 mg daily given in divided doses.112 Each dose should be adjusted separately for an adequate diurnal rhythm of water turnover.112 Total oral daily dosage should be increased or decreased in the range of 0.1-1.2 mg divided into 2 or 3 daily doses as needed to obtain adequate antidiuresis.112 Fluid intake should be restricted.112 (See Cautions: Precautions and Contraindications.)
If oral desmopressin acetate is used for the treatment of primary nocturnal enuresis in patients who previously received the drug intranasally, oral therapy should be initiated the night following (24 hours after) the last intranasal dose.112 The usual initial oral dose of desmopressin acetate for adults and pediatric patients 6 years of age or older is 0.2 mg at bedtime.112 The dose may be titrated up to 0.6 mg to achieve the desired response.112 Duration of desmopressin therapy has not been established in pediatric patients responding to therapy; some experts have suggested that it is reasonable to continue therapy for 3-6 months; after 3-6 months, therapy can be withdrawn and the patient reevaluated.121, 122, 123, 124
Fluid restriction should be in effect for a minimum of 1 hour before desmopressin administration and continued until the next morning or at least 8 hours after desmopressin administration.112, 115 Some experts recommend that not more than 240 mL of fluid should be consumed on any night when desmopressin is used.121 Desmopressin therapy should be interrupted during episodes of fluid and/or electrolyte imbalance (e.g., systemic infections, fever, recurrent vomiting or diarrhea) and under conditions associated with increased water intake (e.g., extremely hot weather, vigorous exercise).112, 115 (See Cautions: Precautions and Contraindications.)
Hemophilia A and von Willebrand Disease
For the management of bleeding in patients with hemophilia A or mild to moderate type 1 von Willebrand disease, dosage of desmopressin acetate should be adjusted according to response. Factor VIII and factor VIII/ristocetin cofactor activities, factor VIII antigen levels, and activated partial thromboplastin activity should be monitored in patients with hemophilia A, and factor VIII and factor VIII/ristocetin cofactor activities and factor VIII/von Willebrand factor antigen levels should be monitored in patients with von Willebrand disease. Determination of bleeding time may also be useful in monitoring therapy in patients with von Willebrand disease.
The usual parenteral dose for adults and children 3 months of age and older with hemophilia A or type 1 von Willebrand disease is 0.3 mcg/kg given by slow IV infusion; if the dose is administered preoperatively, the drug should be injected 30 minutes prior to the scheduled procedure. Fluid intake should be restricted.116 (See Cautions: Precautions and Contraindications.)
The usual intranasal dosage of desmopressin acetate for the management of hemophilia A or type 1 von Willebrand disease is 300 mcg (0.1 mL or 1 spray from the spray pump into each nostril of a solution containing 1.5 mg/mL).114 A dosage of 150 mcg (0.1 mL or 1 spray from the spray pump into a single nostril of a solution containing 1.5 mg/mL) may be sufficient in patients who weigh less than 50 kg.114 If intranasal desmopressin acetate is used preoperatively, the drug should be administered 2 hours prior to surgery.114
The need for additional doses of the desmopressin acetate or use of blood products for hemostasis should be determined by the clinical response of the patient and the response as determined by appropriate laboratory tests. The tendency toward tachyphylaxis (decreasing responsiveness) when doses of desmopressin are repeated more frequently than every 48 hours should be considered. When desmopressin acetate is used for the management of von Willebrand disease, the National Hemophilia Foundation' Medical and Scientific Advisory Council (MASAC) recommends that the drug be administered no more frequently than once every 24 hours and used for no more than 3 consecutive days unless such therapy is recommended by a clinician with expertise in the treatment of the disease.109
To evaluate the urine concentrating ability of the kidneys†, fasting or nonfasting adults have been given 10-40 mcg (0.1-0.4 mL of 0.01% solution or 1-4 sprays from the spray pump) intranasally;12, 22, 23 nonfasting children 2-15 years of age have been given 20 mcg (0.2 mL of 0.01% solution); and nonfasting infants 1-12 weeks of age have been given 10 mcg (0.1 mL of 0.01% solution or 1 spray from the spray pump) intranasally.17 Then, a urine sample is collected in 1-5 hours and specific gravity of the urine is determined. Under test conditions, the average individual should concentrate the urine to a specific gravity of at least 1.020.
In late 2007, the US Food and Drug Administration (FDA) reported the results of a review of 61 postmarketing cases of hyponatremia-related seizures associated with the use of desmopressin.115 In 55 cases, sodium concentrations ranged from 104-130 mEq/L during the seizure event.115 Two of these 55 cases were fatal; although both patients experienced hyponatremia and seizures115 , the direct contribution of desmopressin to the fatalities is not clear.115 Intranasal formulations were used in 36 cases; 25 of these cases involved pediatric patients (i.e., patients younger than 17 years of age).115 The most commonly reported indication for use of desmopressin in the 25 pediatric patients was nocturnal enuresis.115 In 39 of the 61 cases, the patient received at least one concomitant drug or had diseases associated with hyponatremia and/or seizures.115 As a result, FDA withdrew its prior approval for the treatment of primary nocturnal enuresis from desmopressin intranasal preparations; there is no change in the other approved indications for the individual intranasal preparations.115 (See Cautions: Precautions and Contraindications.)
Adverse effects reported with intranasal desmopressin have been infrequent and mild. Rarely, conjunctivitis, ocular edema, lacrimation disorder, transient headache, dizziness, asthenia, chills, nasal congestion, nostril pain, rhinitis, epistaxis, sore throat, cough, upper respiratory infection, flushing, nausea, vomiting, mild abdominal cramps or pain, GI disorder, somnolence, insomnia, pain, chest pain, palpitations, tachycardia, agitation, balanitis, and vulval pain have occurred with usual intranasal doses. Unlike vasopressin and lypressin, usual doses of desmopressin do not cause skin pallor or severe smooth muscle or abdominal cramps. With large intranasal doses, blood pressure may increase. Severe hyponatremia was reported in one patient with neurohypophyseal diabetes insipidus who abused intranasal desmopressin and in one pediatric patient receiving the drug for primary nocturnal enuresis; the pediatric patient also experienced a single tonic-clonic seizure. Hyponatremia, convulsion, and coma were reported in a 13-year-old patient with cystic fibrosis also receiving the drug for primary nocturnal enuresis. Adverse effects with intranasal desmopressin usually disappear when the dose or the frequency of administration is decreased but, rarely, necessitate discontinuance of the drug.
Desmopressin acetate generally is well tolerated when administered orally.112 In patients with diabetes insipidus who received desmopressin acetate tablets for up to 44 months, transient increases in AST (SGOT) (up to 1.5 times the normal upper limit) occurred occasionally but returned to the normal range despite continued administration of the drug.112 In clinical studies evaluating use of oral desmopressin for the treatment of primary nocturnal enuresis, the only adverse effect reported in 3% or more of patients that was probably, possibly, or remotely related to the drug was headache (4% in those receiving desmopressin acetate and 3% in those receiving placebo).112 Abnormal thinking, diarrhea, and edema-weight gain have been reported in patients receiving oral desmopressin acetate but a causal relationship has not been established.112
Adverse effects following parenteral administration of desmopressin have generally been infrequent and mild; however, there have been rare reports of thrombotic events (e.g., acute cerebrovascular thrombosis, acute myocardial infarction) following injection of the drug in patients predisposed to such events. Other reported adverse effects include transient headache, nausea, mild abdominal cramps, and vulval pain; these symptoms usually disappear with a reduction in dosage. Local erythema, swelling, and burning pain have been reported occasionally at the site of injection. Severe pain along the injected vein has been reported with large IV doses. Facial flushing has been reported occasionally following parenteral administration of the drug and slight increases in blood pressure, which disappeared with a reduction in dosage or slight decreases in blood pressure (with compensatory increases in heart rate), have been reported infrequently. With large IV doses of desmopressin, tachycardia, hypotension, and facial flushing have been reported. Water intoxication and hyponatremia are possible in patients who do not require vasopressin for its antidiuretic effect. Excessive water retention occurred in a hemophiliac patient who received an IV dose of desmopressin acetate of 0.5 mcg/kg for bleeding.
Severe allergic reactions, including anaphylaxis, have been reported rarely with parenteral and intranasal desmopressin acetate.101, 111, 114, 116 In addition, fatal anaphylaxis has been reported in patients receiving parenteral desmopressin.116
Precautions and Contraindications
Desmopressin acetate intranasal preparations should be reserved for situations in which oral therapy is not feasible.101, 117
All desmopressin preparations should be used cautiously in patients at risk for water intoxication with hyponatremia.115 Hyponatremia has been reported very rarely during international postmarketing surveillance in patients receiving desmopressin acetate.101, 112, 115, 116, 117 (See Cautions: Adverse Effects.) Desmopressin is a potent antidiuretic; use of desmopressin may result in water intoxication and/or hyponatremia, and hyponatremia may be fatal unless properly diagnosed and treated.101, 112, 116, 117 Therefore, fluid restriction is recommended and should be discussed with the patient and/or guardian; careful medical supervision is required.101, 112, 115, 116, 117 The patient should promptly contact the clinician if water intake changes.115
Fluid intake should be carefully restricted, particularly in pediatric and geriatric patients, to reduce the risk of potential water intoxication and hyponatremia.101, 112, 116, 117 All patients receiving desmopressin therapy should be observed for signs and symptoms associated with hyponatremia (i.e., headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, appetite loss, irritability, muscle weakness, spasms or cramps, abnormal mental status [e.g., hallucinations, decreased consciousness, confusion]); severe symptoms may include seizure, coma, and/or respiratory arrest.101, 112, 115, 116, 117 An extreme decrease in plasma osmolality that may result in seizures, which may lead to coma, has occurred rarely, and this possibility should be considered.101, 112, 116, 117
Desmopressin should be used with caution in patients with habitual or psychogenic polydipsia and in patients who are receiving certain drugs (e.g., tricyclic antidepressants, selective serotonin-reuptake inhibitors [SSRIs]) as these patients may be more likely to drink excessive amounts of water resulting in an increased risk for hyponatremia.101, 112, 115, 116, 117 (See Drug Interactions.)
Desmopressin should be used with caution in patients with conditions associated with fluid and electrolyte imbalances (e.g., cystic fibrosis, heart failure, renal disorders); these patients are prone to hyponatremia.101, 102, 111, 112, 114, 116, 117
When fluid intake is not excessive, there is little danger of water intoxication and hyponatremia with usual intranasal or parenteral doses of desmopressin used to control diabetes insipidus. When the drug is used for its hemostatic effect in patients who do not require exogenous vasopressin for its antidiuretic effect, the risk of potential water intoxication and hyponatremia may be increased and these patients should be cautioned to ingest only enough fluid to satisfy their thirst. Water retention can usually be controlled by decreasing the dosage of desmopressin; severe water retention caused by overdosage may be treated with a diuretic such as furosemide.
Although vasoactive effects are minimal or absent with usual intranasal antidiuretic doses of desmopressin and also are minimal and infrequent and usually respond to dosage reduction when usual parenteral hemostatic doses of the drug are used, caution should be exercised in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease. Desmopressin also should be used with caution in these patients and in patients predisposed to thrombotic events because of the drug's potential prothrombotic effect; although a causal relationship to the drug has not been determined, thrombotic events have been reported rarely in patients predisposed to thrombus formation.
In patients with diabetes insipidus or polyuria and polydipsia associated with head surgery or trauma, urine volume and osmolality and, in some cases, plasma osmolality should be monitored periodically during desmopressin therapy. In otherwise healthy patients with primary nocturnal enuresis, serum electrolytes should be checked at least once if therapy is continued beyond 7 days.
In patients with hemophilia A, factor VIII and factor VIII/ristocetin cofactor (von Willebrand factor) activities, factor VIII antigen levels, and activated partial thromboplastin time should be monitored during desmopressin therapy. Factor VIII activity should be determined prior to initiating desmopressin therapy for hemostasis; desmopressin therapy should not be relied on in patients with a factor VIII activity less than 5% of normal.
In patients with von Willebrand disease, factor VIII and factor VIII/ristocetin cofactor activities and factor VIII/von Willebrand factor antigen levels should be monitored during desmopressin therapy. Determination of bleeding time may also be useful in monitoring therapy in these patients.
Desmopressin is contraindicated in patients with hypersensitivity to the drug or any ingredient in the formulation.101, 112, 116, 117 Desmopressin also is contraindicated in patients with moderate to severe renal impairment (creatinine clearance less than 50 mL/minute) and in patients with hyponatremia or a history of hyponatremia.101, 112, 115, 116, 117 Because of the risk of platelet aggregation and thrombocytopenia, the drug also should not be used in patients with type 2B or platelet-type (pseudo) von Willebrand disease.
Fluid intake should be carefully restricted in pediatric patients to prevent possible hyponatremia and water intoxication;101, 112, 114, 116, 117 fluid restriction should be discussed with the patient and/or guardian.112, 116, 117 (See Cautions: Precautions and Contraindications.)
Desmopressin acetate nasal solutions containing 0.1 mg of desmopressin acetate per mL have been used in children with diabetes insipidus. However, pediatric dosage must be carefully adjusted according to individual patient needs and tolerance, with particular attention to the risk of an extreme decrease in plasma osmolality and resulting seizures in young children. There have been occasional reports of a change in response to desmopressin therapy over time, usually after periods exceeding 6 months. Some patients show a decreased responsiveness to the drug, while others show a shortened duration of effect. There is no evidence that this change in responsiveness results from the development of binding antibodies, but it may result from a local inactivation of the peptide.
Desmopressin acetate nasal solution containing 1.5 mg of desmopressin acetate per mL can be used for the treatment of hemophilia A or von Willebrand disease in children 11 months of age or older; however, safety and efficacy of the nasal solution have not been established in children younger than 11 months of age.114
Desmopressin acetate tablets have been used safely for up to 44 months in pediatric patients 4 years of age or older with diabetes insipidus.112 In younger patients, dosage adjustment of oral desmopressin should be individualized to prevent an excessive decrease in plasma osmolality leading to hyponatremia and possible seizures.112
Desmopressin acetate tablets have been used safely for up to 6 months in pediatric patients 6 years of age and older with primary nocturnal enuresis.112 In patients with primary nocturnal enuresis, desmopressin therapy should be interrupted during acute intercurrent illness characterized by fluid and/or electrolyte imbalance (e.g., systemic infections, fever, recurrent vomiting or diarrhea) and under conditions associated with increased water intake (e.g., extremely hot weather, vigorous exercise).112, 115 (See Cautions: Precautions and Contraindications.)
Safety and efficacy of parenteral desmopressin for the management of diabetes insipidus in children younger than 12 years of age have not been established.116
The manufacturers state that desmopressin acetate injection should not be used in the management of hemophilia A or von Willebrand disease in children younger than 3 months of age.
Fluid intake should be carefully restricted in geriatric patients to prevent possible hyponatremia and water intoxication;101, 112, 114, 116, 117 fluid restriction should be discussed with the patient.112, 116, 117 (See Cautions: Precautions and Contraindications.)
Clinical studies of desmopressin did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.101, 112, 114, 116, 117 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.101, 112, 116, 117 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.101, 112, 116, 117 Desmopressin is known to be substantially excreted by the kidney and the risk of severe adverse reactions to the drug may be increased in patients with impaired renal function.101, 112, 116, 117 Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.101, 112, 116, 117
Safe use of desmopressin during pregnancy or lactation has not been established. Reproduction studies in rats and rabbits using desmopressin dosages up to 12.5 times the usual human hemostatic dosage or 125 times the usual human antidiuretic dosage have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using desmopressin in pregnant women; however, the drug has been used throughout pregnancy without adverse effect to mother or fetus and has been used during lactation without adverse effect to the lactating woman or nursing infant. Although published reports state that desmopressin, unlike preparations containing the natural hormones, has no uterotonic effect at usual antidiuretic doses, the physician must weigh the potential therapeutic benefits against the possible risks. Because it is not known whether desmopressin is distributed into milk, the drug should be used with caution in nursing women.
Although drug interactions have been reported with vasopressin, few specific interactions have been reported with desmopressin. Desmopressin should be used cautiously in patients who are receiving lithium, large doses of epinephrine, demeclocycline, heparin, or alcohol, because the antidiuretic response to desmopressin may be decreased; drugs such as chlorpropamide, urea, or fludrocortisone may potentiate the antidiuretic response. Concurrent administration of clofibrate with desmopressin reportedly potentiates and prolongs the antidiuretic effect of desmopressin. In one patient, prior administration of carbamazepine decreased the duration of action of desmopressin. Patients receiving large doses of desmopressin (e.g., 0.3 mcg/kg) should be carefully monitored if the drug is administered concurrently with other vasopressor agents.101, 102, 111, 112, 114, 116, 117 Desmopressin has been used with aminocaproic acid without adverse effects.111, 114 116
Concomitant use of drugs that may increase the risk of water intoxication with hyponatremia (e.g., tricyclic antidepressants, selective serotonin-reuptake inhibitors [SSRIs], chlorpromazine, opiates, nonsteroidal anti-inflammatory agents [NSAIAs], lamotrigine, carbamazepine) with desmopressin should be undertaken with caution.101, 112, 115, 116, 117 Hyponatremic seizures have been reported rarely in patients receiving desmopressin and imipramine or oxybutynin during postmarketing surveillance.101, 112, 116, 117
Desmopressin elicits a greater antidiuretic response, on a weight basis, than does arginine vasopressin. One important physiologic role of vasopressin is to maintain serum osmolality within a normal range. The antidiuretic potency of IV desmopressin is about 10 times that following intranasal administration of the drug. Vasopressin increases reabsorption of water by the collecting ducts in the kidneys resulting in increased urine osmolality and decreased urinary flow rate. In patients with neurohypophyseal diabetes insipidus, desmopressin has the same effects on water reabsorption as does vasopressin. Therapeutic doses of desmopressin do not directly affect urinary sodium or potassium excretion, or serum sodium, potassium, or creatinine concentrations.
Structural modifications of vasopressin present in desmopressin result in reduced smooth muscle contracting and vasopressor properties compared with vasopressin and lypressin. Intranasal doses of 20 mcg of desmopressin acetate have no effect on blood pressure or pulse rate, but mean arterial pressure may increase as much as 15 mm Hg with doses of 40 mcg or more. Desmopressin has not been reported to stimulate uterine contractions.
Desmopressin, unlike vasopressin, does not stimulate adrenocorticotropic hormone release or increase plasma cortisol concentrations. In children, intranasal administration of desmopressin has no effect on growth hormone, prolactin, or luteinizing hormone concentrations.
Desmopressin causes a dose-dependent increase in plasma factor VIII (antihemophilic factor), plasminogen activator, and, to a smaller degree, factor VIII-related antigen and ristocetin cofactor activities. Large IV doses of desmopressin acetate (0.2-0.5 mcg/kg) increase factor VIII activity in healthy individuals, in patients with mild to moderate hemophilia A and B, in patients with certain types of von Willebrand disease, and in patients with uremia. Desmopressin elicits a greater increase in plasma factor VIII activity, on a weight basis, than does arginine vasopressin in patients with hemophilia or type I von Willebrand's disease. The percentage increase in plasma factor VIII activity in patients with mild hemophilia A or type 1 von Willebrand disease is reportedly similar to that in healthy individuals following IV infusion of a 0.3-mcg/kg dose of the drug over 10 minutes. A gradual diminution in the magnitude of the desmopressin-induced increase in plasma factor VIII activity generally occurs when administration of the drug is repeated every 12-24 hours, but the magnitude is usually the same as the initial response when a period of 2-3 days elapses between administration. Patients with moderate, rather than mild, hemophilia A may or may not respond with an adequate increase in factor VIII to ensure clotting, and patients with type 1 von Willebrand disease may respond better than those with type 2 disease. Patients with severe hemophilia or severe von Willebrand disease are unresponsive to desmopressin. Following intranasal (2-4 mcg/kg) or IV (0.2 mcg/kg) administration of single doses of desmopressin in one study, 3/3 healthy individuals, 27/31 patients with mild or moderate von Willebrand disease, and 6/7 patients with mild to moderate hemophilia A had a greater than 200% increase in plasma factor VIII activity; a lesser but substantial increase in factor VIII-related antigen and ristocetin cofactor also occurred. In this study, 2 patients with severe von Willebrand disease were unresponsive to desmopressin. Although plasminogen activator activity increases rapidly after desmopressin administration, clinically important fibrinolysis has not been reported to date in patients being treated with the drug.
In patients with type 2B von Willebrand disease, desmopressin has been reported to induce platelet aggregation and thrombocytopenia; it was suggested that platelet aggregation resulted from desmopression-induced release of the larger multimers of factor VIII/von Willebrand factor which subsequently were adsorbed to platelets. The drug has also been reported to induce platelet aggregation and thrombocytopenia in patients with platelet-type (pseudo) von Willebrand disease; however, the specific mechanism of this effect may be different in these patients.
Desmopressin has also reportedly increased factor VIII activity and, to a lesser extent, factor VIII-related antigen and ristocetin cofactor in patients with uremia; these changes were accompanied by a shortening of bleeding time. In addition, the drug induced the release into plasma of the larger multimers of factor VIII/von Willebrand factor in these patients.
In a few patients with sickle cell anemia, hyponatremia induced by intranasal desmopressin has resulted in decreased mean corpuscular hemoglobin concentration and a decreased degree of sickling.
Following intranasal administration of desmopressin acetate as directed by the manufacturer, approximately 10-20% of a dose is absorbed through the nasal mucosa. The manufacturer states that nasal congestion does not interfere with the effectiveness of the drug; however, investigators have reported that patients with nasal congestion may require an increased dosage. Following intranasal administration of usual doses of desmopressin acetate in patients with neurohypophyseal diabetes insipidus, antidiuretic effects occur within 15-60 minutes, peak in 1-5 hours, persist 5-21 hours, and then abruptly end over a period of 60-90 minutes. Duration of action varies among individuals with a specific dose. The relatively prolonged duration of action of desmopressin may result from slower enzymatic inactivation of desmopressin than vasopressin or from sequestration of desmopressin in a membrane compartment. Studies using the nasal solution containing 1.5 mg of desmopressin acetate per mL indicate that bioavailability of the drug is 3.3-4.1% and peak plasma concentrations are attained 40-45 minutes after a dose.114 Following intranasal administration of 150-450 mcg of desmopressin acetate (1-3 sprays of a solution containing 1.5 mg/mL), increases in plasma concentrations of factor VIII and von Willebrand factor are evident within 30 minutes and peak at about 1.5 hours.114
Following oral administration of desmopressin acetate tablets, the drug is only minimally absorbed from the GI tract, and bioavailability is about 5% compared with intranasal administration and about 0.16% compared with IV administration of the drug.112 Peak plasma concentrations of desmopressin acetate are attained 0.9 or 1.5 hours following oral or intranasal administration, respectively.112 Antidiuretic effects occur at about 1 hour and peak at about 4-7 hours after an oral dose of the drug.112
Following IV infusion of desmopressin, the increase in plasma factor VIII activity occurs within 15-30 minutes and peaks between 90 minutes and 2 hours after administration; the increase in factor VIII activity is dose dependent, with a 300-400% maximum increase reportedly occurring after IV infusion of a 0.4-mcg/kg dose.
Distribution of desmopressin has not been fully characterized. It is not known if desmopressin crosses the placenta. The drug is distributed into milk.
Desmopressin is excreted principally in the urine.101, 112, 116, 117
Following intranasal administration of 150-450 mcg of desmopressin acetate (1-3 sprays of a solution containing 1.5 mg/mL), half-life of the drug is 3.3-3.5 hours.114
Following oral administration, half-life of desmopressin acetate is independent of dosage and averages 1.5-2.5 hours.112
After IV administration of 2-3 mcg of desmopressin acetate in patients with neurohypophyseal diabetes insipidus, plasma concentrations decline in a biphasic manner with a mean initial plasma half-life of 7.8 minutes and a mean terminal plasma half-life of 75.5 minutes (range: 0.4-4 hours).
The metabolic fate of desmopressin is unknown. Unlike vasopressin, desmopressin apparently is not degraded by aminopeptidases or other peptidases that cleave oxytocin and endogenous vasopressin in the plasma during late pregnancy.
Renal clearance of desmopressin decreases with decreasing renal function.101, 112, 116, 117, 125 Following administration of a single IV dose of 2 mcg of desmopressin acetate in individuals with normal renal function (average creatinine clearance of 103 mL/minute), mild renal impairment (average creatinine clearance of 72 mL/minute), moderate renal impairment (average creatinine clearance of 37 mL/minute), or severe renal impairment (average creatinine clearance of 16 mL/minute; not on dialysis), terminal half-lives of desmopressin averaged 3.7, 4.8, 7.2, or 10 hours, respectively.125
Desmopressin is a synthetic polypeptide structurally related to arginine vasopressin (antidiuretic hormone), the natural human posterior pituitary hormone. Desmopressin acetate is commercially available as nasal solutions for intranasal administration,101, 102, 114, 117 tablets for oral administration,112 and injections for parenteral administration.100, 111, 116
Desmopressin acetate nasal solutions are aqueous solutions of the drug.101, 114 For the treatment of central cranial diabetes insipidus, desmopressin acetate is commercially available as nasal solutions containing 0.1 mg of the drug per mL with 0.75 or 0.9% sodium chloride for administration via a spray pump or nasal tube;101, 102 for the treatment of hemophilia A or von Willebrand disease, desmopressin acetate is commercially available as a nasal solution containing 1.5 mg of the drug per mL with 0.75% sodium chloride for administration via a spray pump.114 These nasal solutions contain either benzalkonium chloride or chlorobutanol as preservatives.101, 114, 117
Desmopressin acetate injection is a sterile, aqueous solution containing 4 mcg of the drug per mL with 0.9% sodium chloride.100, 111 Hydrochloric acid is added during the manufacture of the injection to adjust the pH to approximately 4; the injection also may contain chlorobutanol as a preservative.100, 111
Commercially available nasal solutions of desmopressin acetate preserved with benzalkonium chloride should be stored at controlled room temperature (20-25°C, not to exceed 25°C).101, 114 Commercially available nasal solutions containing 1.5 mg of the drug per mL should be discarded 6 months after opening.114 Commercially available nasal solutions of desmopressin acetate preserved with chlorobutanol should be refrigerated at 2-8°C; when traveling, closed bottles are stable for 3 weeks at controlled room temperature (20-25°C).102, 117
Desmopressin acetate tablets should be stored at 20-25°C; exposure to excessive heat or light should be avoided.112
Commercially available desmopressin acetate injection should be refrigerated at 2-8°C;100, 111, 116 freezing should be avoided.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Nasal | Solution | 0.1 mg/mL* | DDAVP® Nasal Spray (with spray pump) | |
DDAVP® Rhinal Tube (with 2 calibrated nasal tubes; refrigerate) | Sanofi-Aventis | |||
Desmopressin Acetate Rhinal Tube (with 2 calibrated nasal tubes; refrigerate) | ||||
Ferring | ||||
1.5 mg/mL* | Desmopressin Acetate Nasal Spray | |||
Stimate® Nasal Spray (with spray pump) | ||||
Oral | Tablets | 0.1 mg* | DDAVP® | Sanofi-Aventis |
0.2 mg* | DDAVP® | Sanofi-Aventis | ||
Desmopressin Acetate Tablets | ||||
Parenteral | Injection | 4 mcg/mL* | DDAVP® | Sanofi-Aventis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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