ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. Infrequently, DDAVP has produced transient headache, nausea, mild abdominal cramps and vulval pain. These symptoms disappeared with reduction in dosage. Occasionally, injection of DDAVP has produced local erythema, swelling or burning pain. Occasional facial flushing has been reported with the administration of DDAVP. DDAVP Injection has infrequently produced changes in blood pressure causing either slight elevation or transient fall and compensatory increase in heart rate. Severe allergic reactions including anaphylaxis have been reported rarely with DDAVP Injection.See WARNINGS for the possibility of water intoxication and hyponatremia.. Post Marketing. There have been rare reports of thrombotic events (acute cerebrovascular thrombosis, acute myocardial infarction) following DDAVP Injection in patients predisposed to thrombus formation, and rare reports of hyponatremic convulsions associated with concomitant use with the following medications: oxybutinin and imipramine.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenicity, Mutagenicity, Impairment of Fertility. Studies with DDAVP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. DDAVP Injection mcg/mL contains as active substance, desmopressin acetate, synthetic analogue of the natural hormone arginine vasopressin. One mL (4 mcg) of DDAVP (desmopressin acetate) solution has an antidiuretic activity of about 16 IU; mcg of DDAVP is equivalent to IU.DDAVP has been shown to be more potent than arginine vasopressin in increasing plasma levels of factor VIII activity in patients with hemophilia and von Willebrands disease Type I.Dose-response studies were performed in healthy persons, using doses of 0.1 to 0.4 mcg/kg body weight, infused over 10-minute period. Maximal dose response occurred at 0.3 to 0.4 mcg/kg. The response to DDAVP of factor VIII activity and plasminogen activator is dose-related, with maximal plasma levels of 300 to 400 percent of initial concentrations obtained after infusion of 0.4 mcg/kg body weight. The increase is rapid and evident within 30 minutes, reaching maximum at point ranging from 90 minutes to two hours. The factor VIII related antigen and ristocetin cofactor activity were also increased to smaller degree, but still are dose-dependent.The biphasic half-lives of DDAVP were 7.8 and 75.5 minutes for the fast and slow phases, respectively, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the hormone. As result, DDAVP provides prompt onset of antidiuretic action with long duration after each administration.The change in structure of arginine vasopressin to DDAVP has resulted in 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.When administered by injection, DDAVP has an antidiuretic effect about ten times that of an equivalent dose administered intranasally.The bioavailability of the subcutaneous route of administration was determined qualitatively using urine output data. The exact 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 and von Willebrands disease was not significantly different from that observed in normal healthy individuals when treated with 0.3 mcg/kg of DDAVP infused over 10 minutes.Plasminogen activator activity increases rapidly after DDAVP infusion, but there has been no clinically significant fibrinolysis in patients treated with DDAVP.The effect of repeated DDAVP administration when doses were given every 12 to 24 hours has generally shown gradual diminution of the factor VIII activity increase noted with single dose. The initial response is reproducible in any particular patient if there are or days between administrations.. The biphasic half-lives of DDAVP were 7.8 and 75.5 minutes for the fast and slow phases, respectively, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the hormone. As result, DDAVP provides prompt onset of antidiuretic action with long duration after each administration.. The change in structure of arginine vasopressin to DDAVP has resulted in 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.. When administered by injection, DDAVP has an antidiuretic effect about ten times that of an equivalent dose administered intranasally.. The bioavailability of the subcutaneous route of administration was determined qualitatively using urine output data. The exact 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 and von Willebrands disease was not significantly different from that observed in normal healthy individuals when treated with 0.3 mcg/kg of DDAVP infused over 10 minutes.. Plasminogen activator activity increases rapidly after DDAVP infusion, but there has been no clinically significant fibrinolysis in patients treated with DDAVP.. The effect of repeated DDAVP administration when doses were given every 12 to 24 hours has generally shown gradual diminution of the factor VIII activity increase noted with single dose. The initial response is reproducible in any particular patient if there are or days between administrations.. Human Pharmacokinetics. DDAVP is mainly excreted in the urine. pharmacokinetic study conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24, subjects in each group) receiving single dose desmopressin acetate (2 mcg) injection demonstrated difference in DDAVP terminal half-life. Terminal half-life significantly increased from hours in normal healthy patients to hours in patients with severe renal impairment. (See CONTRAINDICATIONS.).

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. DDAVP Injection mcg/mL is contraindicated in individuals with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Injection mcg/mL.DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as creatinine clearance below 50 mL/min).DDAVP is contraindicated in patients with hyponatremia or history of hyponatremia.

DESCRIPTION SECTION.


DESCRIPTION. DDAVP(R) Injection (desmopressin acetate) mcg/mL is synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It is chemically defined as follows:Mol. Wt. 1183.34Empirical Formula: C46H64N14O12S2oC2H4O2o3H2O1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrateDDAVP Injection mcg/mL is provided as sterile, aqueous solution for injection.Each mL provides:Desmopressin acetate4 mcgSodium chloride9 mgHydrochloric acid to adjust pH to 4The 10 mL vial contains chlorobutanol as preservative (5 mg/mL).. FORMULA.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. Hemophilia and von Willebrands Disease (Type I). DDAVP Injection mcg/mL is administered as an intravenous infusion at dose of 0.3 mcg DDAVP/kg body weight diluted in sterile physiological saline and infused slowly over 15 to 30 minutes. In adults and children weighing more than 10 kg, 50 mL of diluent is recommended; in children weighing 10 kg or less, 10 mL of diluent is recommended. Blood pressure and pulse should be monitored during infusion. If DDAVP Injection mcg/mL is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure.The necessity for repeat administration of DDAVP 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.Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.). Diabetes Insipidus. This formulation is administered subcutaneously or by direct intravenous injection. DDAVP Injection mcg/mL dosage must be determined for each patient and adjusted according to the pattern of response. Response should be estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover.The usual dosage range in adults is 0.5 mL (2.0 mcg) to mL (4.0 mcg) daily, administered intravenously or subcutaneously, usually in two divided doses. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. For patients who have been controlled on intranasal DDAVP and who must be switched to the injection form, either because of poor intranasal absorption or because of the need for surgery, the comparable antidiuretic dose of the injection is about one-tenth the intranasal dose.Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.)Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.. Geriatric Use. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Human Pharmcokinetics, CONTRAINDICATIONS, and PRECAUTIONS, Geriatric Use.). Directions for use of One Point Cut (OPC) Ampules for DDAVP Injection. Use aseptic technique to clean ampule. Gently tap the top of the ampule to assist the flow of the solution from the upper portion of the ampule to the lower portion.Locate the blue dot on the upper portion of the ampule. Below this dot is small score on the neck of the ampule. Hold the ampule with the blue dot facing away from you.Cover the vial with an appropriate wipe. Apply pressure to the top and bottom portions of the ampule to snap the ampule open away from you.. Use aseptic technique to clean ampule. Gently tap the top of the ampule to assist the flow of the solution from the upper portion of the ampule to the lower portion.. Locate the blue dot on the upper portion of the ampule. Below this dot is small score on the neck of the ampule. Hold the ampule with the blue dot facing away from you.. Cover the vial with an appropriate wipe. Apply pressure to the top and bottom portions of the ampule to snap the ampule open away from you.

DRUG INTERACTIONS SECTION.


Drug Interactions. Although the pressor activity of DDAVP is very low compared with the antidiuretic activity, use of doses as large as 0.3 mcg/kg of DDAVP with other pressor agents should be done only with careful patient monitoring. The concomitant administration of drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and carbamazepine) should be performed with caution.DDAVP has been used with epsilon aminocaproic acid without adverse effects.

GENERAL PRECAUTIONS SECTION.


General. For injection use only.DDAVP Injection (desmopressin acetate) mcg/mL has infrequently produced changes in blood pressure causing either slight elevation in blood pressure or transient fall in blood pressure and compensatory increase in heart rate. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease.DDAVP (desmopressin acetate) should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders, because these patients are prone to hyponatremia.There have been rare reports of thrombotic events following DDAVP Injection mcg/mL 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. Anaphylaxis has been reported rarely with intravenous and intranasal DDAVP, including isolated cases of fatal anaphylaxis with intravenous DDAVP. It is not known whether antibodies to DDAVP Injection mcg/mL are produced after repeated injections.

GERIATRIC USE SECTION.


Geriatric Use. Clinical studies of DDAVP Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as creatinine clearance below 50 mL/min). (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics, and CONTRAINDICATIONS.) Use of DDAVP injection in geriatric patients will require careful fluid intake restrictions to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient. (See WARNINGS.).

HOW SUPPLIED SECTION.


HOW SUPPLIED. DDAVP Injection mcg/mL is available as sterile solution in cartons of ten mL single-dose ampules (NDC 55566-2200-0) and in 10 mL multiple-dose vials (NDC 55566-2300-0), each containing mcg DDAVP per mL.. Store refrigerated to 8C (36 to 46F).Keep out of the reach of children.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. Hemophilia A. DDAVP Injection mcg/mL is indicated for patients with hemophilia with factor VIII coagulant activity levels greater than 5%.DDAVP will often maintain hemostasis in patients with hemophilia during surgical procedures and postoperatively when administered 30 minutes prior to scheduled procedure.DDAVP will also stop bleeding in hemophilia patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding.DDAVP is not indicated for the treatment of hemophilia with factor VIII coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in patients who have factor VIII antibodies.In certain clinical situations, it may be justified to try DDAVP in patients with factor VIII levels between 2% to 5%; however, these patients should be carefully monitored.. von Willebrands Disease (Type I). DDAVP Injection mcg/mL is indicated for patients with mild to moderate classic von Willebrands disease (Type I) with factor VIII levels greater than 5%. DDAVP will often maintain hemostasis in patients with mild to moderate von Willebrands disease during surgical procedures and postoperatively when administered 30 minutes prior to the scheduled procedure.DDAVP will usually stop bleeding in mild to moderate von Willebrands patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding.Those von Willebrands disease patients who are least likely to respond are those with severe homozygous von Willebrands disease with factor VIII coagulant activity and factor VIII von Willebrand factor antigen levels less than 1%. Other patients may respond in variable fashion depending on the type of molecular defect they have. Bleeding time and factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand factor antigen should be checked during administration of DDAVP to ensure that adequate levels are being achieved.DDAVP is not indicated for the treatment of severe classic von Willebrands disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen. (See WARNINGS.). Diabetes Insipidus. DDAVP Injection mcg/mL 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. DDAVP is ineffective for the treatment of nephrogenic diabetes insipidus.DDAVP is also available as an intranasal preparation. However, this means of delivery can be compromised by 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.

NURSING MOTHERS SECTION.


Nursing Mothers. There have been no controlled studies in nursing mothers. single study in postpartum women demonstrated marked change in plasma, but little if any change in assayable DDAVP in breast milk following an intranasal dose of 10 mcg. 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 DDAVP is administered to nursing woman.

OVERDOSAGE SECTION.


OVERDOSAGE. Signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of overdosage, the dosage should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition.There is no known specific antidote for desmopressin acetate or DDAVP Injection mcg/mL.An oral LD50 has not been established. An intravenous dose of mg/kg in mice demonstrated no effect.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 10 mL Vial Carton. NDC 55566-2300-0Rx ONLYDDAVP(R) Injectiondesmopressinacetate4 mcg/mLFor Intravenous andSubcutaneous Use Only10 mL VialFERRINGPHARMACEUTICALS. PRINCIPAL DISPLAY PANEL 10 mL Vial Carton.

PEDIATRIC USE SECTION.


Pediatric Use. Use in infants and pediatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient and/or guardian. (See WARNINGS.) DDAVP Injection mcg/mL should not be used in infants less than three months of age in the treatment of hemophilia or von Willebrands disease; safety and effectiveness in pediatric patients under 12 years of age with diabetes insipidus have not been established.

PHARMACOKINETICS SECTION.


Human Pharmacokinetics. DDAVP is mainly excreted in the urine. pharmacokinetic study conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24, subjects in each group) receiving single dose desmopressin acetate (2 mcg) injection demonstrated difference in DDAVP terminal half-life. Terminal half-life significantly increased from hours in normal healthy patients to hours in patients with severe renal impairment. (See CONTRAINDICATIONS.).

PRECAUTIONS SECTION.


PRECAUTIONS. General. For injection use only.DDAVP Injection (desmopressin acetate) mcg/mL has infrequently produced changes in blood pressure causing either slight elevation in blood pressure or transient fall in blood pressure and compensatory increase in heart rate. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease.DDAVP (desmopressin acetate) should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders, because these patients are prone to hyponatremia.There have been rare reports of thrombotic events following DDAVP Injection mcg/mL 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. Anaphylaxis has been reported rarely with intravenous and intranasal DDAVP, including isolated cases of fatal anaphylaxis with intravenous DDAVP. It is not known whether antibodies to DDAVP Injection mcg/mL 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 DDAVP for hemostasis. If factor VIII coagulant activity is present at less than 5% of normal, DDAVP should not be relied on.. von Willebrands Disease. Laboratory tests for 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.. Drug Interactions. Although the pressor activity of DDAVP is very low compared with the antidiuretic activity, use of doses as large as 0.3 mcg/kg of DDAVP with other pressor agents should be done only with careful patient monitoring. The concomitant administration of drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and carbamazepine) should be performed with caution.DDAVP has been used with epsilon aminocaproic acid without adverse effects.. Carcinogenicity, Mutagenicity, Impairment of Fertility. Studies with DDAVP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.. Pregnancy Category B. Fertility studies have not been done. Teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Several publications of desmopressin acetates use in the management of diabetes insipidus during pregnancy are available; these include few anecdotal reports of congenital anomalies and low birth weight babies. However, no causal connection between these events and desmopressin acetate has been established. fifteen year, Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however, the statistical power of this study is low. As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic advantages against the possible risks in each case.. Nursing Mothers. There have been no controlled studies in nursing mothers. single study in postpartum women demonstrated marked change in plasma, but little if any change in assayable DDAVP in breast milk following an intranasal dose of 10 mcg. 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 DDAVP is administered to nursing woman.. Pediatric Use. Use in infants and pediatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient and/or guardian. (See WARNINGS.) DDAVP Injection mcg/mL should not be used in infants less than three months of age in the treatment of hemophilia or von Willebrands disease; safety and effectiveness in pediatric patients under 12 years of age with diabetes insipidus have not been established.. Geriatric Use. Clinical studies of DDAVP Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as creatinine clearance below 50 mL/min). (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics, and CONTRAINDICATIONS.) Use of DDAVP injection in geriatric patients will require careful fluid intake restrictions to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient. (See WARNINGS.).

PREGNANCY SECTION.


Pregnancy Category B. Fertility studies have not been done. Teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Several publications of desmopressin acetates use in the management of diabetes insipidus during pregnancy are available; these include few anecdotal reports of congenital anomalies and low birth weight babies. However, no causal connection between these events and desmopressin acetate has been established. fifteen year, Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however, the statistical power of this study is low. As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic advantages against the possible risks in each case.

SPL UNCLASSIFIED SECTION.


4 mcg/mLRx only.

STORAGE AND HANDLING SECTION.


Store refrigerated to 8C (36 to 46F).Keep out of the reach of children.

WARNINGS SECTION.


WARNINGS. Very rare cases of hyponatremia have been reported from world-wide postmarketing experience in patients treated with DDAVP (desmopressin acetate). DDAVP is potent antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia. Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is recommended and should be discussed with the patient and/or guardian. Careful medical supervision is required.When DDAVP Injection is administered to patients who do not have need of antidiuretic hormone for its antidiuretic effect, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward to decrease the potential occurrence of water intoxication and hyponatremia. (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients receiving DDAVP therapy should be observed for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness and confusion. Severe symptoms may include one or combination of the following: seizure, coma and/or respiratory arrest. 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.DDAVP should not be used to treat patients with Type IIB von Willebrands disease since platelet aggregation may be induced.DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who may be more likely to drink excessive amounts of water, putting them at greater risk of hyponatremia.. Very rare cases of hyponatremia have been reported from world-wide postmarketing experience in patients treated with DDAVP (desmopressin acetate). DDAVP is potent antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia. Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is recommended and should be discussed with the patient and/or guardian. Careful medical supervision is required.. When DDAVP Injection is administered to patients who do not have need of antidiuretic hormone for its antidiuretic effect, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward to decrease the potential occurrence of water intoxication and hyponatremia. (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients receiving DDAVP therapy should be observed for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness and confusion. Severe symptoms may include one or combination of the following: seizure, coma and/or respiratory arrest. 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.. DDAVP should not be used to treat patients with Type IIB von Willebrands disease since platelet aggregation may be induced.. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who may be more likely to drink excessive amounts of water, putting them at greater risk of hyponatremia.

BOXED WARNING SECTION.


WARNING: HYPONATREMIA. DDAVP can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death [see Warnings and Precautions (5.1)].DDAVP is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids [see Contraindications (4) and Warnings and Precautions (5.1)].Ensure the serum sodium concentration is normal before starting or resuming DDAVP. Measure serum sodium within days and approximately month after initiating therapy, and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].If hyponatremia occurs, DDAVP may need to be temporarily or permanently discontinued [see Warnings and Precautions (5.1)].. WARNING: HYPONATREMIASee full prescribing information for complete boxed warning.DDAVP can cause hyponatremia, which may be life-threatening if severe. (5.1)DDAVP is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids. (4, 5.1)Ensure serum sodium concentration is normal before starting or resuming DDAVP. Measure serum sodium within week and approximately month after starting therapy and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia. (2.1, 5.1)If hyponatremia occurs, interrupt or discontinue DDAVP. (5.1). DDAVP can cause hyponatremia, which may be life-threatening if severe. (5.1). DDAVP is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids. (4, 5.1). Ensure serum sodium concentration is normal before starting or resuming DDAVP. Measure serum sodium within week and approximately month after starting therapy and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia. (2.1, 5.1). If hyponatremia occurs, interrupt or discontinue DDAVP. (5.1).

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Injection: DDAVP is sterile, aqueous, colorless solution available as:4 mcg/mL in single-dose ampule40 mcg/10 mL (4 mcg/mL) in multiple-dose vial. mcg/mL in single-dose ampule. 40 mcg/10 mL (4 mcg/mL) in multiple-dose vial. Injection: mcg/mL in mL single-dose ampule and 40 mcg/10 mL (4 mcg/mL) in multiple-dose vial. (3).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Hyponatremia and Fluid RestrictionInform patients that DDAVP may cause severe hyponatremia, which may be life-threatening, if it is not promptly diagnosed and treated [see Warnings and Precautions (5.1)]. Inform them about the signs and symptoms associated with hyponatremia, to undergo recommended serum sodium measurements, and to inform their health care provider about new medications. Advise patients to contact healthcare provider if symptoms of hyponatremia occur.Discuss adjustment of fluid intake and monitoring of urine output with patients.. Inform patients that DDAVP may cause severe hyponatremia, which may be life-threatening, if it is not promptly diagnosed and treated [see Warnings and Precautions (5.1)]. Inform them about the signs and symptoms associated with hyponatremia, to undergo recommended serum sodium measurements, and to inform their health care provider about new medications. Advise patients to contact healthcare provider if symptoms of hyponatremia occur.. Discuss adjustment of fluid intake and monitoring of urine output with patients.

LACTATION SECTION.


8.2 Lactation. Risk SummaryBreastfeeding is not expected to result in clinically relevant exposure of the infant to desmopressin following maternal administration. Desmopressin is poorly transferred into human breastmilk at negligible amounts (see Data). There is no information on the effects of desmopressin on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DDAVP Injection and any potential adverse effects on the breastfed child from DDAVP Injection or from the underlying maternal condition. DataThe breast milk of lactating women was collected over hours following administration of 300 mcg desmopressin nasal spray. The expected area under the plasma concentration time curve (AUC) of desmopressin following 300 mcg nasal spray is 2.4-fold higher to that of mcg DDAVP injection. Based on the measured concentrations of desmopressin following intranasal administration, the amounts of desmopressin that may be transferred to breastfed infant correspond to 0.0001-0.005% of the dose administered.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Desmopressin acetate increases plasma levels of factor VIII activity in patients with hemophilia and von Willebrands disease Type I.The antidiuretic effects of desmopressin acetate are mediated by stimulation of vasopressin (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin acetate is replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate resulted in increased duration of action and decreased vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced antidiuretic activity, so that clinically effective antidiuretic doses were usually below threshold levels for effects on vascular or visceral smooth muscle.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies with desmopressin have not been performed to evaluate carcinogenic potential. Desmopressin was not mutagenic in bacterial mutagenicity (Ames) and mouse lymphoma assays.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. The response to DDAVP of factor VIII activity and plasminogen activator is dose-related, with maximal plasma levels of 300 to 400 percent change from baseline obtained after infusion of 0.4 mcg/kg. The increase of factor VIII is rapid and evident within 30 minutes, reaching maximum at point ranging from 90 minutes to two hours. The duration of the hemostatic effect depends on the half-life for VIII:C which is about 8-12 hours. The percentage increase of factor VIII levels in patients with mild hemophilia and von Willebrands disease was not significantly different from that observed in normal healthy individuals when treated with 0.3 mcg/kg of DDAVP infused over 10 minutes.The use of DDAVP Injection in patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma osmolality.

RENAL IMPAIRMENT SUBSECTION.


8.6 Renal Impairment. Desmopressin acetate is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment than patients with normal renal function. DDAVP is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min [see Contraindications (4), Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pediatric Use: Initiate fluid intake restriction to prevent possible hyponatremia and water intoxication. (8.4)Geriatric Use: Carefully select dose and monitor renal function more frequently. (8.5). Pediatric Use: Initiate fluid intake restriction to prevent possible hyponatremia and water intoxication. (8.4). Geriatric Use: Carefully select dose and monitor renal function more frequently. (8.5). 8.1 Pregnancy. Risk SummaryProlonged experience with DDAVP Injection in pregnant women over several decades, based on the available published literature and case reports, have not identified drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.In addition, in vitro studies with human placenta demonstrate poor placental transfer of desmopressin. No adverse developmental outcomes were observed in animal reproductive and developmental studies following administration of desmopressin acetate during organogenesis to pregnant rats and rabbits, at doses 130- and 110- times, respectively, the recommended dose of 18 mcg for 60 kg patient, based on body surface area (mg/m2). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease Associated Maternal and Embryo-fetal Risk:Pregnant women with Hemophilia or von Willebrands disease may be at an increased risk for bleeding diatheses and hemorrhagic events at delivery. An affected newborn may also be at risk of bleeding diatheses.. Data. Animal DataIn developmental toxicity study in rats, desmopressin acetate was administered intravenously at doses of 9.68, 48.4, or 241 mcg/kg/day during the period of organogenesis (gestations days to 17). Laparohysterectomy for fetal examinations were conducted on gestation day 20 for twenty females in each group; the remaining 10 females were allowed to litter in order to determine any postnatal effects that might be attributable to pre-natal treatment. No effects were seen on maternal and fetal survival, growth and morphology or post-natal offspring survival, growth, development, behavior and reproductive performance up to 241 mcg/kg/day (130 times the 18 mcg dose received by 60 kg patient based on body surface area). In an embryo-fetal development study and pre- and postnatal development study in rabbits, desmopressin acetate was administered subcutaneously at doses of 2, 20 or 200 mcg/kg/day (embryo-fetal development) and 0.1, or 10 mcg/kg/day (pre- and postnatal development) during the period of organogenesis (gestation days to 18). No effects on maternal and fetal survival or morphology were observed in both studies at doses of up to 200 mcg/kg/day (215x the 18 mcg dose received by 60 kg patient based on body surface area) nor were there effects in the pre- and postnatal development study on parturition, postnatal survival, growth, development or behavior, up to the highest dose tested of 10 mcg/kg/day (11 times the 18 mcg dose received by 60 kg patient, based on body surface area). 8.2 Lactation. Risk SummaryBreastfeeding is not expected to result in clinically relevant exposure of the infant to desmopressin following maternal administration. Desmopressin is poorly transferred into human breastmilk at negligible amounts (see Data). There is no information on the effects of desmopressin on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DDAVP Injection and any potential adverse effects on the breastfed child from DDAVP Injection or from the underlying maternal condition. DataThe breast milk of lactating women was collected over hours following administration of 300 mcg desmopressin nasal spray. The expected area under the plasma concentration time curve (AUC) of desmopressin following 300 mcg nasal spray is 2.4-fold higher to that of mcg DDAVP injection. Based on the measured concentrations of desmopressin following intranasal administration, the amounts of desmopressin that may be transferred to breastfed infant correspond to 0.0001-0.005% of the dose administered.. 8.4 Pediatric Use. The safety and effectiveness of DDAVP have been established in pediatric patients months of age and older with hemophilia and von Willebrands disease and pediatric patients aged 12 years and older with diabetes insipidus. The safety and effectiveness of DDAVP have not been established in infants less than months of age with hemophilia or von Willebrands disease or pediatric patients under 12 years of age with diabetes insipidus. Use in infants and pediatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient and/or guardian [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use. Clinical studies of DDAVP Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as creatinine clearance below 50 mL/min) [see Contraindications (4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Use of DDAVP injection in geriatric patients will require careful fluid intake restrictions to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment. Desmopressin acetate is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment than patients with normal renal function. DDAVP is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min [see Contraindications (4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hypotension and Hypertension: May cause hypotension with compensatory increase in heart rate or hypertension. Monitor blood pressure during DDAVP administration, especially in patients with heart disease. (5.2)Increased Risk of Thrombosis in Patients with von Willebrands Disease Type IIB: Use of DDAVP in patients with Type IIB von Willebrands disease may cause thrombosis due to platelet aggregation. (5.3)Hypersensitivity Reactions: Severe reactions have occurred. Monitor for reactions during administration and interrupt if reaction occurs. (5.4)Fluid Retention: Fluid retention can worsen underlying conditions that are susceptible to volume status. Not recommended in patients at risk for increased intracranial pressure or with history of urinary retention. (5.5). Hypotension and Hypertension: May cause hypotension with compensatory increase in heart rate or hypertension. Monitor blood pressure during DDAVP administration, especially in patients with heart disease. (5.2). Increased Risk of Thrombosis in Patients with von Willebrands Disease Type IIB: Use of DDAVP in patients with Type IIB von Willebrands disease may cause thrombosis due to platelet aggregation. (5.3). Hypersensitivity Reactions: Severe reactions have occurred. Monitor for reactions during administration and interrupt if reaction occurs. (5.4). Fluid Retention: Fluid retention can worsen underlying conditions that are susceptible to volume status. Not recommended in patients at risk for increased intracranial pressure or with history of urinary retention. (5.5). 5.1Hyponatremia. DDAVP Injection can cause hyponatremia. Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest, or death [see Boxed Warning].DDAVP Injection is contraindicated in patients with hyponatremia (or history of hyponatremia), with excessive fluid intake (e.g., polydipsia), using loop diuretics or systemic or inhaled glucocorticoids, with known or suspected SIADH, and/or illnesses that can cause fluid or electrolyte imbalances [see Contraindications (4), Drug Interactions (7)]. Avoid concomitant treatments that also cause hyponatremia.Prior to starting or resuming DDAVP Injection, ensure that the serum sodium concentration is normal. Limit fluid intake to minimum from hour before administration until hours after administration. Use of DDAVP Injection without concomitant reduction of fluid intake may lead to fluid retention and hyponatremia.Monitor the serum sodium concentration within week and approximately month of initiating DDAVP Injection, and periodically thereafter [see Dosage and Administration (2.1)]. Base the frequency of serum sodium monitoring on the patients risk of hyponatremia.Patients with conditions associated with fluid and electrolyte imbalance (i.e., cystic fibrosis, heart failure, and renal disorders), geriatric and pediatric patients, patients receiving concomitant treatments that also cause hyponatremia (i.e., tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, chlorpromazine, opiate analgesics, carbamazepine, lamotrigine, thiazide diuretics and chlorpropamide), and patients with habitual or psychogenic polydipsia who may drink excessive amounts of water, may be at increased risk of hyponatremia [see Contraindications (4)].If hyponatremia occurs, DDAVP Injection may need to be temporarily or permanently discontinued and treatment for the hyponatremia instituted, depending on the clinical circumstances, including the duration and severity of the hyponatremia.. 5.2Hypotension and Hypertension. DDAVP may cause hypotension (with compensatory increase in heart rate) or hypertension. Monitor blood pressure during DDAVP administration, particularly in patients with history of coronary artery insufficiency and/or hypertensive cardiovascular disease [see Adverse Reactions (6), Drug Interactions (7.2)] 5.3 Increased Risk of Thrombosis in Patients with von Willebrands Disease Type IIB. Use of DDAVP in patients with Type IIB von Willebrands disease may result in platelet aggregation, thrombocytopenia, and possibly thrombosis.. 5.4Hypersensitivity Reactions. Hypersensitivity reactions including anaphylaxis have been reported with intravenous and intranasal DDAVP, including cases of fatal anaphylaxis with intravenous DDAVP. DDAVP Injection is contraindicated in patients with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Injection [see Contraindications (4)]. It is not known whether antibodies to DDAVP Injection are produced after repeated injections. Monitor patients for signs or symptoms of hypersensitivity reactions during administration, interrupt treatment should reaction occur, and manage medically. Permanently discontinue for serious hypersensitivity reaction [see Adverse Reactions (6)]. 5.5Fluid Retention. DDAVP Injection can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Patients with heart failure or uncontrolled hypertension may be at increased risk. DDAVP Injection is not recommended in patients at risk for increased intracranial pressure or those with history of urinary retention. Advise patients to limit fluid intake [see Patient Counseling Information (17)].