DDAVP Injection (desmopressin acetate) is a synthetic vasopressin analog for intravenous or subcutaneous use. It is chemically defined as follows: Mol. Wt

Empirical Formula: C 46 H 64 N 14 O 12 S 2 ∙C 2 H 4 O 2 ∙3H 2 O 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate. DDAVP solution for injection is a sterile solution in a 1 mL single-dose ampule: Each mL contains 4 mcg of desmopressin acetate which is equivalent to 3.6 mcg of desmopressin free base. The inactive ingredients are sodium chloride, hydrochloric acid and water for injection. Sodium chloride is used to adjust tonicity. Hydrochloric acid is used to adjust pH. DDAVP solution for injection is a sterile solution in a 10 mL multiple-dose vial: Each mL contains 4 mcg of desmopressin acetate which is equivalent to 3.6 mcg of desmopressin free base. The inactive ingredients are sodium chloride, chlorobutanol (5 mg per mL), hydrochloric acid and water for injection. Sodium chloride is used to adjust tonicity. Hydrochloric acid is used to adjust pH. Chemical Structure

DDAVP Injection is a vasopressin analog used for: Central Diabetes Insipidus - 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. Hemophilia A- for patients with factor VIII coagulant activity levels greater than 5% to maintain hemostasis during surgical procedures and postoperatively or reduce bleeding with episodes of spontaneous or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding. von Willebrand's disease (Type I) - for patients with mild to moderate disease with factor VIII levels greater than 5% to maintain hemostasis during surgical procedures or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding. Limitations of Use DDAVP is ineffective and not indicated for the treatment of nephrogenic diabetes insipidus. von Willebrand's disease (severe Type I) - not indicated for the treatment of patients with severe Type I von Willebrand's disease and when there is evidence of an abnormal molecular form of factor VIII antigen

Central Diabetes Insipidus DDAVP Injection is indicated as antidiuretic replacement therapy in the management of central (cranial) diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. Limitations of Use: DDAVP is ineffective and not indicated for the treatment of nephrogenic diabetes insipidus

Hemophilia A DDAVP Injection is indicated for patients with hemophilia A with factor VIII coagulant activity levels greater than 5% without factor VIII antibodies to: Maintain hemostasis during surgical procedures and postoperatively Reduce bleeding with episodes of spontaneous or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding

von Willebrand's Disease (Type I) DDAVP Injection is indicated for patients with mild to moderate von Willebrand's disease (Type I) with factor VIII levels greater than 5% to: Maintain hemostasis during surgical procedures and postoperatively Reduce bleeding with episodes of spontaneous or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding. Limitations of Use DDAVP is not indicated for the treatment of severe von Willebrand's disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen .

Injection: DDAVP is a sterile, aqueous, colorless solution available as: 4 mcg/mL in single-dose ampule 40 mcg/10 mL (4 mcg/mL) in multiple-dose vial Injection: 4 mcg/mL in 1 mL single-dose ampule and 40 mcg/10 mL (4 mcg/mL) in a multiple-dose vial.

Diabetes Insipidus: The daily dose is 2 mcg to 4 mcg administered as one or two divided doses by subcutaneous or intravenous injection. The dosage must be determined for each patient and adjusted according to the pattern of response. Hemophilia A and von Willebrand's Disease (Type I): 0.3 mcg/kg (to a maximum of 20 mcg) administered by intravenous infusion. Dilute dose as appropriate. See Full Prescribing Information for instructions on reconstitution, preparation, and administration

Pretreatment Testing and On-Treatment Monitoring Diabetes Insipidus Prior to treatment with DDAVP, assess serum sodium, urine volume and osmolality. Intermittently during treatment, assess serum sodium, urine volume and osmolality or plasma osmolality. Hemophilia A Prior to treatment with DDAVP Injection, verify that factor VIII coagulant activity levels are >5% and exclude the presence of factor VIII autoantibodies. Also assess serum sodium and aPTT prior to treatment. 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 Willebrand's Disease (Type I) Prior to treatment with DDAVP Injection, verify that factor VIII coagulant activity levels are >5% and exclude severe von Willebrand's disease (Type I) and presence of abnormal molecular form of factor VIII antigen. During treatment with DDAVP Injection, assess serum sodium, bleeding time, factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand antigen to ensure that adequate levels are being achieved. For All Patients Receiving Repeated Doses: Restrict free water intake and monitor for hyponatremia. Ensure that serum sodium is normal prior to initiating or resuming treatment with DDAVP Injection

Recommended Dosage Initiate fluid restriction during treatment with DDAVP Injection . Diabetes Insipidus: Treatment naïve patients: The recommended starting daily dosage is 2 mcg to 4 mcg administered as one or two divided doses by subcutaneous or intravenous injection. Do not dilute DDAVP Injection for the Diabetes Insipidus population. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. Adjust dose based upon response to treatment estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients changing from intranasal desmopressin: The recommended starting dose of DDAVP Injection is 1/10 th the daily maintenance intranasal dose administered by subcutaneous or intravenous injection as one or two divided doses Hemophilia A and von Willebrand's Disease (Type I): The recommended dosage is 0.3 mcg/kg actual body weight (to a maximum of 20 mcg) administered by intravenous infusion over 15 minutes to 30 minutes. If used preoperatively, administer 30 minutes prior to the procedure. If used to reduce spontaneous or traumatic bleeding, doses may be repeated after 8 hours to 12 hours and once daily thereafter, if needed, based upon clinical condition and von Willebrand factor and factor VIII levels. 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. Tachyphylaxis (lessening of response) with repeated administration (i.e., given more frequently than every 48 hours) may occur. The initial response is reproducible if DDAVP is administered every 2 to 3 days

Preparation and Administration for Patients with Hemophilia A and von Willebrand's Disease (Type I) Prepare the solution for infusion using aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw the necessary volume of DDAVP Injection from the vial and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, USP per Table 1. Dilute DDAVP Injection in sterile 0.9% Sodium Chloride Injection, USP and infuse slowly over 15 minutes to 30 minutes. The volume of diluent is weight-based. See Table 1 for volume of diluent to use. Table 1: Volume of Diluent Required Patient Weight Volume of 0.9% Sodium Chloride Injection, USP for dilution 10 kg or less 10 mL More than 10 kg 50 mL Monitor blood pressure and pulse during infusion

Switching Between Desmopressin Acetate Formulations DDAVP is also available as nasal spray and tablet dosage forms. When switching between formulations, the below text is meant as guidance for starting dose. However, dose should always be titrated individually according to the diuresis (antidiuretic response) and electrolyte status (serum sodium) of the patient. When switching from DDAVP Nasal Spray to DDAVP Injection, the starting dose is one-tenth times the DDAVP Nasal Spray dose. When switching from DDAVP Tablets to DDAVP Injection, titrate dose individually according to the diuresis (antidiuretic response) and electrolyte status (serum sodium) due to the large variability in both PK and PD. Monitor patients closely during the initial dose titration period.

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. Increased Risk of Thrombosis in Patients with von Willebrand's Disease Type IIB : Use of DDAVP in patients with Type IIB von Willebrand's disease may cause thrombosis due to platelet aggregation. Hypersensitivity Reactions : Severe reactions have occurred. Monitor for reactions during administration and interrupt if reaction occurs. 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 a history of urinary retention. 5.1 Hyponatremia 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 . DDAVP Injection is contraindicated in patients with hyponatremia (or a 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 . 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 a minimum from 1 hour before administration until 8 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 1 week and approximately 1 month of initiating DDAVP Injection, and periodically thereafter . Base the frequency of serum sodium monitoring on the patient's 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 . 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

Hypotension and Hypertension DDAVP may cause hypotension (with compensatory increase in heart rate) or hypertension. Monitor blood pressure during DDAVP administration, particularly in patients with a history of coronary artery insufficiency and/or hypertensive cardiovascular disease 5.3 Increased Risk of Thrombosis in Patients with von Willebrand's Disease Type IIB Use of DDAVP in patients with Type IIB von Willebrand's disease may result in platelet aggregation, thrombocytopenia, and possibly thrombosis

Hypersensitivity 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 . 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 a reaction occur, and manage medically. Permanently discontinue for serious hypersensitivity reaction

Fluid 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 a history of urinary retention. Advise patients to limit fluid intake .

Drugs that increase risk of hyponatremia: Require more frequent serum sodium monitoring. Other vasoconstrictors: May require a reduction of the DDAVP dosage

Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of DDAVP Injection with other drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, thiazide diuretics, NSAIDs, lamotrigine, sulfonylureas, particularly chlorpropamide, oxybutynin and carbamazepine), requires more frequent serum sodium monitoring. Monitor serum sodium more frequently in patients taking DDAVP Injection concomitantly with these drugs and when doses of these drugs are increased

Other Vasoconstrictors DDAVP Injection can elevate blood pressure. Use of DDAVP Injection with other vasoconstrictors may require a reduction of the DDAVP Injection dosage .