DESMOPRESSIN ACETATE

Desmopressin acetate injection, USP is a synthetic vasopressin analog for intravenous or subcutaneous use. It is chemically defined as follows: Mol. Wt. 1183.34 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. Desmopressin acetate injection, USP is a sterile solution in a 10 mL multiple-dose vial: Each mL contains 4 mcg of desmopressin acetate, USP which is equivalent to 3.6 mcg of desmopressin free base. The inactive ingredients are sodium chloride USP, chlorobutanol hemihydrate, USP (5 mg per mL), hydrochloric acid, NF and water for injection, USP. Sodium chloride is used to adjust tonicity. Hydrochloric acid is used to adjust pH. desmopressin-acetate-spl-structure

Desmopressin acetate 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. ( 1.1 ) 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. ( 1.2 ) 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. ( 1.3 ) Limitations of Use Desmopressin acetate is ineffective and not indicated for the treatment of nephrogenic diabetes insipidus. ( 1.3 ) 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. ( 1.3 ) 1.1 Central Diabetes Insipidus Desmopressin acetate 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: Desmopressin acetate is ineffective and not indicated for the treatment of nephrogenic diabetes insipidus. 1.2 Hemophilia A Desmopressin acetate 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. 1.3 von Willebrand’s Disease (Type I) Desmopressin acetate 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 Desmopressin acetate 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 [see Warnings and Precautions ( 5.2 )].

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. ( 2.1 ) 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. ( 2.1 ) See Full Prescribing Information for instructions on reconstitution, preparation, and administration ( 2 ). 2.1 Pretreatment Testing and On-Treatment Monitoring Diabetes Insipidus Prior to treatment with desmopressin acetate, 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 desmopressin acetate 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 desmopressin acetate 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 desmopressin acetate 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 desmopressin acetate 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 desmopressin acetate injection. 2.2 Recommended Dosage Initiate fluid restriction during treatment with desmopressin acetate injection [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 , 8.5 )]. 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 desmopressin acetate 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 desmopressin acetate 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 desmopressin acetate 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 desmopressin acetate is administered every 2 to 3 days. 2.3 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 desmopressin acetate injection from the vial and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, USP per Table 1. Dilute desmopressin acetate 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. 2.4 Switching Between Desmopressin Acetate Formulations Desmopressin acetate 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 desmopressin acetate nasal spray to desmopressin acetate injection, the starting dose is one-tenth times the desmopressin acetate nasal spray dose. When switching from desmopressin acetate tablets to desmopressin acetate 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.

Desmopressin acetate injection is contraindicated in patients with known hypersensitivity to desmopressin acetate or to any of the components of desmopressin acetate injection [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6 ), Description ( 11 )]. Desmopressin acetate injection is contraindicated in patients with the following conditions due to an increased risk of hyponatremia: Moderate to severe renal impairment defined as a creatinine clearance below 50 mL/min [see Use in Specific Populations ( 8.5 , 8.6 ) and Clinical Pharmacology ( 12.3 )]. Hyponatremia or a history of hyponatremia [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )], Use in Specific Populations ( 8.4 , 8.5 )]. Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion [see Warnings and Precautions ( 5.1 )] . Polydipsia [see Warnings and Precautions ( 5.1 )] . Concomitant use with loop diuretics [see Boxed Warning ]. Concomitant use with systemic or inhaled glucocorticoids [see Boxed Warning ] . During illnesses that can cause fluid or electrolyte imbalance, such as gastroenteritis, salt-wasting nephropathies, or systemic infection [see Boxed Warning ] . Desmopressin acetate injection is contraindicated in patients with the following conditions because fluid retention increases the risk of worsening the underlying condition: Heart failure Uncontrolled hypertension Known hypersensitivity to desmopressin acetate or to any of the components ( 4 ) Moderate to severe renal impairment defined as a creatinine clearance below 50 mL/min ( 4 ) Hyponatremia or a history of hyponatremia ( 4 ) Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion ( 4 ) Polydipsia ( 4 ) Concomitant use with loop diuretics or systemic or inhaled glucocorticoids ( 4 ) During illnesses that can cause fluid or electrolyte imbalance ( 4 ) Heart failure or uncontrolled hypertension ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Hyponatremia [see Contraindications, Warnings and Precautions ( 5.1 )] Hypotension and Hypertension [see Warnings and Precautions ( 5.2 )] Increased risk of thrombosis in patients with von Willebrand’s Disease Type IIB [see Warnings and Precautions ( 5.3 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] Fluid retention [see Warnings and Precautions ( 5.5 )] The following adverse reactions have been identified during post-approval use of desmopressin acetate injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: Hypertension, hypotension, tachycardia, thrombotic events, fluid retention Digestive: Nausea, abdominal cramps Immune: Hypersensitivity reactions Integumentary: Erythema, swelling, burning pain, facial flushing Laboratory: Hyponatremia Nervous: Headache, hyponatremic seizures Common adverse reactions are abdominal cramps, burning pain, erythema, facial flushing, fluid retention, headache, hypersensitivity reactions, hypertension, hyponatremia, hyponatremic seizures, hypotension, nausea, swelling, tachycardia, and thrombotic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma Limited at (864-879-9994) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drugs that increase risk of hyponatremia: Require more frequent serum sodium monitoring. ( 7.1 ) Other vasoconstrictors: May require a reduction of the desmopressin acetate dosage. ( 7.2 ) 7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of desmopressin acetate 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 desmopressin acetate injection concomitantly with these drugs and when doses of these drugs are increased [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.4 , 8.5 )]. 7.2 Other Vasoconstrictors Desmopressin acetate injection can elevate blood pressure. Use of desmopressin acetate injection with other vasoconstrictors may require a reduction of the desmopressin acetate injection dosage [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )].