Desmopressin Acetate

STIMATE is a vasopressin analog used for: 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. ( 1.1 ) 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. ( 1.2 ) Limitations of Use STIMATE is not indicated for: 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. ( 1.2 )

1.1 Hemophilia A STIMATE 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. 1.2 von Willebrand’s Disease (Type I) STIMATE 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, mucosal bleeding, or menorrhagia. 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. 5 )].

STIMATE pump delivers 150 mcg (0.1 mL) of desmopressin acetate per spray. STIMATE is available as a 2.5 mL bottle with spray pump delivering 25 sprays. Nasal Spray: 150 mcg per 0.1 mL spray, available in a 2.5 mL bottle with spray pump delivering 25 sprays ( 3 )

STIMATE is contraindicated in patients with: Known hypersensitivity to desmopressin acetate or to any of the components of STIMATE. Severe allergic reactions and anaphylaxis have been reported [see Warnings and Precautions ( 5.4 )]. Hyponatremia or a history of hyponatremia [see Warnings and Precautions ( 5.1 )] . Type IIB von Willebrand's disease [see Warnings and Precautions ( 5.5 ) Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion [see Warnings and Precautions ( 5.1 )] . Known hypersensitivity to desmopressin acetate or to any of the components of STIMATE ( 4 , 5.4 ) Hyponatremia or a history of hyponatremia ( 4 , 5.1 ) Type IIB von Willebrand's disease ( 4 , 5.5 ) Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion. ( 4 )

Hyponatremia : Excessive fluid intake when urine output is limited by the antidiuretic effect of desmopressin may lead to water intoxication with hyponatremia. ( 5.1 ) Hypotension and Hypertension : May cause hypotension with compensatory increase in heart rate or hypertension. Monitor blood pressure during STIMATE administration, especially in patients with heart disease. ( 5.2 ) Altered Absorption in Patients with Nasal Mucosa Abnormalities: changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption. ( 5.3 ) Hypersensitivity Reactions : Severe reactions have occurred. Monitor for reactions during administration and interrupt if reaction occurs. ( 5.4 ) Increased Risk of Thrombosis in Patients with von Willebrand’s Disease Type IIB : Use of STIMATE in patients with Type IIB von Willebrand’s disease may cause thrombosis due to platelet aggregation. ( 5.5 )

5.1 Hyponatremia Serious and fatal hyponatremia may occur with STIMATE use. STIMATE is contraindicated in patients with hyponatremia (or a history of it) and known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion [see Contraindications ( 4 )] . Excessive fluid intake when urine output is limited by the antidiuretic effect of desmopressin may lead to water intoxication with hyponatremia. Cases of hyponatremia have been reported from post-marketing experience in patients treated with desmopressin acetate. Unless properly diagnosed and treated, hyponatremia can be fatal. Observe patients receiving STIMATE for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, malaise, fatigue, lethargy, disorientation, depressed reflexes, loss appetite, irritability, muscle weakness, muscle spasms or cramps, and abnormal mental status such as hallucinations, decreased consciousness, and confusion. Severe symptoms due to an extreme decrease in serum sodium and plasma osmolality may include one or a combination of the following: seizure, coma, and/or respiratory arrest. Advise patients to restrict fluids in order to decrease the risk of water intoxication with hyponatremia. Careful fluid intake restriction is particularly important in pediatric and geriatric patients because these patients are at greater risk of developing hyponatremia [see Use in Specific Populations ( 8.4 , 8.5 )]. More frequent monitoring of serum sodium levels is recommended in the following patients: those with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure, renal disorders, habitual or psychogenic polydipsia or those taking concomitant drugs that may cause hyponatremia or are known to induce SIADH . 5. 2 Hypotension and Hypertension STIMATE may cause changes in blood pressure. Changes have included elevation or reduction in blood pressure which may also cause a compensatory increase in heart rate. Monitor blood pressure and pulse more frequently if used in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease. 5. 3 Altered Absorption in Patients with Nasal Mucosa Abnormalities Since STIMATE is used intranasally, changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in which case STIMATE should be discontinued until the nasal problems resolve. Avoid use of STIMATE in such patients and consider use of other formulations of desmopressin acetate given by other routes of administration [see Dosage and Administration ( 2.4 )] .

5.4 Hypersensitivity Reactions STIMATE is contraindicated in patients with known hypersensitivity to desmopressin acetate or to any of the components of STIMATE [see Contraindications ( 4 )] . Severe allergic reactions, including fatal anaphylaxis, have been reported with desmopressin. It is not known whether antibodies to desmopressin acetate are produced after repeated administration.

5.5 Increased Risk of Thrombosis in Patients with von Willebrand’s Disease Type IIB STIMATE is contraindicated in patients with Type IIB von Willebrand's disease [see Contraindications ( 4 )] . Use of STIMATE in patients with Type IIB von Willebrand’s disease may result in platelet aggregation, thrombocytopenia, and possibly thrombosis.

The following serious reactions are described below and elsewhere in the labeling: Hyponatremia [see Warnings and Precautions ( 5.1 )]. Hypotension and Hypertension [see Warnings and Precautions ( 5.2 )] . Altered Absorption in Patients with Changes in Nasal Mucosa [see Warnings and Precautions ( 5.3 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] . Increased Risk of Thrombosis in Patients with von Willebrand’s Disease Type IIB [see Warnings and Precautions ( 5.5 )] . The following adverse reactions have been identified during post-approval use of desmopressin acetate intranasal formulations. 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: Cardiac disorders : Tachycardia, palpitations Eye disorders : Eye redness, eye itchiness, light sensitivity Gastrointestinal disorders : Nausea*, abdominal cramps/pain*, dyspepsia General disorders and administration site conditions : Peripheral edema*, fatigue*, chills, chest pain Immune system disorders : Hypersensitivity reactions Investigations : Weight increased* Metabolism and nutrition disorders : Hyponatremia Nervous system disorders : Headache, somnolence, dizziness, insomnia, hyponatremic convulsions Psychiatric disorders : Confusional state* Respiratory, thoracic and mediastinal disorders : Nasal congestion, rhinitis, epistaxis, sore throat, cough, upper respiratory infections Skin and subcutaneous disorders : Pruritus Vascular disorders : Hypertension, hypotension, flushing *Reported in association with hyponatremia Adverse reactions that have been identified in patients administered STIMATE are headache, eye redness, tachycardia, flushing, nasal congestion, rhinitis, epistaxis, nausea and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Other Drugs that may Increase Risk of Hyponatremia: Monitor serum sodium more frequently. ( 7.1 ) Other Vasoconstrictors: May require a reduction of the STIMATE dosage. ( 7.2 )

7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of STIMATE 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, NSAIDs, lamotrigine, and carbamazepine) requires more frequent serum sodium monitoring [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6 )] .

7.2 Other Vasoconstrictors Desmopressin acetate can elevate blood pressure. Use of large doses of STIMATE with other vasoconstrictors may require a reduction of the STIMATE dosage [ see Warnings and Precautions ( 5.2 ) ] .

Pediatric Use: Use requires careful fluid intake restriction to prevent hyponatremia with water intoxication ( 5.1 , 8.4 ) Geriatric Use: Carefully monitor renal function; restrict fluid intake to prevent hyponatremia with water intoxication ( 5.1 , 8.5 )

8.1 Pregnancy Risk Summary Available data on the use of desmopressin during pregnancy over decades of use have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated hemophilia A and von Willebrand’s disease during pregnancy (see Clinical Considerations). In vitro studies with human placenta demonstrate poor placental transfer of desmopressin. No adverse developmental outcomes were observed in animal reproduction studies with administration of desmopressin during organogenesis to pregnant rats and rabbits at doses approximately <1 and 38 times, respectively, the maximum recommended human dose based on body surface area (mg/m 2 ) (see Data). The background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease Associated Maternal and Embryo-fetal Risk Pregnant women with Hemophilia A or von Willebrand’s disease may be at an increased risk for bleeding diatheses and hemorrhagic events at delivery. A newborn born to a mother with Hemophilia A or von Willebrand disease may also be at risk for bleeding diatheses. Data Animal Data Desmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 1 to 20 during the period of early embryonic development and organogenesis without teratogenic effects. Desmopressin acetate at up to 10 mcg/kg/day was given to pregnant rabbits by subcutaneous injection from gestation day 6 to 18 during fetal organogenesis without teratogenic effects. These doses of desmopressin acetate represent approximately <1 times (rat) and 38 times (rabbit) the maximum recommended human dose based on body surface area (mg/m 2 ).

8.2 Lactation Risk Summary Breastfeeding is not expected to result in clinically relevant exposure of the infant to desmopressin following maternal intranasal administration. Desmopressin is transferred into human breastmilk at negligible amounts (see Data). There is no information on the effects of desmopressin on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STIMATE and any potential adverse effects on the breastfed infant from STIMATE or from the underlying maternal condition. Data A trial was conducted in six healthy lactating women, at greater than 4 months postpartum, to evaluate intranasal administration of 300 mcg single dose of desmopressin acetate. Samples of maternal plasma and breastmilk were obtained at 0, 30, 60, 120, 240, 360 and 480 min after the drug administration. At 8 hours after dose intake, the levels in the milk ranged between 4.16 and 101 pg/ml, and the plasma levels ranged between 40 and 242 pg/ml. The total amount of desmopressin present in the milk over the 8 hours ranged between 491 pg and 16 ng, which corresponds to 0.0001 – 0.005% of the administered dose to the breastfeeding mother.

8.4 Pediatric Use The safety and effectiveness of STIMATE has been established in children between 11 months and 12 years with hemophilia A or von Willebrand’s disease. 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 )]. The safety and effectiveness of STIMATE have not been established in pediatric patients younger than 11 months old.

8.5 Geriatric Use Clinical studies of STIMATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at a low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and monitoring renal function is recommended . Use of STIMATE in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )].

Desmopressin acetate increases plasma levels of factor VIII activity in patients with hemophilia and von Willebrand’s disease Type I.