The following Structured Product Label (SPL) was submitted to the FDA by Ferring Pharmaceuticals Inc. for the product Stimate (NDC 55566-3000). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1.1 hemophilia a, 1.2 von willebrand’s disease (type i), 2.1 pretreatment testing and on-treatment monitoring, 2.2 recommended dosage, 2.3 switching between desmopressin acetate formulations, 3 dosage forms and strengths, 4 contraindications, 5.1 hyponatremia, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
STIMATE is indicated for patients with hemophilia A with factor VIII coagulant activity levels greater than 5% without factor VIII antibodies to:
STIMATE is indicated for patients with mild to moderate von Willebrand’s disease (Type I) with factor VIII levels greater than 5% to:
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)].
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 STIMATE for hemostasis. If Factor VIII coagulant activity is present at less than 5% of normal, STIMATE should not be relied on.
von Willebrand's Disease
Laboratory tests for assessing patient status include levels of Factor VIII coagulant activity, VWF:RCo and VWF:Ag.
Fluid Restriction
Instruct patients about appropriate fluid restriction during STIMATE treatment. Fluid restriction should be observed, and fluid intake should be limited to a minimum, from 1 hour before desmopressin administration, until at least 24 hours after administration [see Warnings and Precautions (5.1)].
The recommended dosage for patients weighing at least 50 kg is 300 mcg intranasal spray (one spray in each nostril).
The recommended dosage for patients weighing less than 50 kg is 150 mcg administered as a single intranasal spray.
The use of STIMATE is not indicated for patients who require less than a 150 mcg dose or doses that are not multiples of 150 mcg because the spray pump can only deliver doses of 150 mcg [see Indications and Usage (1)]. If other doses are required, DDAVP Injection may be used [see Warnings and Precautions (2.3)].
If STIMATE is used preoperatively, it should be administered 2 hours prior to the scheduled procedure.
The necessity for repeat administration of STIMATE 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 once every 48 hours should be considered in treating each patient.
Must prime the spray pump prior to the first use. Instruct patients to:
Pediatric Patients
STIMATE should not be used in infants younger than 11 months in the treatment of hemophilia A or von Willebrand’s disease.
Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication [see Warnings and Precautions (5.1)].
Desmopressin acetate, for hemostatic use or therapeutic control of bleeding in patients with hemophilia A and mild to moderate von Willebrand’s disease (Type I), is also available as a solution for injection (DDAVP Injection).
For surgical procedures, parenteral administration of desmopressin is primarily recommended.
In situations where the intranasal route may be compromised, parenteral administration of desmopressin should be considered [see Warnings and Precautions (5.3)].
When switching from the parenteral form of desmopressin to STIMATE, administer a test dose of intranasal to establish that the patient shows an appropriate change in the coagulation profile [see Dosage and Administration (2.2)].
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.
STIMATE is contraindicated in patients with:
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.
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.
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)].
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.
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:
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
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)].
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)].
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/m2) (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/m2).
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.
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.
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)].
Signs of desmopressin acetate overdosage may include confusion, drowsiness, continuing headache, problems with passing urine, and rapid weight gain due to fluid retention [see Warnings and Precautions (5.1)]. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue STIMATE. There is no known specific antidote for desmopressin acetate. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
STIMATE (desmopressin acetate) is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It is chemically defined as follows:
Molecular weight: 1183.34
Empirical formula: C46H64N14O12S2•C2H4O2•3H2O
A Black Text On A White Background Ai-generated Content May Be Incorrect. (Stimate 1)
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
STIMATE is an aqueous solution for intranasal use. Each mL contains: Benzalkonium chloride solution 0.1 mg, Citric acid monohydrate 1.7 mg, Desmopressin acetate 1.5 mg, Disodium phosphate dihydrate 3 mg, Purified water to 1 mL, Sodium chloride 7.5 mg.
Desmopressin acetate increases plasma levels of factor VIII activity in patients with hemophilia and von Willebrand’s disease Type I.
The response to STIMATE is dose-related, with maximal plasma levels of 150 to 250 percent of initial concentrations achieved for both Factor VIII and von Willebrand factor. The increase reaches a maximum at about 1.5 hours.
The percentage increase of Factor VIII and von Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was not notably different from that observed in normal healthy individuals when treated with 300 mcg of STIMATE. In patients with von Willebrand's disease, levels of Factor VIII coagulant activity and von Willebrand factor antigen remained greater than 30 U/dL for 8 hours after a 300 mcg dose of STIMATE. After 300 mcg of STIMATE, the percentage increase of Factor VIII and von Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was less than observed after 0.3 mcg/kg of intravenous desmopressin acetate.
Absorption
Plasma concentrations of desmopressin acetate following administration of STIMATE were maximal approximately 40 to 45 minutes after dosing. The absolute bioavailability of STIMATE administered by the intranasal route as a 1.5 mg/mL solution is between 3.3 and 4.1 percent.
Elimination
The half-life of desmopressin acetate following administration of STIMATE is between 3.3 and 3.5 hours, over the range of intranasal doses, 150 to 450 mcg.
Specific Populations
Renal Impairment:
A pharmacokinetic study was conducted in subjects with normal renal function and subjects with mild, moderate, and severe renal impairment (n=24, 6 subjects each group) following administration of a single 2 mcg dose of desmopressin acetate intravenous injection. The geometric mean terminal half-life was 2.8 hours in subjects with normal renal function, and 4, 6.6, and 8.7 hours in subjects with mild, moderate, and severe renal impairment, respectively. In subjects with mild, moderate and severe renal impairment, mean desmopressin area under the plasma drug concentration time curve (AUC) was 1.5-, 2.4- and 3.6-fold higher, respectively, compared to that of subjects with normal renal function.
Studies with desmopressin acetate have not been performed to evaluate carcinogenic potential or effects on fertility. Desmopressin acetate was negative in vitro in Ames and mouse lymphoma cell mutation tests.
In the outpatient setting during two clinical trials where patients recorded bleeding episodes, STIMATE provided effective hemostasis 100% of the time in 2 of the 5 patients. For those patients not responding in 100% of bleeding occasions, 45% (14 of 31) of bleeding episodes were effectively controlled with STIMATE.
In the outpatient setting during two clinical trials where patients recorded bleeding episodes, STIMATE provided effective hemostasis 100% of the time in 75% of the patients (n=16). For those patients not responding in 100% of bleeding occasions, 78% (64 of 82) of bleeding episodes were effectively controlled with STIMATE.
STIMATE is available as a 2.5 mL bottle containing an aqueous solution with the spray pump delivering 25 sprays of 150 mcg (0.1 mL) (NDC 55566-3000-0).
Store at Controlled Room Temperature 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Discard STIMATE six months after being opened. Store bottle in upright position.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hyponatremia and Fluid Restriction
Administration
Manufactured for:
Ferring Pharmaceuticals Inc.
Parsippany, NJ 07054 USA
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NDC 55566-3000-0
STIMATE®
(desmopressin acetate)
Nasal Spray
150 mcg/spray (0.1 mL)
For Intranasal Use Only.
Read the enclosed Instructions for Use prior to use.
1 x 2.5 mL bottle containing
25 sprays of 150 mcg each.
Rx only
FERRING
PHARMACEUTICALS
Stimate Pdp (Stimate 6)
* Please review the disclaimer below.
