Hemophilia

Stimate®, also known as DDAVP Nasal or Noctiva, is the brand name for intranasal desmopressin acetate, which is classified as an antidiuretic hormone drug. Stimate is a synthetic form of the hormone vasopressin, also known as antidiuretic hormone (ADH). Typically produced in the pituitary gland, vasopressin regulates water conservation, affecting kidney function and blood pressure.^1,2 Stimate is manufactured by CSL Behring. It is used to help control bleeding in patients with mild forms of hemophilia.³

Indications

DDAVP is used to treat acute episodes of bleeding in individuals with hemophilia A or von Willebrand disease (VWD) type I. It is also used to treat central cranial diabetes insipidus as well as to control increased thirst and urination following head trauma or brain surgery.¹

In patients with hemophilia A or mild-to-moderate classic VWD type I, DDAVP is indicated when the level of factor VIII coagulant activity is greater than 5% and during spontaneous or trauma-induced acute episodes of bleeding, including intramuscular hematoma, mucosal bleeding, menorrhagia, and hemarthrosis.²

DDAVP is not indicated for patients with severe classic VWD type I, hemophilia B, hemophilia A with factor VIII coagulant activity levels of 5% or lower, in presence of factor VIII antibodies, or abnormal molecular factor VIII antigens.²

Dosage and Administration

One pump of Stimate Nasal Spray delivers 0.1 mL of spray into each nostril. Each pump contains 150 μg of desmopressin acetate, so that a total dose of 300 μg of desmopressin acetate is administered. For proper administration, the spray pump should be primed by depressing the pump 4 times. Following the administration of 25 doses, the bottle should be discarded because the remaining spray may deliver less than the expected 150-μg dose. If different doses that are not multiples of 0.1 mL are required, the patient may require DDAVP Injection.² 

In patients who weigh less than 50 kg, a single spray containing 150 μg of desmopressin acetate will produce target levels of factor VIII coagulant activity and factor VIII ristocetin cofactor activity, and the target skin bleeding time.² 

If Stimate is indicated to maintain hemostasis during a surgical procedure, it must be administered 2 hours before the scheduled operation. Fluid intake must be restricted for 1 hour prior to Stimate administration and for at least 24 hours following administration.² 

The response to the administration of Stimate is assessed via laboratory testing and the patient’s clinical presentation to determine if repeated administration is necessary. The prescribing physician must also consider the possibility of patient tachyphylaxis if the administration of Stimate is repeated within a 48-hour period.²

The antidiuretic effect of an intranasal dose is approximately one-tenth that of an equivalent dose of injectable DDAVP.⁴ 

Get full prescribing information for Stimate on MPR

Mechanism of Action

Stimate activates V2 receptors located throughout renal collecting ducts and distal convoluted tubules. Stimate binds to the V2 receptors, triggering a signaling cascade of adenyl cyclase, which in turn increases intracellular concentrations of cyclic adenosine monophosphate (cAMP).⁵ 

Elevated cAMP concentrations trigger the release of von Willebrand factor (VWF) and factor VIII from their storage sites, including Weibel-Palade bodies in the vascular endothelial cells and alpha granules of platelets, via exocytosis.⁵ 

The release of VWF and factor VIII facilitates the clotting cascade and hemostasis during the treatment of individuals with bleeding disorders caused by deficiencies of VWF and factor VIII.⁵

Efficacy and Safety of Stimate in Clinical Trials

In 1991, a clinical trial demonstrated the safety and efficacy of Stimate in inducing hemostasis during surgery. Abnormal bleeding times were corrected in 62% of patients with VWD, and factor VIII levels adequate for hemostasis were achieved in 82% of patients who had mild hemophilia A or were symptomatic carriers of hemophilia.⁶  

In a 2000 case report that reviewed the adverse events associated with Stimate use in 40 patients, 27 (68%) had signs and symptoms of adverse reactions. Most were mild, although some were moderate to severe. One adult patient required medical intervention for symptomatic hyponatremia.⁷  

In 2001, an open-label multicenter clinical trial demonstrated that high-dose Stimate (1.5 mg/mL) was safe and efficacious in the prevention and treatment of episodes of bleeding in patients who had mild hemophilia A or who were symptomatic carriers of hemophilia A or VWD. The efficacy of Stimate was rated as excellent or good in 743 of 784 episodes of bleeding (95%), excellent in 384 of 413 prophylactic administrations (93%), in 8 of 8 of dental or acute surgical procedures (100%), and in 655 of 721 administrations (91%) for the treatment of menorrhagia. A total of 272 adverse events were reported in 80 patients, which occurred during 172 of 2170 administrations (8%). Of these 272 adverse events, 239 (88%) were mild to moderate. Only one patient discontinued Stimate because of an adverse event.⁸ The results of this clinical trial eventually led to the approval of Stimate by the US Food and Drug Administration.³

Warnings, Precautions, and Adverse Reactions

It is important that individuals provide an accurate medical history so that physicians can decide if Stimate is contraindicated—for example, when the patient is allergic to Stimate. Physicians must determine if Stimate is safe for use in individuals with a medical history of any of the following¹: 

• Hyponatremia
• Uncontrolled hypertension
• Congestive heart failure
• Coronary artery disease
• Head injury or brain tumor
• Cystic fibrosis
• Diabetes
• Moderate-to-severe kidney disease
• SIADH (syndrome of inappropriate antidiuretic hormone secretion)
• Current pregnancy or breastfeeding
• Current runny nose or congested nasal or sinus passages
• Any condition causing excessive thirst, dehydration, or an electrolyte imbalance, such as a psychological disorder, fever, diarrhea, emesis, or infection 
• Thrombotic events (stroke, myocardial infarction, deep vein thrombosis)²

Intranasal swelling or scarring or any sinus or nasal problems, such as congestion or a deviated septum, may reduce the efficacy of Stimate.¹ If Stimate is given to geriatric or pediatric patients, fluid intake must be adjusted to decrease the probability of water intoxication and hyponatremia.²

While they are taking Stimate, patients should limit their water and fluid intake because of the risk for hyponatremia with excess fluid consumption. Drug interactions are possible with diuretics, such as bumetanide, furosemide, torsemide, and ethacrynic acid, or with steroids, such as dexamethasone, fluticasone, budesonide, prednisone, mometasone, and others.¹  

The risk for water intoxication with hyponatremia is increased when Stimate is administered concomitantly with other pressor agents, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, opiate analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), lamotrigine, and carbamazepine.² 

Common side effects include a stuffed or runny nose, nasal discomfort, sinus pain, nosebleeds, sneezing, sore throat, cough, dizziness, increased blood pressure, nausea, stomach cramps, headache, back pain, and flushing.¹

Following the administration of Stimate, if signs of an allergic reaction develop (eg, hives; swelling of the lips, tongue, throat, or face; difficulty breathing), patients are instructed to seek emergency medical attention immediately.¹ 

Patients are also instructed to contact the prescribing physician if they experience a seizure, rapid weight gain, ankle or foot edema, nasal congestion or other problems, or symptoms of hyponatremia, which include headache, confusion, vomiting, restlessness or drowsiness, hallucinations, irritability, loss of appetite, and muscle pain or weakness. Individuals who experience ongoing diarrhea, vomiting, fever, or excessive sweating are instructed to contact the prescribing physician because these may lead to severe hypotension or serious electrolyte imbalance.¹ 

Urine or blood tests may be indicated if a patient has stopped taking Stimate or before treatment with Stimate is initiated so that the physician may prescribe the proper dosage.¹ 

References

1. Stimate nasal uses, side effects & warnings. Drugs.com. Accessed December 29, 2021.
2. Stimate (desmopressin acetate nasal spray): uses, dosage, side effects, interactions, warning. RxList. Accessed December 29, 2021.
3. Atkinson HP. Stimate for hemophilia A. Hemophilia News Today. Accessed December 29, 2021.
4. Desmopressin: uses, interactions, mechanism of action. DrugBank Online. Accessed December 29, 2021. 
5. McCarty TS, Shah AD. Desmopressin. StatPearls [Internet]. Updated May 9, 2021. Accessed December 29, 2021.
6. Rose EH, Aledort LM. Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med. 1991;114(7):563-568. doi:10.7326/0003-4819-114-7-563
7. Dunn AL, Powers JR, Ribeiro MJ, Rickles FR, Abshire TC. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia. 2000;6(1):11-14. doi:10.1046/j.1365-2516.2000.00367.x
8. Leissinger C, Becton D, Cornell C, Cox Gill J. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia. 2001;7(3):258-266. doi:10.1046/j.1365-2516.2001.00500.x

Reviewed by Stimate, on 12/30/2021.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.