Hemophilia

DDAVP® is the brand name for desmopressin acetate, which is classified as an antidiuretic hormone drug.¹ DDAVP is a synthetic form of the hormone vasopressin. Typically produced in the pituitary gland, vasopressin, also known as antidiuretic hormone (ADH), helps in the regulation of water retention by the kidneys, blood flow, and blood pressure.^1,2 

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%, during or following surgical procedures to maintain hemostasis, and during acute spontaneous or trauma-induced episodes of bleeding, including intramuscular hematoma, mucosal bleeding, and hemarthrosis.²

DDAVP is not indicated for patients with hemophilia B, severe classic VWD type I, or in cases with factor VIII antibodies. Patients with hemophilia A or mild-to-moderate classic VWD type I with levels of factor VIII coagulant activity below 5% should not receive DDAVP, although patients with levels of factor VIII activity between 2% and 5% may receive DDAVP if it is clinically justified and with careful monitoring.² 

Dosage and Administration

Each milliliter of injectable DDAVP medication consists of 4 μg of desmopressin acetate, 9 mg of sodium chloride, 5.0 mg of chlorobutanol (a preservative), and enough hydrochloric acid to adjust the pH to 4.²

DDAVP at a concentration of 4 μg per milliliter is administered gradually over a period of 15 to 30 minutes as an intravenous infusion to a total dose of 0.3 μg/kg of body weight. In children who weigh 10 kg or less, 10 mL of diluent is recommended, whereas 50 mL of diluent is advised in children or adults weighing more than 10 kg.²

During the administration of DDAVP to patients with VWD, the bleeding time, factor VIII coagulant activity, von Willebrand factor (VWF) antigen level, and ristocetin cofactor activity must be monitored to ensure that adequate levels are being reached.² 

Blood pressure and pulse must also be monitored during the intravenous infusion. If DDAVP is indicated to maintain hemostasis during a surgical procedure, it must be administered 30 minutes before the scheduled operation.²

The response to the administration of DDAVP is assessed via laboratory testing and the patient’s clinical presentation to determine if repeated DDAVP administration is needed. Prescribing physicians must also consider the possibility of patient tachyphylaxis if the administration of DDAVP is repeated within 48 hours.²

Get full prescribing information on DDAVP at MPR

Mechanism of Action

DDAVP activates V2 receptors, causing an increase in the intracellular concentration of cyclic adenosine monophosphate. This in turn triggers the release of VWF via exocytosis from the Weibel-Palade bodies of endothelial cells in blood vessels, where it is stored. The mechanism of action is particularly helpful for the acute hemostatic treatment of individuals with a diagnosis of VWD type I.³ 

DDAVP is not effective in VWD type III, in which VWF does not accumulate in endothelial storage sites. In theory, DDAVP is also considered ineffective in VWD type II because the VWF that is produced is abnormal. Even if DDAVP caused a release of abnormal VWF from endothelial storage sites, the VWF would not function normally.³ Nonetheless, one study reported laboratory and clinical responses to desmopressin treatment in some patients with severe VWD type II.⁴    

Patients with mild-to-moderate hemophilia A have detectable levels of factor VIII in their blood, whereas those with more severe hemophilia A do not. DDAVP is not beneficial in individuals with severe hemophilia A because of the lack of circulating factor VIII, which is an essential component of the complex formed with VWF that is required for hemostasis. Increasing the concentration of circulating VWF by administering DDAVP benefits only individuals with mild-to-moderate hemophilia A, who have detectable levels of circulating factor VIII. In mild-to-moderate hemophilia A, a single nucleotide substitution in the F8 gene results in the generation of abnormal factor VIII protein with diminished functionality; therefore, affected individuals can still respond to DDAVP.³

Efficacy and Safety of DDAVP in Clinical Trials

In 2010, a clinical assessment of the efficacy and safety of DDAVP in patients with hemophilia A (n=1) and VWD (n=48) demonstrated that most adverse reactions were mild; these included alterations in heart rate, blood pressure, and leukocytes following DDAVP administration.⁵ 

In 2015, investigators analyzed the safety and efficacy of DDAVP in 225 patients with mild-to-moderate inherited VWD in the 24-month ProDesWil study (A Prospective Study on Desmopressin Efficacy and Safety). Of the 225 patients, 184 had VWD type I, 14 had type IC, 15 had type IIA, and 12 had type IIM. Side effects of DDAVP were minor, including flushing, tachycardia, headache, and water retention in the 16 reported cases. Clinical efficacy was rated as excellent/good during episodes of acute bleeding (93.3%), all oral surgeries (100%), deliveries (91.7%), and minor/major surgeries (92.3%). On the basis of these results, the authors recommended DDAVP as a first-line therapy for patients with responsive types of VWD during acute hemorrhagic episodes, oral and minor/major surgeries, and deliveries. DDAVP should be used with caution in patients with VWD types I and IIA with partial responses.⁶ 

According to research, the intravenous administration of DDAVP is effective in most patients with mild hemophilia A during severe bleeds or before surgery.⁷ DDAVP is less frequently used in patients with moderate hemophilia A because their response to treatment is reduced; however, in 2018, a study reported that the response to desmopressin was adequate in 68 of 169 patients (40%) with moderate hemophilia A, of whom 25 (15%) demonstrated an excellent response. Excellent response was defined as a peak factor VIII level of at least 50 IU/dL after the administration of DDAVP; adequate response was defined as a peak factor VIII level of at least 30 IU/dL.⁸

In July 2020, a study demonstrated that a half-dose DDAVP was safe and efficacious for bleeding prophylaxis in patients with bleeding disorders scheduled to undergo low- to moderate-risk surgical procedures. Of the 33 documented procedures, bleeding control was excellent in 87.9% and good in 12.1%.⁹  

Warnings, Precautions, and Adverse Reactions

It is important that patients provide an accurate medical history so that physicians can decide if DDAVP is contraindicated. DDAVP is contraindicated in individuals with allergies to DDAVP, severe kidney disease, or a history of hyponatremia. Warnings indicate that individuals on DDAVP should limit their water and fluid intake during use of the drug because of the risk for hyponatremia with excess fluid consumption.¹  

Physicians must determine if DDAVP is safe to use or if precautions must be taken in individuals with a medical history of electrolyte imbalance, fluid retention, congestive heart failure, coronary artery disease, SIADH (syndrome of inappropriate antidiuretic hormone secretion), urination problems, psychological disorders that cause extreme or unusual thirst, hyper- or hypotension, cystic fibrosis, brain tumor, head injury, blood clots, stroke, or myocardial infarction.¹ Renal function tends to be decreased in elderly patients; therefore, DDAVP must be administered to patient population with caution.²

Nausea, stomach pain, headache, flushing, and injection site reactions were the most common adverse effects reported.¹

Following DDAVP injection, 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 

Rarely, hyponatremic events have been reported when DDAVP is administered concomitantly with oxybutynin, imipramine, tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, opiate analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), lamotrigine, and carbamazepine. When DDAVP is administered along with additional pressor agents, careful patient monitoring is required.² 

Individuals are instructed to contact the prescribing physician if they experience a seizure, weak or shallow breathing, presyncope, or symptoms of hyponatremia, which include headache, confusion, vomiting, restlessness, unsteadiness, loss of coordination, hallucinations, and muscle cramps or weakness.¹ 

References

1. DDAVP injection uses, side effects & warnings. Drugs.com. Accessed December 28, 2021.
2. DDAVP injection (desmopressin acetate injection): uses, dosage, side effects, interactions, warning. RxList. Accessed December 28, 2021.
3. Özgönenel B, Rajpurkar M, Lusher JM. How do you treat bleeding disorders with desmopressin? Postgrad Med J. 2007;83(977):159-163. doi:10.1136/pgmj.2006.052118
4. Federici AB, Mazurier C, Berntorp E, et al. Biologic response to desmopressin in patients with severe type 1 and type 2 VWD: results of a multicenter European study. Blood. 2004;103(6):2032-2038. doi:10.1182/blood-2003-06-2072
5. Miesbach W, Krekeler S, Dück O, et al. Clinical assessment of efficacy and safety of DDAVP. Hamostaseologie. 2010;30(Suppl 1):S172-S175.
6. Federici AB, Castaman G, Iorio A, et al. Safety and effectiveness of desmopressin for the management of delivery and major surgery in patients with mild-moderate VWD: final analysis of the ProDesWil study. Blood. 2015;126(23):759. doi:10.1182/blood.V126.23.759.759
7. Berntorp E. The treatment of haemophilia, including prophylaxis, constant infusion and DDAVP. Baillieres Clin Haematol. 1996; 9(2):259-271. doi:10.1016/s0950-3536(96)80062-x
8. Loomans JI, Kruip MJHA, Carcao M, et al. Desmopressin in moderate hemophilia A patients: a treatment worth considering. Haematologica. 2018;103(3):550-557. doi:10.3324/haematol.2017.180059
9. Furqan F, Sham R, Kouides P. Efficacy and safety of half-dose desmopressin for bleeding prophylaxis in bleeding disorder patients undergoing predominantly low to moderate risk invasive procedures. Am J Hematol. 2020;95(10):E285-E287. doi:10.1002/ajh.25928

Reviewed by Harshi Dhingra, MD, on 12/29/2021.

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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.