By: Oluwafemi Popoola, PharmD Candidate c/o 2021, SUNY Binghamton School of Pharmacy & Pharmaceutical Sciences

             A patient with past medical history of von Willebrand’s disease (VWD) and myasthenia gravis on chronic prednisone therapy, presented for follow-up for VWD at the hematology/oncology clinic. The provider considered having the patient undergo a “desmopressin challenge” with desmopressin sublingual (Nocdurna®). The provider’s goal was to assess the efficacy of desmopressin for future use in minimizing bleeding during an active bleed or peri-procedurally.

Von Willebrand’s Disease is a bleeding disorder in which the body does not produce adequate von Willebrand’s factor, a clotting protein. ¹ Desmopressin is an antidiuretic hormone (ADH) analog that increases cyclic adenosine monophosphate (cAMP) in renal tubular cells. This results in decreased urine volume and increased urine osmolality, as well as increased plasma levels of von Willebrand factor (VWF). ² As such, desmopressin can be used in VWD. Specifically, desmopressin leads to the release of endogenous VWF from storage sites in endothelial cells. ⁵ One of the adverse effects of desmopressin is hyponatremia, for which there is a black box warning. Of note, there is a contraindication with the concurrent use of prednisone and sublingual desmopressin as it also causes severe hyponatremia. ²

The New Drug Application of desmopressin sublingual acknowledged that systemic or inhaled corticosteroids may lead to fluid retention and hyponatremia. However, this contraindication was based on severe cases of hyponatremia occurring in Phase 3 trials for the intranasal desmopressin spray (Noctiva®) for the treatment of nocturia due to nocturnal polyuria. The reason being that concomitant administration of desmopressin and systemic corticosteroids may synergistically decrease serum sodium levels. In the phase 3 trial of intranasal desmopressin spray, no patients with concomitant corticosteroid use had a serum sodium level ≤125 mmol/L at the proposed doses (25 mcg in females and 50 mcg in males): 4 of 8 patients in the treatment group had a decreased serum sodium level to <135 mmol/L versus 0 of 5 patients in the placebo group. ³ However, given the higher incidence of patients who had decreased serum sodium compared to placebo, the contraindication was introduced for intranasal desmopressin, implicating the same contraindication for sublingual desmopressin as well.

That being said, it is worth noting that both studies only looked at the long-term use of desmopressin for nocturia and chronic corticosteroid use.  Additionally, another study found that in patients taking desmopressin, the mean time to the majority of clinically significant hyponatremia events occurred within 2–3 weeks of treatment initiation. ⁴ Given that our patient will be receiving desmopressin at the hematology/oncology infusion clinic for an intermittent period, it may be reasonable to administer desmopressin with concomitant corticosteroid with close monitoring of serum sodium levels. Per the package insert recommendation for hyponatremia concerns, the patient should have normal baseline sodium levels obtained prior to starting or continuing desmopressin. ² Additionally, sodium levels should be monitored within a week to a month after starting desmopressin, modifying the dose, and while receiving desmopressin intermittently to ensure the sodium level are within normal range. ² If the patient is > 65 years old or at an increased risk for hyponatremia, more frequent monitoring is required. ² More importantly, if the patient does have hyponatremia, desmopressin should be held and re-evaluated for modification or potential discontinuation. ²

References:

1. SJCRH. Stimate / DDAVP challenge. St. Jude Children’s Research Hospital Web Site. https://www.stjude.org/treatment/patient-resources/caregiver-resources/patient-family-education-sheets/hematology/stimate-challenge.html. Published 2020. Accessed November 30, 2020.
2. Nocdurna® (Desmopressin) [package insert]. Parsippany, NJ; Ferring Pharmaceuticals; Revised 06/01/2018.
3. Ferring Pharmaceuticals. NDA Multi-Disciplinary Review and Evaluation NDA 022517 Class 2 Resubmission, NOCDURNA (desmopressin acetate sublingual tablets) Web Site. Page 40-41. Published September 8, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/022517Orig1s000MultidisciplineR.pdf. Accessed November 30, 2020.
4. Juul KV, Malmberg A, Meulen E van der, Walle JV, Nørgaard JP. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU International. 2017;119(5):776-784. doi:https://doi.org/10.1111/bju.13718

Published by Rho Chi Post