The UK Medicines and Healthcare products Regulatory Agency and the US Food and Drug Administration (FDA) have recently requested the companies marketing desmopressin products in their respective countries to remove the indication for the treatment of primary noctural enuresis (PNE) from all their nasal preparations. This was due to concerns of a higher incidence of hyponatraemia reported with desmopressin nasal preparations compared to oral preparations when used for the treatment of primary nocturnal enuresis.

Desmopressin is a synthetic analogue of 8-arginine vasopressin (ADH), a natural pituitary hormone that prevents excessive water loss in the urine. It is indicated for the treatment of central diabetes insipidus; polyuria and polydipsia following hypophysectomy or surgery in the hypophyseal area; primary nocturnal enuresis (PNE) from the age of 5 years; and for the diagnosis of diabetes insipidus. 

 

Desmopressin has increased antidiuretic activity and prolonged duration of action compared with the natural peptide. In the presence of an inappropriate fluid intake, the sustained decrease in urine output and decrease in urine osmolality can cause hyponatraemia, water intoxication and convulsions.

FDA reviewed 61 post-marketing cases of hyponatraemic-related seizures associated with the use of desmopressin. Fifty-five cases reported sodium levels ranging from 104 to 130mEq/L during the seizure event. Of these cases, two died. Both patients experienced hyponatraemia and seizures but the direct contribution of desmopressin to the deaths was unclear. Thirty-six cases were associated with intranasal formulations, of which 25 cases occurred in paediatric patients (<17 years old). The most commonly reported indication of use in these 25 paediatric cases was nocturnal enuresis. Thirty-nine of the 61 cases were associated with at least one concomitant drug or disease that was also associated with hyponatraemia and/or seizures.

 

In addition to the removal of the indication of PNE for nasal desmopressin preparations, FDA also requested that the manufacturers update the prescribing information of desmopressin products to include important new safety information about severe hyponatraemia and seizures. Recommendations included that desmopressin nasal preparations should not be used in hyponatraemic patients or patients with a history of hyponatraemia; treatment with desmopressin tablets should be interrupted during episodes of fluid and/or electrolyte imbalance, such as fever, recurrent vomiting or diarrhoea, vigorous exercise or other conditions associated with increased water consumption; fluid intake should be restricted one hour before to eight hours after administration of desmopressin tablets. FDA also recommended that all desmopressin preparations should be used cautiously in patients at risk for water intoxication with hyponatraemia.

To date, HSA has not received any local adverse drug reactions of hyponatraemia associated with desmopressin nasal preparations.

 

In line with the regulatory actions taken internationally, United Italian Trading which markets Minirin® has also sought approval from HSA to remove the approved licensed indication of PNE from its nasal preparation in Singapore. HSA will also be working with the manufacturers of the other brands of desmopressin (namely Octostim® and Presinex®) to ensure the prescribing information is updated to highlight this safety information.