Death Associated With Nadolol for Infantile Hemangioma: A Case for Improving Safety

Abstract

Nadolol is a β-adrenergic antagonist that has been shown to be efficacious in the treatment of infantile hemangioma. It has been suggested that this drug may have fewer side effects compared with the gold standard therapy, propranolol, because it does not exhibit membrane-stabilizing effects and has little ability to cross the blood-brain barrier. However, the pharmacokinetics and safety of nadolol in infants are not well understood, potentially making this therapy dangerous. β-adrenergic antagonist toxicity causes bradycardia, hypotension, hypoglycemia, and even death. We report a case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity. Pharmacokinetics studies show a large fraction of oral nadolol either remains in the feces unchanged or is excreted into feces via the biliary system, allowing continued absorption over time in infants who stool infrequently. Propranolol may be a safer therapy overall. Not only does it have a shorter half-life, but propranolol is hepatically metabolized and renally eliminated, allowing for less drug accumulation in healthy infants with variable stooling patterns. We suggest that if nadolol is selected for therapy, pediatricians should instruct parents to monitor their infants’ bowel movements closely and encourage early intervention in the event of decreased stooling. This intervention may greatly improve the safety of nadolol in this vulnerable patient population.

Beta‐blocker‐associated hypoglycaemia: New insights from a real‐world pharmacovigilance study

“…A second important finding is on β‐blockers with prolonged half‐life. Their association with hypoglycaemia has not been studied in the paediatric population and this may lead to harm if physicians are unsure of how to properly monitor infants undergoing such therapy 49 . We found that these β‐blockers are associated to a greater risk of hypoglycaemia in agreement with previous studies in adult patients 38,50 .…”

“…Their association with hypoglycaemia has not been studied in the paediatric population and this may lead to harm if physicians are unsure of how to properly monitor infants undergoing such therapy. 49 We found that these β-blockers are associated to a greater risk of hypoglycaemia in agreement with previous studies in adult patients. 38,50 However, the elimination half-life of the given β-blocker is influenced by the number of concomitant medications (drug-drug interactions), patient's condition and genetic makeup.…”

Morphological, genetic and clinical correlations in infantile hemangiomas and their mimics

“…To date, Propranolol and Timolol have been maintained as first-line therapy in IH management, due to the efficacy at various locations of IH and the absence of significant adverse effects [3,8,13,14,16,59]. Nadolol has been cited in a case report of a 10-year-old girl who, after being started on a therapy course for IH, died within seven weeks of treatment, with a postmortem concentration of Nadolol of 0.94 mg/L [60]. The infant had no bowel movements 10 days before her death.…”

“…The infant had no bowel movements 10 days before her death. The authors of the case report suggest monitoring bowel movements in pediatric patients receiving systemic therapy with Nadolol, since this particular molecule is excreted in the feces and, in the case of discontinued bowel movements may present increased absorption [60].…”

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

“…Nadolol Nadolol, a β 3 -adrenoceptor antagonist approved by the FDA, is also used in diverse treatments, such as those for angina pectoris, infantile hemangioma, and hypertension [112][113][114]. Cutaneous vascular lesion, bradycardia, hypotension, and hypoglycemia are the more common adverse events correlated with this drug [115].…”