Angioedema Secondary to Sofosbuvir/Ledipasvir

Chronic viral hepatitis C (HCV) is a major cause of morbidity and mortality in the United States. ¹ Approximately 70% of those infected with HCV in the United States are infected with genotype 1. ² Prior to the approval of the first direct-acting antiviral (DAA) agents in May of 2011, cure rates were low and toxicities limited the number of patients who initiated and tolerated therapy. The most recently approved DAAs have improved adverse event profiles. The most commonly reported adverse drug events for sofosbuvir/ledipasvir (Harvoni) include fatigue, headache, and asthenia. ³

A 58-year-old African American man with past medical history significant for HCV, hypertension, and dyslipidemia presented to the clinic for evaluation of angioedema after initiation of sofosbuvir/ledipasvir daily. The patient was monoinfected with HCV genotype 1a, had F3 liver fibrosis by FibroSure, and was treatment naïve at the time of sofosbuvir/ledipasvir initiation. The patient had a baseline HCV ribonucleic acid level of 4.2 million, had normal renal and hepatic function, and was taking the medication as prescribed.

The patient reported that his son first noticed the patient’s facial swelling and redness approximately 7 hours after his second dose. The patient reported progressive swelling around his lower lip and chin, hives around his mouth and eyes, and a tingling and dry sensation in his throat and on his genitalia. He took no additional doses of sofosbuvir/ledipasvir.

The patient denied any changes to soaps or medications. He had been taking metoprolol and amlodipine daily for hypertension and had been on the medications for more than 1 year. He had no known drug allergies and had no personal or family history of angioedema.

He presented to the emergency room 2 days after initiating sofosbuvir/ledipasvir and received 1 dose of methylprednisolone 125 mg intravenously (IV) and diphenhydramine 50 mg IV. The patient was kept in observation for 24 hours, where he received methylprednisolone 60 mg IV every 8 hours, ranitidine 50 mg by mouth daily, and diphenhydramine 25 mg daily. He was then discharged home with 3 days of diphenhydramine 25 mg by mouth daily and was advised not to take any further doses of sofosbuvir/ledipasvir. One week later during the clinic visit, the patient indicated feeling better but still having a “funny feeling” in his throat. The physical exam was significant for obvious swelling on his lower lip and chin area. The patient was provided with a 5-day course of prednisone 40 mg orally daily and was to return to clinic to initiate therapy with Viekira Pak (ombitasvir/paritaprevir/ritonavir and dasabuvir). He did not return for further treatment.

The Naranjo adverse drug reaction probability scale score was used to determine how likely it was that the angioedema was caused by sofosbuvir/ledipasvir. ⁴ A score of 5 was calculated, which indicates a probable relationship between the event and the medication. Using this score, the exposure history, and time frame of symptom development, it was concluded that the angioedema was likely secondary to sofosbuvir/ledipasvir.

Sofosbuvir/ledipasvir is a highly effective and well-tolerated therapy for the treatment of patients with HCV. We report the first case sofosbuvir/ledipasvir-associated angioedema. Despite the limited and mild adverse effect profile for sofosbuvir/ledipasvir, it is important for providers to keep in mind that although rare, serious adverse drug events are possible.