Introduction

Crofelemer is an antidiarrheal agent derived from the red sap of the South American plant Croton lechleri, which is used to treat noninfectious diarrhea in HIV positive patients on antiretroviral therapy. Crofelemer is associated with occasional instances of serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent acute liver injury.

Background

Crofelemer (kroe fel' e mer) is a botanical antidiarrheal agent that is used to treat noninfectious diarrhea in HIV seropositive patients taking antiretroviral medications. Crofelemer is derived from the red sap of the South American plant Croton lechleri, which has been used for centuries to treat diarrheal illness. The active antidiarrheal product in crofelemer appears to be a large macromolecular, oligomeric proanthocyanidin which has been shown to decrease chloride secretion in the intestine by inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR), as well as calcium-activated chloride channels. In large clinical trials, daily therapy with crofelemer was found to decrease watery bowel movements and improve stool consistency in patients with HIV infection receiving antiretroviral therapy, and who had persistent diarrhea that could not be attributed to an infectious cause. Crofelemer was approved for use in the United States in 2013, the first herbal medication to be approved for a specific medical use and first agent approved for therapy of noninfectious diarrhea in HIV positive patients. Crofelemer is available in tablets of 125 mg under the commercial name Mytesi. The typical dose is one tablet twice daily. Side effects are uncommon and generally mild, but can include flatulence, bloating, nausea, constipation, increased bilirubin, cough and symptoms of upper respiratory illness.

Hepatotoxicity

During long term use of crofelemer in preregistration studies, serum ALT elevations occurred in 2.7% of treated subjects, but the background rate of serum enzyme elevations in this population was not defined in these open label studies. The elevations were generally mild and self-limited, rarely leading to dose reduction or discontinuation of therapy. There have been no reports of clinically apparent liver injury attributable to crofelemer, although it has had only limited wide scale use.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which crofelemer might lead to serum enzyme elevations or liver injury is not known. Very little of the agent is absorbed systematically and, although it can be metabolized by the hepatic cytochrome P450 system, there is little evidence that adequate levels are achieved during oral therapy to cause clinically significant drug-drug interactions with other agents. In clinical trials of crofelemer, no evidence of drug-drug interactions was identified.

Outcome and Management

Serum enzyme elevations during crofelemer therapy are generally mild and self-limited, resolving even without drug interruption or dose reduction. Other causes of liver injury should be sought before assuming that the abnormalities are due to crofelemer.

Drug Class: Gastrointestinal Agents; Herbal and Dietary Supplements