Clinical Context

Diarrhea is frequently cited as a reason for patients with HIV or AIDS to discontinue or change treatment regimens. Before approval of crofelemer, there was no US Food and Drug Administration (FDA)–approved treatment for patients with diarrhea in this setting.

Crofelemer is the second botanical prescription drug approved by the FDA, the first being sinecatechins (Veregen) for external genital and perianal warts. Crofelemer is extracted from the red sap of the Croton lechleri plant. As with any botanical drug product, the manufacturer must ensure rigorous control of raw materials, good agricultural and harvest practices, and analytical testing.

Study Synopsis and Perspective

The FDA approved crofelemer (Fulyzaq) to relieve diarrhea in patients with HIV/AIDS who are undergoing antiretroviral therapy.

Diarrhea is a common reason for patients with HIV/AIDS to stop or switch therapies, according to a news release from the FDA. The newly approved drug is intended for use in patients with HIV/AIDS whose diarrhea is not caused by infection by a virus, bacteria, or parasite. The drug is dosed twice daily to manage watery diarrhea caused by secretion of water and electrolytes in the gastrointestinal tract, the news release notes.

"Currently, there are no FDA-approved therapies for HIV-associated diarrhea," said Julie Beitz, MD, director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research, in the release. "[Crofelemer] may be helpful to HIV/AIDS patients with this troublesome condition."

The new drug is derived from the red sap of the Croton lechleri plant and is only the second botanical prescription drug approved by the FDA. A botanical drug product is often a complex mixture derived from 1 or more plant materials with varying degrees of purification, the FDA notes; manufacturers of botanical drugs are required to "ensure rigorous control of raw materials, and good agricultural and collection practices, together with analytical testing of the complex mixture," according to the news release.

In 2006, the FDA approved the first botanical prescription drug, sinecatechins (Veregen), a treatment of external genital and perianal warts.

Crofelemer was first slated for approval September 5, but the review was delayed at that time by the FDA to accommodate further discussion between the agency and the manufacturer on ensuring compliance with the manufacturing and product quality requirements of the Food, Drug & Cosmetic Act.

Approval of crofelemer is based on a clinical trial of 374 HIV-positive patients receiving stable antiretroviral therapy with a history of diarrhea lasting 1 month or longer. The median number of daily watery bowel movements was 2.5 per day at baseline. Patients who had diarrhea caused by an infection or a gastrointestinal disease were excluded. The investigators randomly assigned patients to receive crofelemer or placebo twice daily.

The trial was designed to measure clinical response, defined as the number of patients who had 2 or fewer watery bowel movements weekly. Results showed that 17.6% of treated patients experienced clinical response compared with 8% of those receiving placebo. Crofelemer had a persistent antidiarrheal effect in some patients for up to 20 weeks.

"Before treating patients with [crofelemer], health care professionals should conduct proper testing to confirm the diarrhea is not caused by an infection or a gastrointestinal disease," the FDA release adds. "Common side effects reported in patients taking [crofelemer] in the clinical trial were upper respiratory tract infection, bronchitis, cough, flatulence, and increased levels of bilirubin.”

More information on crofelemer is available on the FDA Web site.

Clinical Implications

• The FDA has approved crofelemer to relieve diarrhea in patients with HIV/AIDS who are undergoing antiretroviral therapy. Crofelemer is indicated to manage watery diarrhea caused by secretion of water and electrolytes in the gastrointestinal tract, provided the diarrhea is not caused by viral, bacterial, or parasitic infection. Dosage is twice daily.
• In the clinical trial leading to FDA approval, 17.6% of patients receiving crofelemer twice daily had clinical response, defined as 2 or fewer watery bowel movements weekly, vs 8% of those receiving placebo. In some patients, the antidiarrheal effect of crofelemer lasted for up to 20 weeks. Patients who had diarrhea caused by an infection or a gastrointestinal disease were excluded from the trial.
• In the clinical trial leading to FDA approval, commonly reported adverse effects associated with crofelemer were upper respiratory tract infection, bronchitis, cough, flatulence, and increased bilirubin levels.

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