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FDA Approves Diarrhea Drug Crofelemer for People with HIV/AIDS

On December 31, the U.S. Food and Drug Administration (FDA) approved crofelemer (brand name Fulyzaq) for treatment of diarrhea in people with HIV/AIDS on antiretroviral therapy (ART) -- the first approved medication for this indication.

Diarrhea is a common side effect of certain antiretroviral drugs that can lead to patients switching or stopping therapy. Crofelemer, discovered by Napo Pharmaceuticals and developed jointly with Salix Pharmaceuticals, is derived from the sap of the Croton lechleri or Sangre de Drago (Dragon's Blood) plant, which grows in the Amazon rainforest.

Crofelemer is indicated for treatment of watery diarrhea due to secretion of electrolytes and water into the gastrointestinal tract. It is not intended to treat infectious diarrhea caused by bacteria, viruses, or parasites. The drug is thought to work by 2 different mechanisms to inhibit chloride secretion into the gut and thereby reduce the high-volume water loss seen in HIV-associated diarrhea, Salix Chief Development Officer Bill Forbes explained in a press release announcing the approval. It does not appear to interfere with intestinal motility like some other anti-diarrhea medications.

Approval of crofelemer was based on data from a Phase 3 placebo-controlled clinical trial showing that the drug was safe and effective. As described at the 2011 Conference on Retroviruses and Opportunistic Infections, the ADVENT study included 374 HIV positive participants on combination ART who experienced watery diarrhea lasting at least a month; people with evidence of intestinal pathogens were excluded. About 85% were men and the average age was approximately 45 years.

More than twice as many people in the crofelemer arm compared with the placebo arm -- 18% vs 8%, respectively -- experienced clinical response, defined as 2 or fewer watery stools per week for at least 2 of 4 weeks in a month.Some participants experienced a persistent anti-diarrhea effect over 5 months of follow-up. Crofelemer seemed to work similarly regardless of HIV viral load or CD4 T-cell count, although African-Americans had a lower response rate than whites.

The drug was generally safe and well-tolerated, with only 2% of participants experiencing serious adverse events and none discontinuing treatment for this reason. The most common side effects included upper respiratory tract infection, cough, flatulence, and increased bilirubin levels.

The recommended crofelemer dose is a single 125 mg delayed-release tablet taken twice-daily with or without food. Before prescribing the new therapy, "health care professionals should conduct proper testing to confirm the diarrhea is not caused by an infection or a gastrointestinal disease," the FDA cautioned. "If infectious etiologies are not considered, and [crofelemer] is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen."

Crofelemer is only the second prescription botanical therapy approved by the FDA (the other is a treatment for genital warts approved in 2006), and it had a convoluted path to approval. It was initially submitted for consideration in late 2011 and the FDA granted priority review status, but the expected decision date under the Prescription Drug User Fee Act was extended twice, reportedly due to issues related to consistent production of the complex botanical mixture.

"Since the introduction of antiretroviral therapy, people with HIV are living longer and thus medication compliance and tolerability as well as quality of life issues are increasingly important components of their overall health outlook," said Salix president and CEO Carolyn Logan. "Diarrhea negatively affects quality of life and is a common reason for discontinuing or switching ART regimen."

Full crofelemer product label information is available online at www.accessdata.fda.gov/drugsatfda_docs/label/2012/202292s000lbl.pdf.

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Sources

Food and Drug Administration. FDA Approves First Anti-Diarrheal Drug for HIV/AIDS Patients. Press release. December 31, 2012.

R Klein and K Struble, Food and Drug Administration. Approval of  Fulyzaq (crofelemer) to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy. HIV/AIDS Update. January 2, 2013.

Salix Pharmaceuticals. FDA Approves Fulyzaq (Crofelemer) 125 mg Delayed-Release Tablets for the Symptomatic Relief of Diarrhea in Patients with HIV/AIDS on Anti-Retroviral Therapy (ART). Press release. January 2, 2013.