Fulyzaq™ (crofelemer) - Oral Therapy Approved to Relieve Diarrhea in Patients with HIV/AIDS

The FDA approved Fulyzaq^™ (crofelemer) in December 2012 to relieve noninfectious diarrhea in adults with HIV or AIDS who are taking anti-retroviral therapy. The drug, a 125 mg delayed-release tablet marketed by Salix Pharmaceuticals, Inc., is the first FDA-approved therapy for HIV-associated diarrhea.

Patients with HIV or AIDS typically experience diarrhea and subsequently discontinue antiretroviral therapies or switch treatment. Approximately 1.2 million people 13 years of age or older in the United States have HIV. In addition, an estimated 150,000 to 180,000 people who are taking anti-retroviral therapy have non-infectious diarrhea, according to a Salix Pharmaceuticals news release.

If these patients have diarrhea, they may have reduced quality of life, weight loss, depression, and reduced social interaction. The disease is also associated with an increase in direct and indirect healthcare costs.

Crofelemer, which inhibits chloride secretion into the gut, is intended for patients whose diarrhea is not caused by an infection from a virus, bacteria, or parasite. Patients are advised to take one 125-mg tablet of crofelemer twice daily with or without food. The tablets should be swallowed whole and should not be crushed or chewed.

“The FDA approval of [crofelemer] is a significant step forward in addressing the unmet medical need of people with HIV/AIDS on ART who experience noninfectious diarrhea, which often can lead to reduced treatment compliance,” Carolyn Logan, Salix Pharmaceuticals president and chief executive officer, said in a news release.

“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. Diarrhea negatively affects quality of life and is a common reason for discontinuing or switching ART regimen. Salix’s expertise in gastrointestinal medicine should position the Company to deliver this much-needed treatment to HIV patients.”

Crofelemer is derived from the red sap of the Croton lechleri plant and is the second botanical drug approved by the FDA following the 2006 approval of Veregen^® (sinecatechins) to treat external genital and perianal warts. An FDA news release indicated that a botanical product is typically a mixture derived from 1 or more plant materials.

The approval of crofelemer was based on a study that included 374 HIV-positive patients who were on stable anti-retroviral therapy and had diarrhea for at least a month. The most frequently used anti-retroviral therapies were tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.

The trial began with a screening period, during which patients received placebo for 10 days. Patients with at least 1 watery bowel movements per day on at least 5 of the last 7 days during the screening period were then randomized in a 1:1:1:1 ratio to receive 125 mg, 250 mg, or 500 mg of crofelemer twice daily or placebo for 31 days. After that, patients entered a placebo-free period, where they received 125 mg, 250 mg, or 500 mg of crofelemer for 5 months.

There was then a second stage of the trial in which patients received placebo for 10 days followed by a 31-day treatment period in which patients were randomized in a 1:1 ratio to receive 125 mg of crofelemer twice daily or placebo. The trial ended with a 5-month placebo-free period during which all patients received 125 mg of crofelemer 2 times per day.

Of the patients, 85% were male, 46% were Caucasian, and 32% were African Americans. The median age was 45 years, the median time since HIV diagnosis was 12 years, the median time since the diarrhea started was 4 years, and the median number of daily watery bowel movements was 2.5.

Exclusion criteria included patients who had a positive gastrointestinal biopsy, gastrointestinal culture, or a stool test for multiple bacteria, bacterial toxin, ova and parasites, or viruses. Patients with a history of ulcerative colitis, Crohn’s disease, or other gastrointestinal diseases associated with diarrhea were excluded from the study, as well.

Of the patients who received 125 mg of crofelemer twice daily, 17.6% had a clinical response compared with 8.0% of patients in the placebo group (P<.01). The authors defined a clinical response as 2 or fewer watery bowel movements per week during at least 2 of the 4 weeks in the placebo-controlled phase. A persistent ant-diarrheal effect was seen for up to 20 weeks in some patients.

The most common side effects among the patients taking 125 mg of crofelemer twice daily were upper respiratory tract infection (5.7%), bronchitis (3.9%), cough (3.5%), flatulence (3.1%), increased bilirubin (3.1%), nausea (2.6%), back pain (2.6%), arthralgia (2.6%), urinary tract infection (2.2%), nasopharyngitis (2.2%), musculoskeletal pain (2.2%), hemorrhoids (2.2%), giardiasis (2.2%), anxiety (2.2%), increased alanine aminotransferase (2.2%), and abdominal distension (2.2%).

There are no studies evaluating the use of crofelemer in patients who are <18 years of age or in pregnant women. Trials have also not included a sufficient number of patients ≥65 years of age, according to the drug’s Prescribing Information.

A drug-drug interaction trial found that crofelemer did not have a clinically relevant interaction with nelfinavir, zidovudine, or lamivudine. However, in vitro studies have shown that the drug may inhibit cytochrome P450 isoenzyme 3A and transporters MRP2 and OATP1 A2 at concentrations expected in the gut.

Before prescribing crofelemer, healthcare professionals are advised to consider infectious causes of diarrhea. The drug is only intended to treat noninfectious diarrhea, and people with infectious diarrhea who take crofelemer could see their disease worsen.

Fulyzaq Facts

•    Fulyzaq was approved by the FDA on December 31, 2012, for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS who are on anti-retroviral therapy

•    Fulyzaq is marketed by Salix Pharmaceuticals, Inc.