Crofelemer (Fulyzaq)


Fulyzaq

Indication:  Crofelemer (Fulyzaq) is indicated for symptomatic relief of noninfectious diarrhea in patients older than 18 years of age with HIV/AIDS taking antiretroviral therapy (ART).

Pharmacology: Crofelemer reduces cyclic adenosine monophosphate (cAMP)-dependent chloride secretion by inhibiting the cystic fibrosis transmembrane conductance regulator (CFTR) and the calcium-activated chloride ion (Cl-) channels (CaCC). Crofelemer blocks Cl- secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl- and water in the gastrointestinal (GI) tract.1

There is minimal absorption of the drug with plasma levels below 50 ng/mL and limited data available on the distribution, metabolism, and elimination of crofelemer.

Clinical Trials: Results of a two-stage, randomized, double-blind, dose-ranging, multicenter study of HIV-positive patients who were stable on ART and with a history of diarrhea for at least 4 weeks showed that those who received crofelemer 125 mg/bid achieved a statistically significant clinical response compared with 138 patients in the placebo group (2 or fewer watery bowel movements per week during at least 2 of the 4-week, placebo-controlled phase [17.6% vs 8.0%, P <0 .01]).1,2

An earlier review, Crutchley and colleagues showed that crofelemer compared with placebo showed reduced abnormal stool weight and frequency in patients with AIDS-associated diarrhea.3

Warnings/Precautions: Crofelemer should not be administered unless infectious etiologies for diarrhea have been ruled out. Crofelemer is only indicated for noninfectious diarrhea in patients on ART for management of HIV/AIDS.

Pregnancy: Crofelemer is pregnancy Category C.  Animal studies in rats and rabbits achieved serum levels from oral doses up to 177 times and 96 times the recommended human dose of 4.2 mg/kg, respectively, with no evidence of impaired fertility or harm to the fetus. Animal reproduction studies are not always predictive of human response; therefore, crofelemer should only be used during pregnancy if it is absolutely necessary.1

Adverse Reactions: The most common adverse effects in patients taking crofelemer 125 mg twice daily  experienced upper respiratory tract infections (13%). Adverse events associated with infection include bronchitis, cough, urinary tract infection, herpres zoster, gastroenteritis, nasopharyngitis, and giardiasis. Patients may experience anxiety and different types of pain such as back pain, arthralgia, and musculoskeletal pain. GI effects include flatulence, nausea, hemorrhoids, constipation, and abdominal distention. Bilirubin, alanine aminotransferase (ALT), and white blood cell count should be monitored carefully while taking crofelemer. Adverse reactions were similar for patients who received more than 250 mg daily as well.1

Drug Interactions: In vivo studies show that crofelemer has the potential to inhibit CYP3A and transporters MRP2 and OATP1A2 located in the gut, leading to higher concentrations of concurrently administered drugs. However, there is minimal absorption of crofelemer and, therefore, it is unlikely to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and CYP3A4 systemically.1

Crofelemer can be safely administered with antiretrovirals such as nelfinavir, zidovudine, or lamivudine. A 20% decrease in lamivudine was seen in patients who received 500 mg of crofelemer given four times a day for five days; however, there was no clinically significant effect. 1

Dosage and Administration: Crofelemer is a 125 mg tablet taken twice daily by mouth with or without food. It is available as enteric-coated, delayed-release tablets, which should be swallowed whole and not crushed or chewed.1

Dose modifications are not needed with respect to CD4 cell count and HIV viral load. The crofelemer safety profile was similar in patients between subgroups, CD4 cell count less than or greater than 404 cells/mL vs baseline HIV viral loads less than and greater than 400 copies/mL.1


References

  1. Fulyzaq [package insert]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2013. http://www.fulyzaq.com/assets/pdf/fulyzaq-pi.pdf.
  2. US National Institutes of Health. Safety and Effectiveness of 3 Doses of Crofelemer Compared to Placebo in the Treatment of HIV Associated Diarrhea (ADVENT). ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT00547898?term=crofelemer&rank=1. Published December 22, 2011. Accessed March 4, 2013.
  3. Crutchley RD, Miller J, Garey KW, et al. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. 2010;44(5):878-884.


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