Crofelemer

Pregnancy Category C.

Reproduction studies performed with crofelemer in rats at oral doses up to 177 times the recommended daily human dose of 250 mg (approximately 4.2 mg/kg) revealed no evidence of impaired fertility or harm to the fetus. In pregnant rabbits, crofelemer at an oral dose of about 96 times the recommended daily human dose of 4.2 mg/kg caused abortions and resorptions of fetuses. However, it is not clear whether these effects are related to the maternal toxicity observed. A pre- and postnatal development study performed with crofelemer in rats at oral doses of up to 177 times the recommended daily human dose of 4.2 mg/kg revealed no evidence of adverse pre- and postnatal effects in offspring. There are, however, no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

It is not known whether crofelemer is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from crofelemer, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of crofelemer.

Mutagenesis

Crofelemer was negative in the bacterial reverse mutation assay, chromosomal aberration assay, and rat bone marrow micronucleus assay.

Impairment of Fertility

Crofelemer, at oral doses of up to 738 mg/kg/day (177 times the recommended human daily dose of 125 mg twice daily), had no effects on fertility or reproductive performance of male and female rats.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 696 HIV-positive patients in three placebo-controlled trials received crofelemer for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dosage of 125 mg twice a day for a mean duration of 141 days, and 171 patients received one of four higher than recommended dosages for a mean duration of 139 days (N=69) 14 days (N=102), 146 days (N=54), and 14 days (N=242), respectively.

Adverse reactions in patients treated with crofelemer 125 mg twice daily that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.

Table 1. Common Adverse Reactions^* in HIV-Positive Patients in Three Placebo-Controlled Trials:

* occurring in at least 2% of patients and at a higher incidence than placebo

Less common adverse reactions that occurred in between 1% and 2% of patients taking 125 mg twice daily of crofelemer were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, sinusitis and decreased white blood cell count.