SAN DIEGO, CA—A study presented at IDWeek 2012 of patients with mycobacterial infections treated with clofazimine under the U.S. Food and Drug Administration’s (FDA) Single Patient Investigational New Drug (SPIND) program found limited safety information, despite mandatory reporting requirements for the program.

“Conclusions cannot be drawn regarding clinical and/or microbiologic efficacy” of clofazimine in this population, noted Pujita Vaidya, MPH, from the FDA, Silver Spring, MD, and colleagues. “A randomized controlled trial with reliable clinical end points is warranted to evaluate the risk and benefit of clofazimine in the treatment of mycobacterial infections.”

Currently, clofazimine is approved for the treatment of lepromatous leprosy and is available under SPIND for treatment of other mycobacterial infections in patients failing therapy, Vaidya stated.

Between 2005 and 2011, the FDA granted 649 SPINDs for clofazimine to treat mycobacterial infections, of which 350 were available for review and 216 provided adequate clinical information for safety assessment. The study population included 147 females, 59 males, and 10 unreported genders with positive sputum or skin mycobacterial cultures at diagnosis to evaluate adverse events reported for clofazimine-containing regimens. Median age was 60 years (range, 3-82 years); all patients were HIV negative.

“As expected, Mycobacterium avium complex (MAC; 170 patients, 79%) was the most frequently identified pathogen, followed by multi-drug resistant tuberculosis (22, 10%), Mycobacterium abscessus (10, 4%), MAC and M. abscessus (4, 2%), Mycobacterium simiae (6, 3%), Mycobacterium fortuitum (1, 0.5%, Mycobacterium haemophilum (1, 0.5%), and Mycobacterium avium paratuberculosis (2, 1%),” they found. Patient requests for clofazimine use came from 34 U.S. states; the highest requesting states were California, Florida, Maryland, and Colorado.

The majority of patients were on clofazimine  (50mg or 100mg daily) for 12, 18, or 24 months, which was administered in combination with a number of other agents, primarily antibiotics. Of the 216 patients, 58 patients (27%) had completed treatment; 77 (36%) were on treatment; and 33 (15%) had discontinued due to AEs or ineffective treatment. There were 47 (20%) deaths that were reported by investigators to be unrelated to clofazimine; however, the actual cause of death was not stated.

Follow-up sputum cultures were available for 53 patients (25%); of these, conversion to negative culture occurred in 34 (64%). Adverse events reported in 68 of 208 patients (33%) included skin pigmentation (37, 54%), gastrointestinal reactions (27, 40%), and other (4, 6%).

Use of clofazimine was found at doses well in excess of the labeled dose for leprosy. Torsades de Pointes was reported in 7 of 11 patients taking 300-400mg/day—three to four times higher than the recommended labeled dose of 100mg/day—“suggesting that clofazimine should not be used at high doses,” they concluded.