Clofazimine

Substrates of CYP3A4/5: Monitor for toxicities when used concomitantly with LAMPRENE.

7.1 Effect of LAMPRENE on Substrates of CYP3A Concomitant use of LAMPRENE may increase concentrations of drugs that are substrates of CYP3A4/5 [see Clinical Pharmacology (12.3)] which may increase the risk of toxicity of these drugs. Monitor for toxicities of these drugs when used concomitantly with LAMPRENE.

7.2 Drugs that Prolong QT Interval QT prolongation and Torsade de Pointes have been reported in patients receiving LAMPRENE in combination with QT prolonging medications, such as bedaquiline. Monitor ECGs for QT prolongation when LAMPRENE is administered with other drugs known to prolong the QT interval [see Warnings and Precautions (5.2)] .

8.1 Pregnancy Risk Summary There are no data with LAMPRENE use in pregnant women to inform associated risk. Retardation of fetal skull ossification, increased incidences of abortions and stillbirths, and impaired neonatal survival were observed in mice following prenatal exposure to LAMPRENE at 25 mg/kg, equivalent to the 0.6 times maximum recommended human daily dose (200 mg), based on body surface area comparisons. Advise pregnant women of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S.

general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions The skin of infants born to pregnant mothers who had received LAMPRENE during pregnancy is pigmented at birth. Limited data is available regarding the reversibility of discoloration. Based on previous observations, discoloration gradually faded over the first year. Data Human Data There are no studies of LAMPRENE use in pregnant women. Few cases of clofazimine use during pregnancy have been reported in the literature.

These reports indicate that the skin of infants born to women who had received LAMPRENE during pregnancy was deeply pigmented at birth. LAMPRENE should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Animal Data Embryo-fetal toxicity studies were conducted in rats, rabbits and mice. In mice, LAMPRENE-induced embryotoxicity and fetotoxicity was evident.

Retardation of fetal skull ossification, increased incidences of abortions and stillbirths, and impaired neonatal survival were observed following prenatal exposure to LAMPRENE at 25 mg/kg, equivalent to the 0.6 times maximum recommended human daily dose [MRHD] (200 mg), based on body surface area comparisons. The skin and fatty tissue of offspring became discolored approximately 3 days after birth, which was attributed to the presence of clofazimine in the maternal milk.

No developmental effects were observed in rat or rabbits orally administered clofazimine during organogenesis at doses up to 50 mg/kg and 15 mg/kg, (equivalent to about 2.4 and 1.5 times the MRHD of 200 mg based on body surface area) respectively. These animal studies were conducted according to the standards at the time of initial drug approval (1986) and not under current regulatory standards.