Chlofazimine Other names: Clofazimine

Risk Summary

There are no data with clofazimine 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 clofazimine 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 clofazimine 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 clofazimine 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 clofazimine during pregnancy was deeply pigmented at birth. Clofazimine should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Animal Data

Embryofetal toxicity studies were conducted in rats, rabbits and mice. In mice clofazimine-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 clofazimine 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.

Risk summary

Clofazimine is excreted in human milk. Skin discoloration has been observed in breast fed neonates of mothers receiving clofazimine.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clofazimine and any potential adverse effects on the breastfed infant from clofazimine or from the underlying maternal condition.

Long-term carcinogenicity studies in animals have not been conducted with clofazimine. Results of mutagenicity studies (Ames test) were negative. There is some evidence of clastogenic potential in mice.

Impaired female fertility (reduced number of offspring and lower proportion of implantations) was observed in one study in rats receiving clofazimine (from 9 weeks before mating until weaning) at 50 mg/kg/day, equivalent to about 2.4 times the maximum recommended clinical dose. No non-clinical data on male fertility are available.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Abdominal Obstruction and Gastrointestinal Adverse Reactions
• QT Prolongation
• Skin and Body Fluid Discoloration and Other Skin Reactions
• Psychological Effects of Skin Discoloration

The following adverse reactions associated with the use of clofazimine were identified. Because these adverse reactions are reported from different studies, these adverse reactions cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions Occurring In More Than 1% of Patients

Skin: Pigmentation from pink to brownish-black in 75% to 100% of the patients within a few weeks of treatment; ichthyosis and dryness (8% to 28%); rash and pruritus (1% to 5%).

Gastrointestinal: Abdominal and epigastric pain, diarrhea, nausea, vomiting, gastrointestinal intolerance (40%- to-50%).

Ocular: Conjunctival and corneal pigmentation due to clofazimine crystal deposits; dryness; burning; itching; irritation.

Other: Discoloration of urine, feces, sputum, sweat; elevated blood sugar; elevated erythrocyte sedimentation rate (ESR).

Adverse Reactions Occurring In Less Than 1% of Patients

Skin: Phototoxicity, erythroderma, acneiform eruptions, monilial cheilosis.

Gastrointestinal: Bowel obstruction, gastrointestinal bleeding, anorexia, constipation, weight loss, hepatitis, jaundice, eosinophilic enteritis, enlarged liver.

Ocular: Diminished vision, maculopathy (bull’s eye retinopathy).

Nervous: Dizziness, drowsiness, fatigue, headache, giddiness, neuralgia, taste disorder.

Psychiatric: Depression and suicide secondary to skin discoloration.

Laboratory: Elevated levels of albumin, serum bilirubin, and aspartate aminotransferase (AST); eosinophilia; hypokalemia.

Other: Splenic infarction, thromboembolism, anemia, cystitis, bone pain, edema, fever, lymphadenopathy, vascular pain.