Clofazimine

1 INDICATIONS AND USAGE LAMPRENE is an antimycobacterial indicated for the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. ( 1.1 ) To prevent the development of drug-resistance, LAMPRENE should be used only as a part of combination therapy for initial treatment of lepromatous leprosy. ( 1.2 ) 1.1 Lepromatous Leprosy LAMPRENE is indicated in combination with other anti-leprosy drugs for the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy, and lepromatous leprosy complicated by erythema nodosum leprosum. 1.2 Usage To prevent the development of drug-resistance, LAMPRENE should be used only as a part of combination therapy for initial treatment of lepromatous (multibacillary) leprosy [see Dosage and Administration (2.1)] . For further guidance on the treatment of leprosy, contact the National Hansen’s Disease Clinical Center, Baton Rouge, Louisiana (LA) at (1-800-642-2477) or http://www.hrsa.gov/hansensdisease/clinicalcenter.html .

12.1 Mechanism of Action LAMPRENE is an anti-mycobacterial drug [see Microbiology (12.4)] .

2 DOSAGE AND ADMINISTRATION For dapsone-sensitive lepromatous leprosy, 100 mg (two 50 mg capsules) daily with meals as a part of a combination regimen for at least 2 years is recommended. ( 2.1 ) For dapsone-resistant lepromatous leprosy, 100 mg (two 50 mg capsules) daily with meals in combination with one or more other agents for 3 years. ( 2.1 ) For lepromatous leprosy complicated by erythema nodosum leprosum, 100 mg (two 50 mg capsules) to 200 mg (four 50 mg capsules) daily for up to 3 months. Taper dose to 100 mg (two 50 mg capsules) as quickly as possible. (2.1 ) 2.1 Dosage Dapsone-sensitive Lepromatous (multibacillary) Leprosy Administer 100 mg (two 50 mg capsules) of LAMPRENE daily with meals in combination with two other anti-leprosy drugs for at least 2 years and if possible, until negative skin smears are obtained, followed by monotherapy with an appropriate anti-leprosy drug. Dapsone-resistant Lepromatous Leprosy Administer 100 mg (two 50 mg capsules) of LAMPRENE daily with meals in combination with one or more other anti-leprosy drugs for 3 years, followed by monotherapy with 100 mg (two 50 mg capsules) of LAMPRENE daily. Lepromatous Leprosy complicated by Erythema Nodosum Leprosum Reactions Administer LAMPRENE at 100 mg (two 50 mg capsules) to 200 mg (four 50 mg capsules) daily, in conjunction with baseline anti-leprosy treatment and steroids as clinically indicated. If LAMPRENE is administered at 200 mg (four 50 mg capsules) dose, taper to 100 mg (two 50 mg capsules) as soon as possible after the erythema nodosum reaction is controlled. Doses of LAMPRENE of more than 100 mg daily should be given for as short a period as possible and only under close medical supervision [see Warnings and Precautions (5.1)] . 2.2 Important Pre-test Prior to Administration Sexually-active females of reproductive potential should have a pregnancy test prior to LAMPRENE administration [see Use in Specific Populations (8.3)] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Abdominal Obstruction and Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)] QT Prolongation [see Warnings and Precautions (5.2)] Skin and Body Fluid Discoloration and Other Skin Reactions [see Warnings and Precautions (5.3)] Psychological Effects of Skin Discoloration [see Warnings and Precautions (5.4)] The following adverse reactions associated with the use of LAMPRENE 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 : Diminished vision, 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 : 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. Most common adverse reactions reported in 40% to 50% of patients are skin and body fluid discoloration, abdominal and epigastric pain, diarrhea, nausea, vomiting, gastrointestinal intolerance. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

5 WARNINGS AND PRECAUTIONS Abdominal obstruction and other gastrointestinal adverse reactions: LAMPRENE may deposit in intestinal mucosa causing intestinal disturbances, including abdominal obstruction, bleeding, splenic infarction and death. Reduce dose or discontinue LAMPRENE if patient complains of pain in abdomen or other gastrointestinal symptoms. ( 5.1 ) QT prolongation: QT prolongation and Torsade de Pointes may occur with LAMPRENE. Concomitant use with other QT prolonging drugs or bedaquiline may cause additive QT prolongation. Monitor ECGs and discontinue LAMPRENE if significant ventricular arrhythmia or QTcF interval greater than or equal to 500 ms develop. ( 5.2 ) Skin and body fluid discoloration and other skin reactions: Advise patients that skin and body fluid discoloration frequently occur with use of LAMPRENE. ( 5.3 ) Depression and suicide due to skin discoloration. Monitor patients for psychological effects of skin discoloration. ( 5.4 ) 5.1 Abdominal Obstruction and Other Gastrointestinal Adverse Reactions Clofazimine may accumulate in various organs as crystals, including the mesenteric lymph nodes and histiocytes at the lamina propria of the intestinal mucosa, spleen and liver. Deposition in the intestinal mucosa may lead to intestinal obstruction that may necessitate exploratory laparotomy. Splenic infarction, gastrointestinal bleeding, and death have been reported. If a patient complains of pain in the abdomen, nausea, vomiting, or diarrhea, initiate appropriate medical investigations and reduce the daily dose of LAMPRENE, or increase the dosing interval or discontinue the drug. Doses of LAMPRENE of more than 100 mg daily should be given for as short a period as possible (less than 3 months) and only under close medical supervision. 5.2 QT Prolongation Cases of Torsade de Pointes with QT prolongation have been reported in patients receiving dosage regimens containing higher than 100 mg daily dose of LAMPRENE or in combination with QT prolonging medications. For QT prolongation and Torsade de Pointes cases, the patient must remain under medical surveillance. In all these patients, monitor electrocardiograms (ECGs) for QT prolongation and cardiac rhythm disturbances [see Dosage and Administration (2.1), Drug Interactions (7.1)] . QT prolongation has also been reported in patients who were receiving concomitant LAMPRENE and bedaquiline at the recommended dosages. Monitor ECGs in patients taking LAMPRENE and bedaquiline concomitantly, and discontinue LAMPRENE if clinically significant ventricular arrhythmia is noted or if the QTcF interval is 500 ms or greater. If syncope occurs, obtain an ECG to detect QT prolongation. 5.3 Skin and Body Fluid Discoloration and Other Skin Reactions LAMPRENE causes orange-pink to brownish-black discoloration of the skin, as well as discoloration of the conjunctivae, tears, sweat, sputum, urine and feces in 75%-100% of patients. Advise patients that skin discoloration is likely to occur and that it may take several months or years to reverse after the conclusion of therapy. Other skin reactions associated with LAMPRENE therapy include ichthyosis, dry skin, and pruritus. 5.4 Psychological Effects of Skin Discoloration Skin discoloration due to LAMPRENE therapy has been reported to result in depression and suicide. Advise patients regarding skin discoloration and monitor for depression or suicidal ideation during LAMPRENE therapy.

4 CONTRAINDICATIONS LAMPRENE is contraindicated in patients with known hypersensitivity to clofazimine or any of the excipients of LAMPRENE. Known hypersensitivity to clofazimine or to any of the excipients of LAMPRENE. ( 4 )

10 OVERDOSAGE No specific data are available on the treatment of over dosage with LAMPRENE. However, in case of overdose, the stomach should be emptied by inducing vomiting or by gastric lavage, and supportive symptomatic treatment should be employed.