Miltefosine

12.1 Mechanism of Action Miltefosine is an anti-leishmanial agent [see Clinical Pharmacology ( 12.4 )] .

1 INDICATIONS AND USAGE IMPAVIDO (miltefosine) capsules are indicated in adults and adolescents ≥12 years of age weighing ≥ 30 kg for the treatment of: Visceral leishmaniasis caused by Leishmania donovani [see Clinical Trials ( 14.1 )] . Cutaneous leishmaniasis caused by Leishmania braziliensis , Leishmania guyanensis , and Leishmania panamensis [see Clinical Trials ( 14.2 )] . Mucosal leishmaniasis caused by Leishmania braziliensis [see Clinical Trials ( 14.3 )] . Limitations of Use: Leishmania species studied in clinical trials evaluating IMPAVIDO were based on epidemiologic data [see Clinical Trials ( 14.1 , 14.2 )] . There may be geographic variation in clinical response of the same Leishmania species to IMPAVIDO [see Clinical Trials ( 14.1 , 14.2 )] . The efficacy of IMPAVIDO in the treatment of other Leishmania species has not been evaluated. IMPAVIDO is an antileishmanial drug indicated in adults and adolescents ≥12 years of age weighing ≥30 kg (66 lbs) for treatment of: Visceral leishmaniasis due to Leishmania donovani ( 1 ). Cutaneous leishmaniasis due to Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis ( 1 ). Mucosal leishmaniasis due to Leishmania braziliensis ( 1 ). Limitations of use : Leishmania species evaluated in clinical trials were based on epidemiologic data. There may be geographic variation in the response of the same Leishmania species to IMPAVIDO ( 1 , 14 ). The efficacy of IMPAVIDO in the treatment of other Leishmania species has not been evaluated.

2 DOSAGE AND ADMINISTRATION The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions. Table 1: Miltefosine Dosage Weight Dosage and Administration 30 kg to 44 kg One 50 mg capsule twice daily with food (breakfast and dinner) 45 kg or greater One 50 mg capsule three times daily with food (breakfast, lunch, and dinner) Administer with food to ameliorate gastrointestinal adverse reactions. 30 to 44 kg: one 50 mg capsule twice daily for 28 consecutive days ( 2 ). 45 kg or greater: one 50 mg capsule three times daily for 28 consecutive days ( 2 ).

6 ADVERSE REACTIONS 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. Adverse reactions occurring in ≥2% of patients include nausea, vomiting, diarrhea, headache, decreased appetite, dizziness, abdominal pain, pruritus, somnolence, elevated transaminases, and elevated creatinine (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Profounda, Inc. at 1-866-588-5405 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Visceral Leishmaniasis One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral IMPAVIDO at a target dose of 2.5 mg/kg/day for 28 days (50 mg capsule once daily if weight was less than 25 kg and 50 mg capsule twice daily if weight was 25 kg or greater). Patients ranged between 12 and 64 years of age. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). Ninety-nine (99) patients received 1 mg/kg/day amphotericin B deoxycholate intravenously every other day for 15 doses. A statistically significant higher percentage of men received IMPAVIDO compared to amphotericin B. Less than 1% of patients who received IMPAVIDO died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of IMPAVIDO recipients (6/299) and 1% of amphotericin B recipients (1/99). Approximately 3% of patients discontinued treatment in each treatment arm due to an adverse reaction. Serious adverse reactions and adverse reactions leading to drug discontinuation that were thought to be related or possibly related to IMPAVIDO included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE Common Terminology Criteria for Adverse Events Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN). Table 2: Treatment Emergent Adverse Reactions Occurring in ≥2% of Visceral Leishmaniasis Patients Receiving IMPAVIDO System Organ Class Preferred Term IMPAVIDO N = 299 Amphotericin B Deoxycholate N = 99 Gastrointestinal Disorders Diarrhea 61 (20.4%) 6 (6.1%) Vomiting 113 (37.8%) 20 (20.0%) General Disorders Asthenia 19 (6.3%) 4 (4.0%) Metabolism and Nutrition Disorders Decreased Appetite 69 (23.1%) 22 (22.2%) In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of IMPAVIDO recipients and in 40% of amphotericin B recipients at the end of therapy. Ten percent of subjects in each arm had Cr elevations ≥1.5 times above baseline at 6 months follow up. No IMPAVIDO recipient discontinued therapy due to Cr elevation. Elevations of transaminases during therapy occurred in up to half of IMPAVIDO recipients and up to a third of amphotericin B recipients. The elevations were mild (< 3x ULN) or moderate (3-5x ULN) in 94% and 6% respectively of IMPAVIDO-treated patients who experienced an elevation. No patient discontinued therapy due to elevations in transaminases. At the end of therapy, 62% and 2.4% of IMPAVIDO recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively. Cutaneous Leishmaniasis The efficacy of IMPAVIDO in the treatment of cutaneous leishmaniasis was evaluated in one placebo-controlled trial conducted in Colombia and Guatemala and in two comparative trials conducted in Bolivia and Brazil respectively. In the placebo-controlled trial, eighty-nine (89) patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and forty-four (44) received placebo. In the comparative trials, one hundred and twenty (120) patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and fifty eight (58) patients received 20 mg/kg/day pentavalent antimony (meglumine) parenterally for 20 days. Table 3: Adverse Reactions Occurring in ≥2% of IMPAVIDO-Treated Patients ≥12 Years of Age with Cutaneous Leishmaniasis in the Placebo-Controlled Trial System Organ Class Preferred Term IMPAVIDO N = 89 Placebo N = 44 Ear and Labyrinth Disorders Motion Sickness 26 (29.2%) 10 (22.7%) Gastrointestinal Disorders Abdominal Pain 10 (11.2%) 3 (6.8%) Diarrhea 7 (7.9%) 2 (4.5%) Nausea 32 (35.9%) 5 (11.1%) Vomiting 4 (4.5%) 0 General and Administration Site Disorders Malaise 3 (3.4%) 1 (2.3%) Pyrexia 5 (5.6%) 2 (4.5%) Nervous System Disorders Dizziness 4 (4.5%) 0 Headache 25 (28.1%) 10 (22.7%) Somnolence 3 (3.4%) 0 Skin and Subcutaneous Tissue Disorders Pruritus 4 (4.5%) 0 Table 4: Adverse Reactions Occurring in ≥2% of IMPAVIDO-Treated Patients ≥ 12 Years of Age with Cutaneous Leishmaniasis in Two Comparative Trials System Organ Class Preferred Term IMPAVIDO N = 120 Meglumine N = 58 Gastrointestinal Disorders Abdominal Pain 9 (7.5%) 3

7 DRUG INTERACTIONS In vitro and animal metabolism studies showed that miltefosine did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes [see Clinical Pharmacology ( 12.3 )] . The potential of miltefosine to interact with drug transporters has not been evaluated. IMPAVIDO did not inhibit human cytochrome P450 enzymes in vitro. IMPAVIDO did not induce cytochrome 3A activity in rats( 7 , 12.3 ).