Impavido Drug Information

Clinical Trials Experience Visceral Leishmaniasis One Phase 3 trial was conducted in

patients ≥ 12 years of age in India. Two-hundred and ninety-nine 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 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 patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and forty-four received placebo. In the comparative trials, one hundred and twenty patients ≥12 years of age received a target IMPAVIDO dose of 2.5 mg/kg/day for 28 days and fifty eight 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 (5.2%) Diarrhea 18 (15.0%) 3 (5.2%) Nausea 50 (41.7%) 3 (5.2%) Vomiting 33 (27.5%) 0 Infections and Infestations Lymphangitis 7 (5.8%) 0 Metabolism and Nutrition Disorders Decreased Appetite 13 (10.8%) 4 (5.8%) Nervous System Disorders Dizziness 15 (12.5%) 4 (6.9%) Skin and Subcutaneous Tissue Disorders Pruritus 7 (5.8%) 0 In the placebo controlled trial, 12/89 (13.4%) IMPAVIDO subjects had Cr increases of 1.5-3 times above baseline, compared to 2/44 (4.5%) placebo subjects at end of therapy. In the comparative trial, a similar percentage of subjects who received IMPAVIDO or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of IMPAVIDO subjects and 11% of pentavalent antimony subjects had Cr elevations 1.5-3 times above baseline at the end of therapy in the two active controlled trials. The frequency of AST and ALT increase above upper limit of normal at end of therapy was similar in IMPAVIDO and placebo recipients (approximately 5%). Other adverse events seen at <2% incidence in the IMPAVIDO group included anemia, lymphadenopathy, abdominal distension, constipation, dysphagia, flatulence, fatigue, malaise, abscess, cellulitis, ecthyma, paresthesia, testicular pain, testicular swelling, Stevens-Johnson syndrome, urticaria, rash, pyoderma.

Postmarketing Experience

The following adverse reactions have been identified during use of IMPAVIDO worldwide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatics Disorders : thrombocytopenia, agranulocytosis Gastrointestinal Disorders : melena General Disorders : generalized edema, peripheral edema Hepatobiliary Disorders : jaundice Nervous System Disorders : seizure Reproductive System and Breast Disorders : scrotal pain, decreased ejaculate volume, absent ejaculation.

Vascular Disorders : epistaxis

In vitro and animal metabolism studies showed that miltefosine did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes . 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.

Pregnancy Pregnancy Category D Risk Summary IMPAVIDO may cause fetal harm. Human pregnancy data are not available, however, embryo-fetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparison. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer IMPAVIDO to pregnant women.

Clinical Considerations During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and stillbirths. Animal Data Miltefosine administration in rat embryo-fetal toxicity studies during early embryonic development (Day 6 to Day 15 of gestation) caused embryo-fetal toxicity including death and teratogenicity at dosages of ≥ 1.2 mg/kg/day (0.06 times the MRHD based on BSA comparison). Teratogenic effects included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema.

Embryo-fetal toxicity was also observed in rabbits after oral administration of miltefosine during organogenesis (Day 6 to Day 18 of gestation) at doses ≥ 2.4 mg/kg/day (0.2 times the MRHD based on BSA comparison). In both rats and rabbits, there were no viable litters at miltefosine doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively). In a separate female fertility study in rats, miltefosine doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) administered for four weeks before mating and up to Day 7 of pregnancy produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations. .

Pediatric Use Safety and effectiveness in pediatric patients < 12 years have not been established. Juvenile rats were more sensitive to the miltefosine-induced effects, especially retinal and kidney effects, than adult rats .

Pregnancy

IMPAVIDO may cause fetal harm. IMPAVIDO is contraindicated in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing IMPAVIDO .

Sjögren-Larsson-Syndrome

IMPAVIDO is contraindicated in patients who have Sjögren-Larsson-Syndrome .

Hypersensitivity

IMPAVIDO is contraindicated in patients who are hypersensitive to miltefosine or any IMPAVIDO excipients.

The common adverse effects of vomiting, diarrhea, and abdominal pain are likely in case of overdose. Institute adequate hydration to prevent the risk of impaired renal function, and replace electrolytes as necessary. Because miltefosine is only slightly excreted in the urine, forced diuresis will not increase miltefosine excretion.

Gastrointestinal lavage is of unknown value. A specific antidote to treat miltefosine overdose is not known.