Miltex

Miltex (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.
• Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
• Mucosal leishmaniasis caused by Leishmania braziliensis.

Limitations of Use

• Leishmania species studied in clinical trials evaluating Miltex were based on epidemiologic data.
• There may be geographic variation in clinical response of the same Leishmania species to Miltex.
• The efficacy of Miltex in the treatment of other Leishmania species has not been evaluated.

The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.

Table 1: Miltefosine Dosage

Pregnancy

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

Sjögren-Larsson-Syndrome

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

Hypersensitivity

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryo-Fetal Toxicity

Miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use Miltex in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Miltex to females of reproductive potential. Advise females of reproductive potential to use effective contraception during Miltex therapy and for 5 months after completion of therapy.

Reproductive Effects

Females

Miltefosine caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons.

Effects on human female fertility have not been formally studied.

Males

Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.

Scrotal pain and decreased or absent ejaculation during therapy have been reported during Miltex therapy. The effects of Miltex on human male fertility have not been adequately studied.

Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Miltex therapy in humans has not been adequately evaluated.

Renal Effects

Elevations of serum creatinine (Cr) were noted in clinical trials evaluating Miltex in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving Miltex during therapy and for 4 weeks after end of therapy.

Hepatic Effects

Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating Miltex in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving Miltex.

Gastrointestinal Effects

Vomiting and/or diarrhea commonly occur during Miltex administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion.

Thrombocytopenia

Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis.

Absorption Of Oral Contraceptives

Vomiting and/or diarrhea occurring during Miltex therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during Miltex therapy, advise females to use additional non-hormonal or alternative method(s) of effective contraception.

Stevens-Johnson Syndrome

Stevens-Johnson syndrome has been reported during Miltex therapy. Discontinue Miltex if an exfoliative or bullous rash is noted during therapy.

Patient Counseling Information

See the FDA-approved Medication Guide

Dosing Instructions

• Miltex is administered with food to ameliorate gastrointestinal side effects.
• Instruct the patient to swallow the capsule whole and not to chew it or break it apart. Instruct the patient to complete the full course of therapy.
• Inform the patient that abdominal pain, nausea, vomiting, and diarrhea are common side effects of therapy with Miltex and instruct the patient to inform their healthcare provider if these gastrointestinal side effects are severe or persistent. Instruct the patient to consume sufficient fluids to avoid dehydration and, consequently, the risk of kidney injury.

Females and Males of Reproductive Potential

• Advise women of reproductive potential to use effective contraception during Miltex therapy and for 5 months after therapy ends.
• Advise women who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during Miltex therapy if vomiting and/or diarrhea occurs.
• Advise nursing mothers not to breastfeed during Miltex therapy and for 5 months after therapy is completed.
• Advise women and men that Miltex caused infertility in male rats, impaired fertility in female rats, and caused atresia in ovarian follicles in female dogs. Advise patients that the potential of impaired fertility in humans has not been adequately evaluated.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Mutagenicity/Carcinogenicity: Miltefosine tested negative in the AMES-Salmonella test, DNAamplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, and oral mouse micronucleus test in vivo. The V 79 mammalian cell HPRT gene mutation test showed an increase in mutant frequency without dose dependency. In view of all mutagenicity test results, the single positive finding in the V 79 HPRT test is considered to be not of toxicological relevance with respect to a mutagenic risk to humans.

Carcinogenicity studies were not performed. In a 52-week oral rat toxicity study, testicular Leydig cell adenoma was observed in 3 of 30 male rats with daily administration of 21.5 mg/kg/day miltefosine (1.0 times the MRHD based on BSA comparison). The carcinogenic potential of miltefosine in humans is unknown.

In a Segment I fertility study in male rats, testicular atrophy, reduced numbers of viable sperm, and impaired fertility were observed in rats following daily oral doses of ≥ 8.25 mg/kg (0.4 times the MRHD based on BSA comparison). These findings were reversible within a recovery period of 10 weeks except at the highest dose tested, 21.5 mg/kg/day ( 1.0 times the MRHD based on BSA comparison), where effects were not fully reversible.

In a female fertility study in rats, estrus cycle arrest in the metestrus or diestrus phases occurred with the high-dose of 21.5 mg/kg (1.0 times the MRHD based on BSA comparison). At doses of 6.81 and 21.5 mg/kg (0.3 and 1.0 times the MRHD respectively based on BSA comparison) increased numbers of embryonic and fetal resorptions and dead fetuses were observed. In a 52- week toxicology study in dogs, increased numbers of atretic follicles in the ovaries, and cycle arrest in the uterus, vagina, and mammary gland with morphology consistent with anestrus or diestrus was observed at doses ≥ 1 mg/kg/day (0.2 times the MRHD based on BSA comparison). The effects in dogs were fully reversible after a recovery period of 6 weeks.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Miltex may cause fetal harm. Human pregnancy data are not available, however, embryofetal 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 Miltex 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..

Nursing Mothers

It is not known whether Miltex is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Miltex, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Breastfeeding should be avoided for 5 months after Miltex therapy.

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.

Geriatric Use

Clinical studies of Miltex did not include sufficient numbers of subjects 65 years of age and over to determine if they respond differently than younger subjects.

Renal Impairment

Patients with serum creatinine or BUN levels ≥ 1.5 times the upper limit of normal were excluded from the clinical studies. Miltefosine pharmacokinetics have not been studied in patients with renal impairment.

Hepatic Impairment

Patients with serum levels of ALT or AST ≥ 3 times the upper limit of normal and bilirubin levels ≥ 2 times the upper limit of normal were excluded from the clinical studies. Miltefosine pharmacokinetics have not been studied in patients with hepatic impairment.

Females And Males Of Reproductive Potential

Contraception

Miltex may cause fetal harm when used during pregnancy. Advise females of reproductive potential to use effective contraception during Miltex therapy and for 5 months after therapy is completed.

Vomiting and/or diarrhea occurring during Miltex therapy may affect absorption of oral contraceptives and therefore may compromise their efficacy. Advise females who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during Miltex therapy if vomiting and/or diarrhea occurs during therapy.

Infertility

Females

Miltefosine caused impaired fertility in rats and caused reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD. The effects of Miltex on human female fertility have not been formally studied.

Males

Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended. The effects of Miltex on human male fertility have not been adequately studied.

Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Miltex therapy has not been adequately evaluated.

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.

Clinical Trials Experience

Visceral Leishmaniasis

One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninetynine (299) patients (211 men and 88 women) received oral Miltex 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 Miltex compared to amphotericin B.

Less than 1% of patients who received Miltex died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of Miltex 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 Miltex included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE1 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 Miltex

In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of Miltex 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 Miltex recipient discontinued therapy due to Cr elevation.

Elevations of transaminases during therapy occurred in up to half of Miltex 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 Miltex-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 Miltex recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively.

Cutaneous Leishmaniasis

The efficacy of Miltex 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 Miltex 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 Miltex 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 Miltex-Treated Patients ≥ 12 Years of Age with Cutaneous Leishmaniasis in the Placebo-Controlled Trial

Table 4: Adverse Reactions Occurring in ≥ 2% of Miltex-Treated Patients ≥ 12 Years of Age with Cutaneous Leishmaniasis in Two Comparative Trials

In the placebo controlled trial, 12/89 (13.4%) Miltex 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 Miltex or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of Miltex 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 Miltex and placebo recipients (approximately 5%). Other adverse events seen at < 2% incidence in the Miltex 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 Miltex 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

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.

The pharmacokinetic parameters of miltefosine in patients with visceral and cutaneous leishmaniasis treated for 28 days with Miltex are listed in Table 5. Due to the long half-life of miltefosine ( > 6 days), trough plasma concentrations did not appear to reach a steady state at the end of treatment (i.e., Day 28).

Table 5: Mean (%CV) Pharmacokinetic Parameters for Miltefosine Following Oral Capsule Administration to Adult Patients with Visceral and Cutaneous Leishmaniasis

Absorption

Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of Miltex capsules were reached right before the next dose in many patients, indicating that the absorption of miltefosine may proceed throughout the dosing interval.

Distribution

The distribution of miltefosine has not been studied in humans. Human plasma protein binding of miltefosine, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 μg/mL. In rats, radioactivity of [14C] miltefosine is widely distributed after both single and repeated oral administration with highest uptake of radioactivity in kidney, liver, and spleen. Placental transfer and excretion into milk have not been investigated.

Metabolism and Excretion

No in vitro oxidative metabolism by 15 different human cytochrome P450 enzymes (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and 4A1) was observed.

A slow metabolic breakdown could be shown in human hepatocytes, resulting in the release of choline by phospholipase D-like cleavage of the miltefosine molecule. The fatty alcoholcontaining fragment of miltefosine can enter the metabolism of fatty acids after being oxidized to palmitic acid. This oxidation is blocked in patients with Sjögren-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Miltex is contraindicated in patients who have Sjögren-Larsson-Syndrome.

There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 μg/mL miltefosine.

Oral administration of miltefosine did not markedly induce the content of hepatic CYP3A assayed by demethylation activity of erythromycin in rats.

In visceral leishmaniasis patients, < 0.2% of the administered dose was excreted into the urine.