Miltefosine

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Miltefosine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Disclaimer

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Black Box Warning

WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
IMPAVIDO may cause fetal harm. Fetal death and teratogenicity occurred in animals administered miltefosine at doses lower than the recommended human dose. Do not administer IMPAVIDO to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing IMPAVIDO. Females of reproductive potential should be advised to use effective contraception during IMPAVIDO therapy and for 5 months after therapy.

Overview

Miltefosine is an antimicrobial drug that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

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

Dosage

  • The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
This image is provided by the National Library of Medicine.

DOSAGE FORMS AND STRENGTHS

  • IMPAVIDO® (miltefosine) oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Miltefosine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in pediatric patients.

Contraindications

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.

Warnings

WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
IMPAVIDO may cause fetal harm. Fetal death and teratogenicity occurred in animals administered miltefosine at doses lower than the recommended human dose. Do not administer IMPAVIDO to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing IMPAVIDO. Females of reproductive potential should be advised to use effective contraception during IMPAVIDO therapy and for 5 months after therapy.

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 IMPAVIDO in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing IMPAVIDO to females of reproductive potential. Advise females of reproductive potential to use effective contraception during IMPAVIDO 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 IMPAVIDO therapy [see Adverse Reactions (6.2)]. The effects of IMPAVIDO 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 IMPAVIDO therapy in humans has not been adequately evaluated.

Renal Effects

Elevations of serum creatinine (Cr) were noted in clinical trials evaluating IMPAVIDO in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving IMPAVIDO 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 IMPAVIDO in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving IMPAVIDO.

Gastrointestinal Effects

Vomiting and/or diarrhea commonly occur during IMPAVIDO 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 IMPAVIDO therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during IMPAVIDO 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 IMPAVIDO therapy.Discontinue IMPAVIDO if an exfoliative or bullous rash is noted during therapy.

Adverse Reactions

Clinical Trials Experience

  • 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 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, CTCAE1 Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).
This image is provided by the National Library of Medicine.
  • 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.
This image is provided by the National Library of Medicine.


This image is provided by the National Library of Medicine.
  • 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%).

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.
  • Gastrointestinal Disorders: melena
  • Reproductive System and Breast Disorders: scrotal pain, decreased ejaculate volume, absent ejaculation.

Drug Interactions

  • Drug
  • Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miltefosine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Miltefosine during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Miltefosine with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Miltefosine with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Miltefosine with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Miltefosine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Miltefosine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Miltefosine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Miltefosine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Miltefosine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Miltefosine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Miltefosine in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Miltefosine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Miltefosine in the drug label.

Pharmacology

There is limited information regarding Miltefosine Pharmacology in the drug label.

Mechanism of Action

Structure

File:Miltefosine01.png
This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Miltefosine in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Miltefosine in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Miltefosine in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Miltefosine in the drug label.

How Supplied

Storage

There is limited information regarding Miltefosine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Miltefosine in the drug label.

Precautions with Alcohol

  • Alcohol-Miltefosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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