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Impavido

Generic Name: Miltefosine
Class: Antiprotozoals, Miscellaneous
Chemical Name: Choline hydroxide, hexadecyl hydrogen phosphate, inner salt
Molecular Formula: C21H46NO4P
CAS Number: 58066-85-6

Warning(s)

  • Fetal/Neonatal Morbidity and Mortality
  • Miltefosine may cause fetal harm.1 Fetal death and teratogenicity observed in animals receiving doses lower than recommended human dose.1

  • Do not administer miltefosine to pregnant women.1 Prior to prescribing miltefosine for women of reproductive potential, obtain a serum or urine pregnancy test.1 Advise women of reproductive potential to use effective contraception during and for 5 months after miltefosine treatment.1

Introduction

Antiprotozoal agent; alkylphosphocholine analog.1 2 5 6 7 12 23

Uses for Impavido

Leishmaniasis

Treatment of cutaneous leishmaniasis caused by Leishmania braziliensis, L. guyanensis, or L. panamensis; 1 mucosal leishmaniasis caused by L. braziliensis;1 and visceral leishmaniasis (also known as kala-azar) caused by L. donovani.1

Efficacy for treatment of leishmaniasis caused by other Leishmania species not evaluated.1 When used for treatment of infections caused by a specific Leishmania species, consider that clinical response to the drug may vary based on geographic location.1

Leishmaniasis is caused by >15 different Leishmania species that are transmitted to humans by bite of infected sand flies;46 371 372 373 377 also can be transmitted via blood (e.g., blood transfusions, needles shared by IV drug abusers) and perinatally from mother to infant.46 371 377 In Eastern Hemisphere (Old World), leishmaniasis found most frequently in parts of Asia, the Middle East, Africa, and southern Europe;377 in Western Hemisphere (New World), found most frequently in Mexico and Central and South America and reported occasionally in Texas and Oklahoma.377 Leishmaniasis reported in short-term travelers to endemic areas and in immigrants and expatriates from such areas;46 372 373 377 also reported in US military personnel and contract workers serving or working in endemic areas (e.g., Iraq, Afghanistan).46 377

Specific form of leishmaniasis and disease severity depend on Leishmania species involved, geographic area of origin, location of sand fly bite, and patient factors (e.g., nutritional and immune status).46 371 372 373 374 375 Treatment (e.g., drug, dosage, duration of treatment) must be individualized based on region where disease was acquired, likely infecting species, drug susceptibilities reported in area of origin, form of disease, and patient factors (e.g., age, pregnancy, immune status).46 371 372 374 375 377 No single treatment approach is appropriate for all possible clinical presentations.46 Consultation with clinicians experienced in management of leishmaniasis recommended.371 377

For assistance with diagnosis or treatment of leishmaniasis in the US, contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays.382 Contact CDC Drug Service at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in US.382

Free-living Ameba Infections

Treatment of free-living ameba infections, including primary amebic meningoencephalitis caused by Naegleria fowleri8 14 15 and granulomatous amebic encephalitis or other infections caused by Balamuthia mandrillaris22 24 or Acanthamoeba.19 21 25

CNS infections caused by free-living ameba associated with high mortality rate;8 13 14 15 19 22 24 early diagnosis and treatment may increase chance of survival.8 14 15 Although data limited, these infections usually treated empirically with multiple-drug regimens.8 13 14 15 19 21 Depending on specific organism, treatment regimens have included several anti-infectives (e.g., albendazole, amphotericin B, azole antifungals [fluconazole, ketoconazole, itraconazole, or voriconazole], flucytosine, macrolides [azithromycin or clarithromycin], miltefosine, rifampin, pentamidine, sulfonamides [co-trimoxazole or sulfadiazine]) and other therapies (e.g., dexamethasone, phenytoin, therapeutic hypothermia).8 13 14 15 19 21 24

Miltefosine has been used in these infections because of in vitro evidence of activity against N. fowleri,8 16 18 Balamuthia,16 17 and Acanthamoeba16 20 and possible amebicidal activity against some strains.8 16 17 18 20

For assistance with diagnosis or treatment of suspected free-living ameba infections, contact CDC Emergency Operations Center at 770-488-7100.8 24 25 CDC can supply miltefosine for treatment of N. fowleri, B. madrillaris, or Acanthamoeba infections.8 24 25

Impavido Dosage and Administration

Administration

Oral Administration

Administer orally with food to ameliorate adverse GI effects.1

Swallow capsule whole;1 do not break, chew, or crush.1

Dosage

Pediatric Patients

Leishmaniasis
Treatment of Cutaneous, Mucocutaneous, or Visceral Leishmaniasis
Oral

Children and adolescents ≥12 years of age weighing ≥30 kg: Dosage based on weight.1 (See Table 1.)

Table 1: Dosage of Miltefosine for the Treatment of Cutaneous, Mucocutaneous, or Visceral Leishmaniasis1

Body Weight

Miltefosine Dosage

30–44 kg

One 50-mg capsule twice daily (with breakfast and dinner)

≥45 kg

One 50-mg capsule 3 times daily (with breakfast, lunch, and dinner)

Usual treatment duration is 28 consecutive days.1 2 3 4 5 6 7 46 372 374 375 376

Adults

Leishmaniasis
Treatment of Cutaneous, Mucocutaneous, or Visceral Leishmaniasis
Oral

Dosage based on weight.1 (See Table 2.)

Table 2: Dosage of Miltefosine for the Treatment of Cutaneous, Mucocutaneous, or Visceral Leishmaniasis1

Body Weight

Miltefosine Dosage

30–44 kg

One 50-mg capsule twice daily (with breakfast and dinner)

≥45 kg

One 50-mg capsule 3 times daily (with breakfast, lunch, and dinner)

Usual treatment duration is 28 consecutive days.1 2 3 4 5 6 7 46 372 374 375 376

Special Populations

Hepatic Impairment

Manufacturer makes no dosage recommendations.1

Renal Impairment

Manufacturer makes no dosage recommendations.1

Cautions for Impavido

Contraindications

  • Pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Hypersensitivity to miltefosine or any ingredient in the formulation.1

  • Sjögren-Larsson syndrome.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity, including death and teratogenicity, observed in animals that received miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose.1

Do not use in pregnant women.1

Prior to prescribing for women of reproductive potential, obtain urine or serum pregnancy test.1 Advise women of reproductive potential to use effective contraception during and for 5 months after completion of treatment.1 If adverse GI effects occur in such patients receiving oral contraceptives, additional nonhormonal or alternative methods of effective contraception should be used.1

Sensitivity Reactions

Stevens-Johnson syndrome reported.1

Discontinue if an exfoliative or bullous rash occurs.1

General Precautions

Reproductive Effects

Impaired fertility observed in female rats; 1 reversible follicular atresia and diestrus observed in female dogs.1 Effects on fertility not adequately studied in female patients.1

Reduced viable sperm counts, impaired fertility, and testicular atrophy observed in male rats;1 these effects not fully reversed 10 weeks after miltefosine discontinued.1

Scrotal pain and decreased or absent ejaculation reported in male patients receiving miltefosine.1 Effects on fertility not adequately studied in male patients.1

Advise patients of animal fertility findings;1 advise patients that potential for impaired fertility in humans receiving miltefosine not adequately evaluated.1

GI Effects

Vomiting and/or diarrhea commonly occur during miltefosine therapy;1 vomiting reported in up to 48% of patients.1 2 3 5

Because vomiting and/or diarrhea may result in volume depletion, encourage fluid intake.1

Since GI absorption and efficacy of oral contraceptives may be affected by vomiting and/or diarrhea, women of reproductive potential should use additional nonhormonal or alternative methods of effective contraception if these adverse GI effects occur.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Hepatic Effects

Elevated hepatic aminotransferase (ALT, AST) and bilirubin concentrations observed in clinical trials evaluating miltefosine for treatment of visceral leishmaniasis.1

Monitor liver aminotransferases (ALT, AST) and bilirubin in patients receiving miltefosine.1

Renal Effects

Elevated Scr observed in clinical trials evaluating miltefosine for treatment of cutaneous, mucocutaneous, and visceral leishmaniasis.1

Monitor renal function weekly during and for 4 weeks after completion of miltefosine treatment.1

Hematologic Effects

Thrombocytopenia reported in patients receiving miltefosine for treatment of visceral leishmaniasis.1 Monitor platelet counts in patients being treated for visceral leishmaniasis.1

Specific Populations

Pregnancy

Category D.1

Do not use in pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Embryofetal toxicity, including death and teratogenicity, observed in rats and rabbits receiving miltefosine during organogenesis;1 numerous visceral and skeletal fetal malformations observed in rats receiving miltefosine prior to mating through day 7 of pregnancy.1

Lactation

Not known if miltefosine distributed into human milk.1

Discontinue nursing or the drug.1

Avoid breast-feeding for 5 months after completion of miltefosine treatment.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Animal studies indicate juvenile rats are more sensitive to miltefosine-induced adverse effects, especially retinal degeneration and kidney effects, than adult rats.1

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.1 Patients with ALT or AST concentrations ≥3 times ULN and bilirubin levels ≥2 times ULN were excluded from clinical studies.1

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment.1 Patients with Scr or BUN levels ≥1.5 times ULN were excluded from clinical studies.1

Common Adverse Effects

Adverse GI effects (e.g., diarrhea, nausea, vomiting, abdominal pain, epigastralgia, decreased appetite),1 2 3 5 6 CNS effects (dizziness,1 5 6 headache,1 3 6 somnolence),1 motion sickness,1 3 asthenia,1 malaise,1 pyrexia,1 pruritus,1 5 lymphangitis,1 increased Scr,1 2 3 increased BUN,2 increased hepatic aminotransferases (ALT, AST).1 2 3

Interactions for Impavido

Does not markedly induce or inhibit activity of CYP isoenzymes in vitro or in animal studies.1

Potential for interaction with drug transporters not established.1

Impavido Pharmacokinetics

Absorption

Absolute oral bioavailability not determined.1

Following oral administration in patients with visceral leishmaniasis, peak plasma concentrations attained just before next dose in many patients, indicating that absorption may persist throughout dosing interval.1

Distribution

Extent

Distribution in humans not evaluated;1 in rats, widely distributed following oral administration with highest concentrations in the kidney, liver, and spleen.1 12

Some evidence that the drug may be distributed into CSF.12 15

Plasma Protein Binding

98%.1 12

Elimination

Metabolism

No in vitro evidence of oxidative metabolism by CYP isoenzymes.1 12

Elimination Route

Following an oral dose in patients with visceral leishmaniasis, <0.2% excreted in urine.1 12

Half-life

Primary elimination half-life approximately 7 days;1 12 terminal half-life approximately 31 days.1 12

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Dispense in original container;1 protect from moisture.1

Actions

  • Antiprotozoal agent with activity against Leishmania and some other organisms.1 2 5 6 7 12 23

  • Precise mechanisms of antileishmanial effects not fully elucidated, but may involve interaction with phospholipids and sterols (including membrane lipids), inhibition of mitochondrial cytochrome c oxidase (mitochondrial function), and an apoptosis-like effect and cell death.1 7 9 11 12 23

  • Active in vitro and in clinical infections against L. donovani, L. braziliensis, L. guyanensis, and L. panamensis.1 2 3 4 5 6 11 12 23 Also active in vitro against L. aethiopica,23 L. amazonensis,9 L. mexicana,23 and L. tropica.23

  • Susceptibility of the different Leishmania species to miltefosine varies.1 12 23 In addition, susceptibility of a specific species may vary based on geographic location.1 12 23

  • Resistance to miltefosine can occur.1 12 Miltefosine-resistant Leishmania have been produced in vitro,12 and strains of L. braziliensis with intrinsic resistance to miltefosine identified.1 12

  • Resistance may be due to decreased miltefosine accumulation within Leishmania caused by increased drug efflux, mediated by overexpression of the ABC transporter P-glycoprotein, and/or decreased drug uptake due to inactivation of miltefosine transport.1 11 12 23

Advice to Patients

  • Importance of completing full course of treatment.1

  • Advise patients to swallow miltefosine capsules whole; do not break, chew, or crush.1

  • Importance of taking with food to ameliorate adverse GI effects.1

  • Advise patients that abdominal pain, nausea, vomiting, and diarrhea are common adverse effects of miltefosine;1 importance of informing clinicians if adverse GI effects are severe or persistent.1

  • Instruct patients to consume sufficient fluids to avoid dehydration and, consequently, the risk of kidney injury.1

  • Advise women of reproductive potential to use effective contraception during and for 5 months after miltefosine treatment.1

  • Advise women who use oral contraceptives of the importance of using additional nonhormonal or alternative methods of effective contraception during miltefosine treatment if vomiting and/or diarrhea occurs;1 these adverse GI effects may decrease effectiveness of oral contraceptives.1

  • Advise men and women that miltefosine has caused infertility in male rats, impaired fertility in female rats, and atresia in ovarian follicles in female dogs.1 Also advise patients that potential effects on fertility in humans not adequately evaluated.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise nursing mothers not to breast-feed during and for 5 months after miltefosine treatment.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Miltefosine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Impavido

Paladin

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Paladin Therapeutics. Impavido (miltefosine) capsules prescribing information. Wilmington, DE; 2014 Mar.

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3. Soto J, Arana BA, Toledo J et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004; 38:1266-72. [PubMed 15127339]

4. Soto J, Toledo J, Valda L et al. Treatment of Bolivian mucosal leishmaniasis with miltefosine. Clin Infect Dis. 2007; 44:350-6. [PubMed 17205440]

5. Chrusciak-Talhari A, Dietze R, Chrusciak Talhari C et al. Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil. Am J Trop Med Hyg. 2011; 84:255-60. [PubMed 21292895]

6. Machado PR, Ampuero J, Guimarães LH et al. Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial. PLoS Negl Trop Dis. 2010; 4:e912. [PubMed 21200420]

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