Miltefosine is an oral anti-leishmanial agent indicated for the treatment of visceral leishmaniasis due to L. donovani, cutaneous leishmaniasis due to L. braziliensis, L. guyanensis, and L. panamensis, and mucosal leishmaniasis due to L. braziliensis in adults and pediatric patients 12 years of age and older and weighing at least 30 kg. Leishmania is an intracellular protozoan parasite transmitted to humans via the bite of a female sandfly. Visceral leishmaniasis is a systemic infection that affects internal organs and fatal if left untreated. Cutaneous leishmaniasis affects the skin and presents as ulcers at the site of the bite; most cases of cutaneous leishmaniasis will resolve spontaneously after forming a scar. Mucosal leishmaniasis occurs after dissemination of Leishmania from the skin to the naso-oropharyngeal mucosa and results in destruction of nasal and pharyngeal tissue. Clinical trial data for miltefosine demonstrated a 94% final cure rate for visceral leishmaniasis, 66% to 85% definitive cure rate for cutaneous leishmaniasis, and a 62% complete resolution rate for mucosal leishmaniasis. Miltefosine is contraindicated during pregnancy based on animal reproduction studies where fetal death and fetal malformations occurred in animals given miltefosine at doses lower than the maximum recommended human dose. Miltefosine has been shown to reduce sperm parameters and may impair male fertility.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 2
-Approved by FDA after NIOSH 2016 list published. NIOSH recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer with a meal.
-Swallow capsule whole.
Gastrointestinal disorders were among the most commonly reported adverse events associated with the use of miltefosine during clinical trials. Adverse events experienced by drug recipients included abdominal pain (7.5% to 11.2%), decreased appetite (10.8% to 23.1%), diarrhea (7.9% to 20.4%), nausea (35.9% to 41.7%), and vomiting (4.5% to 37.8%). Given vomiting and/or diarrhea commonly occur during miltefosine administration and may result in volume depletion, encourage fluid intake to avoid volume depletion. Other GI events reported in less than 2% of patients included abdominal distension, constipation, dysphagia, and flatulence. Cases of melena have also been noted during postmarketing use.
Patients receiving miltefosine during clinical trials experienced asthenia (6.3%), drowsiness (3.4%), malaise (3.4%), fatigue (less than 2%), and fever (5.6%). During postmarketing use, generalized edema and peripheral edema have been reported.
Neurologic adverse events associated with the use of miltefosine during clinical trials included dizziness (4.5% to 12.5%), headache (28.1%), motion sickness (29.2%), and paresthesias (less than 2%). Seizures were reported during postmarketing use.
Elevated hepatic enzymes have been observed in patients receiving treatment with miltefosine. During clinical trials, increases in transaminase concentrations were observed in up to half of the drug recipients; however, the majority (94%) were mild (less than 3 times upper limit of normal) elevations. Cases of jaundice have also been noted during postmarketing use. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving miltefosine. Elevations of serum creatinine were noted in clinical trials evaluating miltefosine in the treatment of cutaneous, mucosal, and visceral leishmaniasis. Monitor renal function weekly in patients receiving miltefosine during therapy and for 4 weeks after end of therapy. In a visceral leishmaniasis trial, serum creatinine elevations of 1.5 times or more above baseline occurred in approximately 10% of miltefosine recipients (n = 299) at the end of therapy; at 6 months follow-up, 10% of miltefosine-treated patients had serum creatinine elevations of 1.5 times or more above baseline. In a placebo-controlled trial in patients with cutaneous leishmaniasis, 12/89 (13.4%) miltefosine-treated patients had serum creatinine increases of 1.5 to 3 times above baseline at end of therapy. In an active comparator trial in patients with cutaneous leishmaniasis, approximately 5% of miltefosine-treated patients had serum creatinine elevations above baseline at 3 and 6 months after therapy. Approximately 25% of miltefosine-treated patients had serum creatinine elevations of 1.5 to 3 times above baseline at the end of therapy in 2 active-controlled trials.
Thrombocytopenia has been associated with the use of miltefosine. During the visceral leishmaniasis clinical trial, platelet counts of less than 150,000 and less than 50,000 were observed in 62% and 2.4% of drug recipients, respectively. Monitor platelet count during therapy for visceral leishmaniasis. Other hematologic adverse events noted in patients receiving treatment with miltefosine included anemia (less than 2%) and lymphadenopathy (less than 2%). Agranulocytosis and epistaxis were reported during postmarketing use of miltefosine.
Pruritus (4.5% to 5.8%) and lymphangitis (5.8%) were reported by patients receiving treatment with miltefosine during the cutaneous leishmaniasis clinical trials. Other less frequently reported (less than 2%) dermatologic adverse events included abscess, cellulitis, ecthyma, pyoderma, rash, Stevens-Johnson syndrome, and urticaria. Discontinue miltefosine if an exfoliative or bullous rash is noted during therapy.
Spermatogenesis inhibition has been observed in an open-label study (n = 58) in males receiving a target dose of miltefosine 2.5 mg/kg/day for 28 days; reductions in sperm parameters (semen volume, total sperm count, sperm concentration, sperm morphology, and sperm motility) were observed. For all parameters, except sperm concentration, the observed reductions were reversible in most affected patients and improved within 3 to 6 months. Sperm concentration reductions of 50% or more persisted in approximately 26% of patients on follow-up assessments at 3 and 6 months after treatment completion, and sperm concentration reductions to the lower limit of normal (less than 20 million/mL) persisted in up to 8% of patients on their last observed assessment. Semen analyses were not conducted beyond 6 months, therefore the duration of effect of miltefosine on sperm concentration after treatment is unknown. Reductions in ejaculate volume (64%) and temporary absence of ejaculate (6%) were reported in an observational study of male patients (n = 33) receiving miltefosine. These adverse effects resolved in all patients upon completion of therapy. Scrotal tenderness (12%) and epididymitis (3%) were also reported. Testicular pain and testicular swelling were reported in less than 2% of patients treated with miltefosine during clinical trials. Scrotal pain, decreased ejaculate volume, and absent ejaculation have been noted in other observational studies. Whether miltefosine affects male fertility is unknown.
Fetal death and fetal malformations (teratogenesis) occurred in animals given miltefosine at doses lower than the recommended human dose. Malformations included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate, and generalized edema.
Miltefosine is contraindicated in patients who are hypersensitive to miltefosine or any of the product excipients.
Miltefosine is contraindicated in patients with Sjogren-Larsson-Syndrome due to impaired miltefosine metabolism, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity.
Patients with serum creatinine or BUN concentrations of 1.5 times or more the upper limit of normal were excluded from miltefosine clinical studies. Miltefosine pharmacokinetics have not been studied in patients with renal impairment.
Patients with ALT or AST serum concentrations of 3 times or more the upper limit of normal and bilirubin concentrations of 2 times or more the upper limit of normal were excluded from miltefosine clinical studies. Miltefosine pharmacokinetics have not been studied in patients with hepatic disease.
Miltefosine is contraindicated for use during pregnancy. If a woman becomes pregnant while being treated with miltefosine, discontinue therapy and counsel the patient about the potential risk to the fetus. Based on data from animal reproduction studies, miltefosine may cause embryo-fetal toxicity when administered to pregnant women. There are no available data on miltefosine use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal and/or fetal outcomes. In animal studies, fetal death and fetal malformations occurred at oral doses that were 0.06 to 0.3 times the maximum recommended human dose (MRHD), respectively. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to miltefosine during pregnancy. Register patients by calling 1-866-588-5405 or visiting online at http://www.impavido.com/mother-registry.
There are no data on the presence of miltefosine in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Due to the potential for serious adverse reactions, breast-feeding is not recommended during treatment and for 5 months after the last miltefosine dose.
Miltefosine is associated with reproductive risk. Verify the pregnancy status in females of reproductive potential with pregnancy testing before initiating treatment with miltefosine. Discuss contraception requirements with the patients. Advise females of reproductive potential to use effective contraception during treatment with miltefosine and for 5 months after the last dose. Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting and/or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception. Miltefosine may cause infertility in males and females of reproductive potential. Reductions in sperm parameters (semen volume, total sperm count, sperm concentration, sperm morphology, and sperm motility) were observed in an open-label clinical study (n = 58) in males receiving a target dose of miltefosine 2.5 mg/kg/day for 28 days. For all parameters, except sperm concentration, the observed reductions were reversible in most affected patients and improved within 3 to 6 months. Sperm concentration reductions of 50% or more persisted in approximately 26% of patients on follow-up assessments at 3 and 6 months after treatment completion, and sperm concentration reductions to the lower limit of normal (less than 20 million/mL) persisted in up to 8% of patients on their last observed assessment. There were no clinically meaningful changes in serum testosterone of FSH concentrations. Semen analyses were not conducted beyond 6 months, therefore the duration of effect of miltefosine on sperm concentration after treatment is unknown. Reductions in ejaculate volume and temporary absence of ejaculate were reported in an observational study of male patients receiving miltefosine. These adverse effects resolved in all patients upon completion of therapy. Based on animal fertility studies, miltefosine may also impair fertility in females of reproductive potential. When miltefosine was administered to rats at the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison, estrus cycle arrest occurred. At doses of 0.3 to 1 times the MRHD based on BSA comparison, increased numbers of embryonic and fetal resorptions and dead fetuses were observed. Female dogs administered doses of 0.2 times MRHD based on BSA comparison, experienced reversible follicular atresia and diestrus. The effects in dogs were fully reversible after a recovery period of 6 weeks.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Leishmania braziliensis, Leishmania donovani, Leishmania guyanensis, Leishmania panamensis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of leishmaniasis:
NOTE: Susceptibility of different Leishmania species, as well as susceptibility of different strains of the same Leishmania species, may vary in different geographic regions.
Oral dosage:
Adults weighing 45 kg or more: 50 mg PO 3 times daily for 28 days. For visceral disease, miltefosine is an alternative to liposomal amphotericin B. Combination therapy with liposomal amphotericin B may be considered in HIV-infected patients with refractory visceral disease. Chronic maintenance therapy with a lipid formulation amphotericin B or alternately, pentavalent antimony is recommended for HIV-infected patients with visceral disease and immunocompromised patients with multiple cutaneous relapses.
Adults weighing 30 to 44 kg: 50 mg PO twice daily for 28 days. For visceral disease, miltefosine is an alternative to liposomal amphotericin B. Combination therapy with liposomal amphotericin B may be considered in HIV-infected patients with refractory visceral disease. Chronic maintenance therapy with a lipid formulation amphotericin B or alternately, pentavalent antimony is recommended for HIV-infected patients with visceral disease and immunocompromised patients with multiple cutaneous relapses.
Children 12 years and Adolescents weighing 45 kg or more: 50 mg PO 3 times daily for 28 days. For visceral disease, miltefosine is an alternative to liposomal amphotericin B. Combination therapy with liposomal amphotericin B may be considered in HIV-infected patients with refractory visceral disease. Chronic maintenance therapy with a lipid formulation amphotericin B or alternately, pentavalent antimony is recommended for HIV-infected patients with visceral disease and immunocompromised patients with multiple cutaneous relapses.
Children 12 years and Adolescents weighing 30 to 44 kg: 50 mg PO twice daily for 28 days. For visceral disease, miltefosine is an alternative to liposomal amphotericin B. Combination therapy with liposomal amphotericin B may be considered in HIV-infected patients with refractory visceral disease. Chronic maintenance therapy with a lipid formulation amphotericin B or alternately, pentavalent antimony is recommended for HIV-infected patients with visceral disease and immunocompromised patients with multiple cutaneous relapses.
Children 2 to 11 years* or Children 12 years weighing less than 30 kg*: 2.5 mg/kg/day PO divided once or twice daily (rounded to nearest 10-mg [international] or 50-mg strength [US]) for 28 days. In clinical studies, lower cure rates and lower plasma drug exposures have been observed in younger children with this dosing regimen. An allometric dosing regimen, based on fat-free mass and height, has been studied. This proposed dosing algorithm results in higher daily doses for those with very low body weights (i.e., 3 to 4 mg/kg/day).
Maximum Dosage Limits:
-Adults
weighing 45 kg or more: 150 mg/day PO.
weighing 30 to 44 kg: 100 mg/day PO.
-Geriatric
weighing 45 kg or more: 150 mg/day PO.
weighing 30 to 44 kg: 100 mg/day PO.
-Adolescents
weighing 45 kg or more: 150 mg/day PO.
weighing 30 to 44 kg: 100 mg/day PO.
-Children
12 years and weighing 45 kg or more: 150 mg/day PO.
12 years and weighing 30 to 44 kg: 100 mg/day PO.
12 years and weighing less than 30 kg: 2.5 mg/kg/day PO has been used off-label.
2 to 11 years: 2.5 mg/kg/day PO has been used off-label.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. Patients with baseline serum ALT or AST >= 3x upper limit of normal and/or bilirubin >= 2x upper limit of normal were excluded from clinical trials.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Patients with baseline serum creatinine or BUN >= 1.5x upper limit of normal were excluded from clinical trials.
*non-FDA-approved indication
Anticoagulants: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Antithrombin III: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Apixaban: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Argatroban: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Betrixaban: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Bivalirudin: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Dabigatran: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Dalteparin: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Desogestrel; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Dienogest; Estradiol valerate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Drospirenone: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Drospirenone; Estetrol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Drospirenone; Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Drospirenone; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Edoxaban: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Enoxaparin: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Estradiol; Levonorgestrel: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Estradiol; Norethindrone: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Estradiol; Norgestimate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Ethinyl Estradiol; Norelgestromin: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Ethinyl Estradiol; Norgestrel: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Etonogestrel; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Fondaparinux: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Heparin: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Leuprolide; Norethindrone: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Levonorgestrel: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norethindrone: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norethindrone; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norgestimate; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Norgestrel: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Oral Contraceptives: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Pentosan: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Rivaroxaban: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception.
Warfarin: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Miltefosine is an alkyllysophospholipid analog with activity against certain Leishmania species in the amastigote (leishmanial) and promastigote (leptomonad) stages. The drug has been shown to be effective against L. donovani, L. braziliensis, L. guyanensis, and L. panamensis, with L. donovani being most susceptible and L. braziliensis being least susceptible. The proposed mechanism by which the drug exerts its antiprotozoan activity includes interacting with Leishmania phospholipids/sterols (including membrane lipids), and inhibiting the mitochondrial cytochrome c oxidase enzyme; thus resulting in apoptosis-like cell death. Miltefosine requires transportation into the cell via protein complexes on the plasma membrane. Resistance (intrinsic and acquired) may occur with reduced concentrations of these translocation proteins or from increased concentrations of drug efflux pumps; both will result in decreased accumulation of the drug within the parasite.
Miltefosine is administered orally. Following administration, it is widely distributed with 98% bound to plasma protein. Miltefosine is not a substrate for the cytochrome P450 (CYP) enzymes; instead, it undergoes a slow metabolic breakdown by phospholipase D-like cleavage to release choline and hexadecanol. The choline metabolite is incorporated into tissues, while hexadecanol is oxidized to form palmitic acid. The terminal half-life is approximately 30 days, with < 0.2% of the daily dose excreted unchanged in the urine.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of oral miltefosine has not been determined. In many patients, maximum plasma concentrations are achieved just prior to the next dose, suggesting absorption continues throughout the entire dosing interval. In addition, because of the long half-life, plasma concentrations do not reach steady-state during the 28 day treatment period.
-Special Populations
Hepatic Impairment
The pharmacokinetics of miltefosine have not been evaluated in patients with hepatic impairment.
Renal Impairment
The pharmacokinetics of miltefosine have not been evaluated in patients with renal impairment.