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    Agents for Leishmaniasis and Trypanosomiasis

    BOXED WARNING

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Miltefosine is associated with reproductive risk. Conduct urine or serum pregnancy testing before prescribing miltefosine to females of reproductive potential. In addition, discuss contraception requirements with these females; effective contraception must be used during and for 5 months after completion of miltefosine therapy. Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, instruct females who experience such reactions to use additional or alternative non-hormonal methods of contraception. Additionally, advise patients of animal fertility findings and that the potential for infertility with miltefosine therapy in humans has not been studied. Scrotal pain and decreased or absent ejaculation have been reported by male recipients of miltefosine. Data from animal studies suggest a potential for infertility in both males and females. In rats, impaired fertility that did not fully reverse was observed in both females and males at doses 0.4 to 1 times the maximum recommended human dose (MRHD). At these same doses, male rats also experienced reduced viable sperm counts and testicular atrophy. Female dogs administered doses of 0.2 times MRHD, experienced reversible follicular atresia and diestrus.

    DEA CLASS

    Rx

    DESCRIPTION

    Alkyllysophospholipid analog indicated for visceral, mucosal, and cutaneous leishmaniasis
    First drug to receive FDA-approval for all three infections
    Contraindicated during pregnancy; contraception required during/5 months after therapy

    COMMON BRAND NAMES

    IMPAVIDO

    HOW SUPPLIED

    IMPAVIDO Oral Cap: 50mg

    DOSAGE & INDICATIONS

    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.[56867]
    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.[34362] [56867] [63762]

    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.[34362] [56867] [63762]

    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.[34362] [56867] [63245] [63762]

    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.[34362] [56867] [63245] [63762]

    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.[63762] [64598] [64600] [64601] [64602] 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).[64597] [64598] [64599]

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.
     

    Renal Impairment

    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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer with a meal.
    Swallow capsule whole.

    STORAGE

    IMPAVIDO:
    - Dispense in original container or USP equivalent tight container
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Miltefosine is classified as FDA pregnancy category D. Miltefosine may cause fetal harm and is contraindicated for use during pregnancy. In animal studies, fetal death and teratogenicity occurred in rats and rabbits administered oral doses that were 0.06 and 0.2 times the maximum recommended human dose (MRHD), respectively. Although studies have not been conducted in pregnant humans, information obtained from animal studies suggests the potential risk to the fetus outweighs the potential benefit of treatment. However, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes. In addition, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions during pregnancy, and may be associated with increased risk for adverse fetal outcomes.

    Breast-feeding

    It is not known if miltefosine is excreted in human milk. Because many drugs are present in human milk and because of the potential for adverse reactions in breast-feeding infants from miltefosine, discontinue breast-feeding or discontinue miltefosine, taking into consideration the importance of the drug to the mother. Avoid breast-feeding for 5 months after miltefosine therapy.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Miltefosine is associated with reproductive risk. Conduct urine or serum pregnancy testing before prescribing miltefosine to females of reproductive potential. In addition, discuss contraception requirements with these females; effective contraception must be used during and for 5 months after completion of miltefosine therapy. Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, instruct females who experience such reactions to use additional or alternative non-hormonal methods of contraception. Additionally, advise patients of animal fertility findings and that the potential for infertility with miltefosine therapy in humans has not been studied. Scrotal pain and decreased or absent ejaculation have been reported by male recipients of miltefosine. Data from animal studies suggest a potential for infertility in both males and females. In rats, impaired fertility that did not fully reverse was observed in both females and males at doses 0.4 to 1 times the maximum recommended human dose (MRHD). At these same doses, male rats also experienced reduced viable sperm counts and testicular atrophy. Female dogs administered doses of 0.2 times MRHD, experienced reversible follicular atresia and diestrus.

    Renal impairment

    Treatment with miltefosine has been associated with elevated serum creatinine (Scr). All patients should have renal function monitored weekly during treatment and for 4 weeks after completion of therapy. Use with caution in patients with renal dysfunction as individuals with pre-existing renal impairment (i.e., Scr and/or BUN >= 1.5x upper limits of normal) were excluded from clinical trials.

    Hepatic disease

    Treatment with miltefosine has been associated with elevated liver transaminases and bilirubin. All patients should have liver function tests and bilirubin concentrations monitored during therapy. Use with caution in patients with hepatic disease as individuals with pre-existing hepatic impairment (i.e., ALT/AST >= 3x upper limits of normal, bilirubin >= 2x upper limits of normal) were excluded from clinical trials.

    Dehydration

    Some patients may experience dehydration resulting for miltefosine induced vomiting and/or diarrhea. Encourage adequate fluid intake to avoid volume depletion.

    Thrombocytopenia

    Cases of thrombocytopenia have been reported in patients receiving treatment with miltefosine for visceral leishmaniasis. Health care providers are advised for monitor platelet counts in patients receiving treatment for this indication.

    Serious rash

    Serious rash, including Stevens-Johnson syndrome, have been noted in recipients of miltefosine. Instruct patients to discontinue use of the drug if sign of an exfoliative or bullous rash develop during therapy.

    ADVERSE REACTIONS

    Severe

    Stevens-Johnson syndrome / Delayed / 0-2.0
    seizures / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0-50.0
    thrombocytopenia / Delayed / 2.4-2.4
    dysphagia / Delayed / 0-2.0
    constipation / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    lymphadenopathy / Delayed / 0-2.0
    testicular swelling / Early / 0-2.0
    melena / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known

    Mild

    nausea / Early / 35.9-41.7
    vomiting / Early / 4.5-37.8
    headache / Early / 28.1-28.1
    diarrhea / Early / 7.9-20.4
    dizziness / Early / 4.5-12.5
    abdominal pain / Early / 7.5-11.2
    asthenia / Delayed / 6.3-6.3
    pruritus / Rapid / 4.5-5.8
    fever / Early / 5.6-5.6
    malaise / Early / 3.4-3.4
    drowsiness / Early / 3.4-3.4
    flatulence / Early / 0-2.0
    fatigue / Early / 0-2.0
    paresthesias / Delayed / 0-2.0
    urticaria / Rapid / 0-2.0
    rash / Early / 0-2.0
    testicular pain / Early / 0-2.0
    epistaxis / Delayed / Incidence not known
    decreased ejaculate volume / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    Danaparoid: (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.
    Desirudin: (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.
    Dienogest; Estradiol valerate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Drospirenone: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Drospirenone; Estradiol: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Drospirenone; Ethinyl Estradiol: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of 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.
    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; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Estradiol; Norethindrone: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Estradiol; Norgestimate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Desogestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norethindrone: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norgestimate: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Ethinyl Estradiol; Norgestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of 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.
    Lepirudin: (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; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Levonorgestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Mestranol; Norethindrone: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Norethindrone: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Norgestrel: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Oral Contraceptives: (Moderate) Miltefosine induced vomiting and/or diarrhea may affect absorption of oral contraceptives; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of 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.
    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; therefore, females who experience such reactions should be instructed to use additional/alternative non-hormonal methods of contraception.
    Tinzaparin: (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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Miltefosine is classified as FDA pregnancy category D. Miltefosine may cause fetal harm and is contraindicated for use during pregnancy. In animal studies, fetal death and teratogenicity occurred in rats and rabbits administered oral doses that were 0.06 and 0.2 times the maximum recommended human dose (MRHD), respectively. Although studies have not been conducted in pregnant humans, information obtained from animal studies suggests the potential risk to the fetus outweighs the potential benefit of treatment. However, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes. In addition, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions during pregnancy, and may be associated with increased risk for adverse fetal outcomes.

    It is not known if miltefosine is excreted in human milk. Because many drugs are present in human milk and because of the potential for adverse reactions in breast-feeding infants from miltefosine, discontinue breast-feeding or discontinue miltefosine, taking into consideration the importance of the drug to the mother. Avoid breast-feeding for 5 months after miltefosine therapy.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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

    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.