1) COMMON: The most frequently reported adverse events include: nausea, vomiting, diarrhea, headache, decreased appetite, dizziness, abdominal pain, elevated transaminases and elevated serum creatinine.
2) LESS FREQUENT: Asthenia, malaise, pyrexia, pruritus, somnolence and lymphangitis have been reported during miltefosine therapy.
3) SERIOUS: Grade 4 hyperbilirubinemia (ie, greater than or equal to 10 times the upper limit of normal), thrombocytopenia, Stevens-Johnson syndrome, Grade 4 diarrhea (greater than 10 stools/day), and melena have led to drug cessation during miltefosine therapy.
4) POSTMARKETING EXPERIENCE: Agranulocytosis, melena, generalized and/or peripheral edema, jaundice, seizure, and epistaxis have been reported.

1) OVERDOSE: Overdose has not been reported. Clinical events following exposure are anticipated to be an extension of adverse events reported.
2) MILD TO MODERATE TOXICITY: Gastrointestinal events (ie, nausea, vomiting, diarrhea) are likely to occur.
3) SEVERE TOXICITY: Significant dehydration, electrolyte imbalance and possible impaired renal function may develop as a result of severe, persistent gastrointestinal events. Elevated liver enzymes may occur. Alterations in CBC (ie, thrombocytopenia and agranulocytosis) may develop.

1) Fever has been reported during miltefosine therapy.

1) Treatment is symptomatic and supportive. Significant toxicity is not anticipated. Gastrointestinal events (ie, vomiting and diarrhea) are likely to occur. Monitor fluid and serum electrolytes as indicated. Replace fluids (ie, oral fluids; administer intravenous fluids as needed) and electrolytes as necessary.

1) Treatment is symptomatic and supportive. Severe toxicity is not anticipated. Correct any significant electrolyte abnormalities in patients with severe vomiting and/or diarrhea. Thrombocytopenia may occur. Monitor CBC and platelet count. For severe thrombocytopenia, administer platelets, packed red cells as necessary. Monitor renal function and liver enzymes as indicated.

1) PREHOSPITAL: Prehospital activated charcoal should be avoided, due to the likely development of vomiting following exposure.
2) HOSPITAL: Consider activated charcoal if the overdose is recent and the patient is not vomiting or other significant coingestants are suspected and the airway is protected.

1) Airway management is unlikely to be necessary unless more toxic agents are involved.

1) There is no known antidote.

1) Miltefosine is highly protein bound (98%) and widely distributed; therefore, hemodialysis is UNLIKELY to be effective.

1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. An asymptomatic child with an inadvertent ingestion (1 tablet) or mild gastrointestinal symptoms can be monitored at home with adult supervision.
2) OBSERVATION CRITERIA: Patients that have more than mild gastrointestinal symptoms or who had a deliberate ingestion should be referred to a healthcare facility for evaluation and treatment.
3) ADMISSION CRITERIA: Patients that develop persistent signs or symptoms of significant dehydration or electrolyte imbalance or other toxicity should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.

1) Absolute bioavailability of miltefosine has not been determined. A mean Cmax of 66.2 mcg/mL was achieved at a median Tmax of 7 hours (range, 2 to 12 hours) after administration of miltefosine 50 mg orally twice daily for 4 weeks in adults and adolescents (12 years or older) with visceral leishmaniasis. Protein binding was 98% over concentrations of 0.1 to 10 mcg/mL. In animal studies, radioactivity of miltefosine is widely distributed after single and repeated oral administration with the highest uptake observed in the kidneys, liver and spleen. In visceral leishmaniasis patients, less than 0.2% of a dose was excreted in the urine. Half-life is greater than 6 days after administrations of 50 mg of miltefosine orally twice daily for 4 weeks in adults and adolescents with visceral leishmaniasis, and half-life was further prolonged (8.5 days) in patients receiving 50 mg for 1 week or 50 mg 3 times daily for 3 weeks. Miltefosine undergoes a slow metabolic breakdown in human hepatocytes by phospholipase D-like cleavage into an inactive choline and a fatty alcohol-containing remnant. No oxidative metabolism of miltefosine was observed in in-vitro studies with 15 different human CYP450 enzymes.

1) Fever has been reported during miltefosine therapy.

1) Fever has been reported during miltefosine therapy in the treatment of cutaneous leishmaniasis (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) Motion sickness was reported in 29.2% of 89 patients with cutaneous leishmaniasis administered miltefosine during a placebo-controlled trial receiving 2.5 mg/kg/day for 28 days, compared to 22.7% of those treated with placebo (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) During animal studies, administration of miltefosine greater than or equal to 1.2 mg/kg/day (approximately 0.06 times the maximum recommended human dose (MRHD)) during early embryonic development (gestation day 6 to day 15) in rats resulted in embryofetal toxicity, including teratogenicity (ie, undeveloped cerebrum, hemorrhagic fluid in the lumina of the skull, generalized edema, and cleft palate) and death. Administration of oral miltefosine greater than or equal to 2.4 mg/kg/day (approximately 0.2 times the MRHD) in rabbits during organogenesis (gestation day 6 to day 18) also resulted in embryofetal toxicity. There were no reports of viable litters in either rats or rabbits at miltefosine doses greater than or equal to 6 mg/kg/day (approximately 0.3 or 0.6 times the MRHD, respectively). In a separate fertility study, miltefosine doses greater than or equal to 6.81 mg/kg/day (approximately 0.3 times the MRHD), administered to rats for 4 weeks prior to mating through gestation day 7 resulted in numerous visceral (eg, misshapen cerebral structure, dilated ventricles filled with brown masses, misshapen spinal cord) and skeletal (eg, cleft palate, markedly enlarged skull bones) fetal malformations (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) Human pregnancy data for miltefosine are not available (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) Miltefosine is classified as FDA pregnancy category D (Prod Info IMPAVIDO(R) oral capsules, 2014).
2) Visceral leishmaniasis may be life-threatening for pregnant women and may result in adverse effects for the fetus. This may include spontaneous abortion, congenital disease (due to vertical transmission), small gestational age, or severe anemia. Cutaneous leishmaniasis may also manifest during pregnancy resulting in adverse fetal effects, including preterm birth and stillbirth. Due to the potential for harm, the use of miltefosine during human pregnancy should be avoided. Verify pregnancy status prior to treatment initiation and instruct female patients of reproductive potential to use effective contraception during treatment and for at least 5 months after discontinuation (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) Lactation studies with miltefosine have not been conducted. It is not known whether miltefosine is present in human milk. Because many drugs are known to be present in human milk and due the potential for adverse effects in a nursing infant, the manufacturer recommends discontinuing drug or discontinuing nursing, taking into account the importance of the drug to the mother. Avoid breastfeeding for at least 5 months following miltefosine use (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) Human male and female fertility data are not available (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) In rats, miltefosine impaired male and female fertility. It caused reduced viable sperm counts and impaired male fertility in rats at doses approximately 0.4 times the maximum recommended human dose (MHRD). In rats administered doses of approximately 1 times the MRHD, testicular atrophy and impaired fertility were observed and did not fully reverse 10 weeks after drug cessation. In dogs, reversible follicular atresia and diestrus was observed at 0.2 times the maximum recommended human dose (MRHD). Impaired fertility was observed in female rats at doses of 1 times the MHRD (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) At the time of this review, human carcinogenicity studies have not been conducted. The carcinogenic potential of miltefosine in humans is unknown (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) In rats, testicular Leydig cell adenoma occurred in 3 of 30 male rats administered miltefosine at doses of 21.5 mg/kg/day (1 time the maximum human recommended dose (MRHD) based on BSA comparison) (Prod Info IMPAVIDO(R) oral capsules, 2014).

A) Patients that develop persistent signs or symptoms of significant dehydration and/or electrolyte imbalance or other toxicity should be admitted.

A) Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. An asymptomatic child with an inadvertent ingestion (1 tablet) or mild gastrointestinal symptoms can be monitored at home with adult supervision.

A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.

A) Patients that have more than mild gastrointestinal symptoms or who had a deliberate ingestion should be referred to a healthcare facility for evaluation and treatment.

1) Prehospital activated charcoal should be avoided, due to the likely development of vomiting following exposure.

1) Consider activated charcoal if the overdose is recent or other significant coingestants are suspected and the airway is protected.

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Significant toxicity is not anticipated. Gastrointestinal events (ie, vomiting and diarrhea) are likely to occur. Monitor fluid and serum electrolytes as indicated. Replace fluids (ie, oral fluids; administer intravenous fluids as needed) and electrolytes as necessary.
2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Severe toxicity is not anticipated. Correct any significant electrolyte abnormalities in patients with severe vomiting and/or diarrhea. Thrombocytopenia may occur. Monitor CBC and platelet count. For severe thrombocytopenia, administer platelets, packed red cells as necessary. Monitor renal function and liver enzymes as indicated.

1) Monitor serum electrolytes and fluid volume in patients with significant vomiting and/or diarrhea.
2) Monitor renal function and liver enzymes following a significant exposure or as indicated.
3) Monitor CBC and platelet count following a significant overdose; repeat as necessary.
4) Due to the risk of fetal harm, obtain a urine or serum pregnancy test following an inadvertent or intentional exposure in a female of childbearing age.
5) Plasma concentrations are not readily available or clinically useful in the management of overdose.

1) 30 to 44 kg: A 50 mg capsule twice daily with food (ie, breakfast and dinner) for 28 consecutive days (Prod Info IMPAVIDO(R) oral capsules, 2014).
2) 45 kg or greater: A 50 mg capsule 3 times daily with food (ie, breakfast, lunch and dinner) for 28 consecutive days (Prod Info IMPAVIDO(R) oral capsules, 2014).

1) 30 to 44 kg: A 50 mg capsule twice daily with food (ie, breakfast and dinner) for 28 consecutive days (Prod Info IMPAVIDO(R) oral capsules, 2014).
2) 45 kg or greater: A 50 mg capsule 3 times daily with food (ie, breakfast, lunch and dinner) for 28 consecutive days (Prod Info IMPAVIDO(R) oral capsules, 2014).