miltefosine (Rx)

>10%

Visceral leishmaniasis

• Increased transaminases, <3 x ULN (94%)
• Decreased platelets <150,000 (62%)
• Vomiting (37.8%)
• Decreased appetite (23.1%)
• Diarrhea (20.4%)

Cutaneous leishmaniasis

• Nausea (35.9-41.7%)
• Motion sickness (29.2%)
• Headache (28.1%)
• Vomiting (4.5-27.5%)
• Increased serum creatinine, 1.5-3 x baseline (25%)
• Diarrhea (15%) Dizziness (4.5-12.5%)
• Abdominal pain (7.5-11.2%)
• Decreased appetite (10.8%)

1-10%

Visceral leishmaniasis

• Increased serum creatinine, ≥1.5 x baseline (10%)
• Asthenia (6.3%)
• Increased transaminases, 3-5 x ULN (6%)
• Decreased platelets <50,000 (2.4%)

Cutaneous leishmaniasis

• Diarrhea (7.9%)
• Lymphangitis (5.8%)
• Pyrexia (5.6%)
• Pruritus (4.5-5.8%)
• Malaise (3.4%)
• Somnolence (3.4%)

Postmarketing Reports

Blood and lymphatics disorders: Thrombocytopenia, agranulocytosis

GI disorders: Melena

General disorders: Generalized edema, peripheral edema

Hepatobiliary disorders: Jaundice

Nervous system disorders: Seizure

Reproductive system and breast disorders: Scrotal pain, decreased ejaculate volume, absent ejaculation

Vascular disorders: Epistaxis

Contraindications

Pregnancy (see Black Box Warnings)

SjÖgren-Larsson syndrome

Hypersensitivity

Cautions

May cause fetal harm; do not use during pregnancy or become pregnancy within 5 months following therapy completion (see Black Box Warnings)

Causes impaired fertility in rats and reversible follicular atresia and diestrus in dogs; reduced viable sperm counts and impaired fertility in rats; effects on human fertility have not been studied

Vomiting and/or diarrhea commonly occur; encourage fluid intake to avoid volume depletion

Vomiting and/or diarrhea occurring during therapy may affect oral contraceptive absorption and thereby compromise their efficacy; advise females to use additional nonhormonal or alternative method(s) of effective contraception

Increased serum creatinine, ALT, AST, bilirubin reported; monitor

Thrombocytopenia reported; monitor platelets

Stevens-Johnson syndrome reported; discontinue if an exfoliative or bullous rash occurs

Pregnancy

There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to IMPAVIDO during pregnancy; Healthcare providers are encouraged to register patients by calling 1-866-588-5405 or vising online at http://www.impavido.com/mother-registry

Contraindicated during pregnancy; based on data from animal reproduction studies, therapy may cause embryo-fetal toxicity when administered to pregnant women; there are no available data on use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal and/or fetal outcomes

If a woman becomes pregnant while being treated, treatment should be discontinued and the patient counseled about potential risk to the fetus

Embryo-fetal toxicity, including death and fetal malformations, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD) of 3.33 mg/kg/day

Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD

Verify pregnancy status prior to initiating therapy in females of reproductive potential

Advise females of reproductive potential to use effective contraception during treatment and for 5 months after last dose

Vomiting and/or diarrhea occurring during therapy may affect absorption of oral contraceptives and therefore compromise their efficacy

If vomiting and/or diarrhea occur during therapy, advise females to use an additional non-oral method of effective contraception

Infertility

• Females

  • Based on animal fertility studies, therapy may impair fertility in females of reproductive potential
  • The effects of therapy on human female fertility have not been formally studied

• Males

  • Based on animal fertility and postmarketing studies, therapy may impair fertility in males of reproductive potential
  • In an open-label, uncontrolled, single-center study that assessed the effects of the drug on sperm parameters; treatment was associated with reductions in all sperm parameters at the end of treatment; all sperm parameters, except for sperm concentration, recovered on follow-up assessments at 3 and 6 months after treatment completion; for sperm concentration, small mean decreases persisted on follow-up assessments at 3 and 6 months after treatment completion
  • No clinically meaningful changes were observed in serum testosterone or FSH concentrations
  • Reductions in ejaculate volume and temporary absence of ejaculate were reported in an observational study of male patients who received the therapy; these adverse reactions resolved in all patients in this study upon completion of therapy
  • The effect of therapy on spermatogenesis may persist for an unknown duration; whether therapy affects male fertility is unknown

Lactation

There are no data on presence of miltefosine in human or animal milk, the effects on breastfed infants or on milk production; because of the potential for serious adverse reactions, breastfeeding is not recommended during treatment and for 5 months after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Specific mode of action against Leishmania species is unknown; the mechanism is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome C oxidase (mitochondrial function), and apoptosislike cell death

Absorption

Absolute bioavailability not determined

Distribution

Protein bound: >98%

Metabolism

Metabolized by phospholipase D to choline, which is incorporated into tissues, and hexadecanol, which is oxidized to palmitic acid

Not a substrate, inhibitor, or inducer of CYP450 enzymes

Elimination

Excretion: Urine, <0.2% of administered dose

Oral Administration

Administer with meals to decrease GI adverse effects

Swallow capsule whole; do not chew or break apart

Instruct patient to complete full course of therapy