Miltefosine

Approved Indications

• Visceral Leishmaniasis (VL):
  Miltefosine is indicated for the treatment of visceral leishmaniasis (kala-azar) caused by Leishmania donovani in adults and adolescents aged 12 years and older.
• Cutaneous Leishmaniasis (CL):
  Approved for treatment of cutaneous leishmaniasis due to Leishmania braziliensis, L. guyanensis, and L. panamensis.
• Mucosal Leishmaniasis (ML):
  Indicated for mucosal leishmaniasis caused by Leishmania braziliensis.

Clinically Accepted Off-label Uses

• Post-Kala-Azar Dermal Leishmaniasis (PKDL):
  Used in endemic regions as part of combination therapy with other antileishmanial agents.
• Primary Amoebic Meningoencephalitis (PAM):
  Used off-label, often in combination with other antimicrobials, for treatment of Naegleria fowleri infections.
• Disseminated Acanthamoeba and Balamuthia Infections:
  Used as salvage therapy in severe amoebic CNS infections in combination regimens.

Adults and Adolescents (≥12 years and ≥45 kg)

• Dose: 50 mg orally three times daily for 28 consecutive days.

Adults or Adolescents <45 kg

• Dose: 2.5 mg/kg/day, divided into two or three doses daily, for 28 days.

Pediatrics (<12 years)

• Not approved. Use only in clinical research or under special protocols.

Elderly

• Same dosing as adults. Monitor renal and hepatic function during therapy.

Renal Impairment

• Contraindicated in severe renal impairment.
• Use with caution in mild-to-moderate impairment; monitor serum creatinine regularly.

Hepatic Impairment

• Contraindicated in severe hepatic impairment.
• Use with caution in mild cases; monitor liver enzymes regularly.

Administration Instructions

• Take with food to reduce gastrointestinal side effects.
• Swallow tablets whole with water. Do not crush or chew.
• If vomiting occurs within 30 minutes, repeat the dose.

Miltefosine is an alkylphosphocholine compound that exerts antiprotozoal effects primarily by disrupting cell membrane function in Leishmania parasites. It inhibits phosphatidylcholine biosynthesis and interferes with lipid-dependent signaling pathways, including protein kinase C. Miltefosine accumulates in parasite mitochondria, inducing mitochondrial dysfunction and apoptosis-like cell death. Its immunomodulatory activity also enhances host macrophage responses, aiding in parasite clearance.

• Absorption:
  Oral bioavailability is approximately 82%; absorption improves with food.
• Time to Peak (Tmax): 4–8 hours after dosing.
• Distribution:
  Large volume of distribution (~1,000 L); low plasma protein binding; widely distributed in tissues.
• Metabolism:
  Minimal metabolism; not significantly processed by cytochrome P450 enzymes.
• Elimination:
  Primarily excreted unchanged in urine and feces.
  Half-life: ~6–8 days
  Steady state achieved in 7–10 days.

• Pregnancy:
  FDA Category D – Contraindicated in pregnancy due to teratogenicity observed in animal studies.
  A negative pregnancy test is required before starting therapy.
  Effective contraception is mandatory during treatment and for 5 months after the last dose.
• Lactation:
  It is unknown if miltefosine is excreted in human milk.
  Breastfeeding is not recommended during treatment due to the potential for serious adverse effects in infants.

• Primary Class: Antiprotozoal Agent
• Subclass: Oral Alkylphosphocholine Antileishmanial

• Known hypersensitivity to miltefosine or any excipients
• Pregnancy or women planning to become pregnant
• Breastfeeding
• Severe renal or hepatic impairment
• Inability to adhere to effective contraception (for women of childbearing potential)
• Use in children under 12 years (in the U.S. and many regions)

• Teratogenicity:
  Miltefosine can cause fetal harm. Pregnancy must be excluded before therapy and prevented during and after treatment.
• Gastrointestinal Effects:
  Commonly causes nausea, vomiting, diarrhea, and abdominal pain. Advise patients to take with meals.
• Renal & Hepatic Monitoring:
  Regular monitoring of liver enzymes and serum creatinine is advised throughout treatment.
• QT Interval Prolongation:
  Use cautiously with other QT-prolonging agents; baseline ECG recommended in at-risk patients.
• Eye Toxicity:
  Rare reports of blurred vision and optic disorders. Discontinue therapy if visual symptoms develop.
• Adherence Issues:
  Long half-life may contribute to resistance if doses are missed. Full course must be completed.

Common Adverse Effects:

• Gastrointestinal:
  Nausea, vomiting, abdominal discomfort, diarrhea, anorexia
• Neurological:
  Headache, dizziness, fatigue
• Dermatological:
  Rash, pruritus

Serious or Rare Adverse Effects:

• Hepatotoxicity (elevated AST/ALT)
• Nephrotoxicity (elevated creatinine, BUN)
• Blurred vision or visual disturbance
• QT prolongation (rare)
• Teratogenic effects in pregnancy
• Hypersensitivity reactions

• QT-Prolonging Drugs (e.g., macrolides, fluoroquinolones, antipsychotics):
  Additive risk of QT prolongation.
• Nephrotoxic Agents (e.g., amphotericin B, aminoglycosides):
  Increased risk of renal toxicity.
• Hormonal Contraceptives:
  Miltefosine may reduce their effectiveness. Use barrier contraception in addition.
• Enzyme System Interactions:
  Minimal involvement with CYP450 enzymes.
  Does not induce or inhibit major CYP isoenzymes.

• WHO Guidelines (2023–2024):
  Miltefosine remains a key oral agent for VL, CL, and ML, particularly in combination regimens to reduce relapse and resistance.
• CDC Recommendations:
  Included in the U.S. CDC guidelines for leishmaniasis and investigational use in free-living amoebae infections such as Naegleria fowleri.
• Clinical Trials:
  Ongoing pediatric studies aim to extend approval for children under 12 years.
  Emerging data support expanded use in amoebic encephalitis cases.

• Temperature:
  Store at 25°C (77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F).
• Humidity:
  Store in a dry environment. Protect from excessive humidity.
• Light Protection:
  Keep tablets in original blister pack to protect from light exposure.
• Handling Precautions:
• Do not use if tablets are broken or damaged.
• No refrigeration or reconstitution needed.
• Keep out of reach of children and pregnant individuals.