miltefosine


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miltefosine

(mil-te-fos-een),

Impavido

(trade name)

Classification

Therapeutic: temporary class
Pharmacologic: temporary class
Pregnancy Category: D

Indications

Treatment visceral leishmaniasis, cutaneous leishmaniasis and mucocal leishmanisis in adults and adolescents.

Action

Interacts with lipids and sterols in the Leismania membrane resulting in inhibition of mitochondria and apoptotic cell death.

Therapeutic effects

Resolution of Leismania infections.

Pharmacokinetics

Absorption: Absorption is prolonged and may persist for 8–12 hr.
Distribution: Unknown.
Protein Binding: 98%.
Metabolism and Excretion: Slowly broken in the liver, releasing choline; remaining portion is further metabolized and enters fatty acid metabolism ; <0.2% excreted in urine.
Half-life: >6 days.

Time/action profile

ROUTEONSETPEAKDURATION
POunknown4–7 hr (blood level)unknown†
† Persists in the body for up to 5 mos.

Contraindications/Precautions

Contraindicated in: Hypersensitvity; Sjögren-Larsson-Syndrome (due to metabolic defect); Obstetric: Pregnancy (may cause fetal harm); Obstetric: Discontinue miltefosine or discontinue breastfeeding during treatment and for 5 mos following treatment.
Use Cautiously in: Renal impairment (BUN or Cr ≥1.5 x upper limit of normal); Hepatic impairment (ALT or AST ≥3 x upper limit of normal); Patients with reproductive potential..) Pediatric: Safe and effective use in children <12 yr has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • drowsiness
  • headache
  • weakness

Gastrointestinal

  • abdominal pain (most frequent)
  • ↓ appetite (most frequent)
  • diarrhea (most frequent)
  • vomiting (most frequent)
  • abdominal distention
  • constipation
  • dysphagia
  • flatulence
  • ↑ liver enzymes
  • nausea

Genitourinary

  • ↑ creatinine
  • testicular pain/swelling

Dermatologic

  • pruritus
  • rash including Stevens-Johnson Syndrome (life-threatening)
  • urticaria

Fluid and Electrolyte

  • volume depletions (due to GI effects)

Hematologic

  • anemia
  • thrombocytopenia

Miscellaneous

  • fever
  • lymphadenopathy
  • lymphangitis
  • malaise

Interactions

Drug-Drug interaction

May ↓ absorption and effectiveness of oral hormonal contraceptives..

Route/Dosage

Oral (Adults and adolescents ≥45 kg) 50 mg three times daily for 28 consecutive days.
Oral (Adults and adolescents 30–44 kg) 50 mg twice daily for 28 consecutive days.

Availability

Capsules: 50 mg

Nursing implications

Nursing assessment

  • Assess visible lesions periodically during therapy.
  • Monitor for vomiting and diarrhea. Encourage fluid intake to avoid dehydration.
  • Lab Test Considerations: Obtain a negative urine pregnancy test prior to beginning therapy.
    • Monitor renal function weekly and for 4 wks after completion of therapy. May ↑ serum creatinine.
    • Monitor AST, ALT, and serum bilirubin periodically during therapy. May cause ↑ in AST, ALT, and bilirubin.
    • Monitor platelet count periodically during therapy. May cause thrombocytopenia and agranulocytosis.

Potential Nursing Diagnoses

Impaired skin integrity (Indications)
Deficient knowledge, related to disease process and medication regimen (Patient/Family Teaching)

Implementation

  • Administer with food to decrease GI side effects for 28 consecutive days. Swallow capsule whole; do not open, dissolve or chew.

Patient/Family Teaching

  • Instruct patient to take miltefosine as directed for 28 consecutive days. Advise patient to read the Medication Guide before beginning therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional immediately if skin rash with blisters occurs. Discontinue therapy if exfoliative or bullous rash occurs.
  • May cause dizziness and drowsiness. Caution patient to avoid driving and other activities requiring alertness until response t medication is known.
  • Instruct patient to notify healthcare professional if abdominal pain, nausea, vomiting, or diarrhea are persistent or severe. Advise to maintain hydration to prevent kidney damage.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Caution patient that miltefosine may cause teratogenic effects during pregnancy and may impair fertility. Advise female patient to use effective contraception during and for at least 5 mo after completion of therapy. Nausea and vomiting may decrease absorption of hormonal contraceptives. Advise patient to use a non-hormonal or alternative method of effective contraception. May cause scrotal pain and decreased or absent ejaculation in males. Advise females to avoid breastfeeding during and for at least 5 mo after completion of therapy.

Evaluation/Desired Outcomes

  • Resolution of signs and symptoms of leishmaniasis.

miltefosine

An oral alkyl phosphocholine analogue used to treat cutaneous and visceral leishmaniasis.

Adverse events
Nausea, vomiting, diarrhoea, rigors, increased transaminases, grade-III hepatotoxicity and renal damage.

Mechanism
Miltefosine interferes with cell-signalling pathways and membrane synthesis of Leishmania donovani and L infantum, as well as with mitogenic signal transduction; it also induces apoptosis. It has been used in treating HIV disease because miltefosine inhibits the PI3K/Akt pathway, removing HIV-infected macrophages from circulation without affecting normal cells.
References in periodicals archive ?
However, appropriate therapy is not well defined; success has been sparsely reported with the simultaneous use of azoles, flucytosine, pentamidine, sulfazidine, macrolide antimicrobial drugs, phenothiazines, and miltefosine (2,7,10).
The seven new anti-infectives and their indications are dalbavancin (Dalvance) for treatment of skin infections caused by gram-positive organisms; efinaconazole (Jublia), for treatment of fungal infections of the toenails; miltefosine (Impavido) for treatment of visceral, cutaneous, and mucosal infections by various Leishmania species; oritavancin (Orbactiv) for skin infections caused by gram-positive bacteria; peramivir (Rapivab), for acute uncomplicated influenza; tavaborole (Kerydin) for treatment of fungal infections of the toenails; and tedizolid (Sivextro) for treatment of bacterial skin infections.
Although miltefosine caused severe toxicity in two animal species, visceral and cutaneous leishmaniasis may be life threatening for the mother and can cause severe developmental toxicity in the embryo and fetus, so the drug should not be withheld in pregnancy.
Other drugs such as pentamidine, amphotericin B and miltefosine have limited use due to their high cost, severe side effects or resistance (Sanchez-Canete et al.
New treatment approach in Indian visceral leishmaniasis: Single-dose liposomal amphotericin B followed by short-course oral miltefosine.
From case detection and management to implementation of new treatment modalities, including liposomal amphotericin B (AmBisome) in monotherapy and several combination therapies - with AmBisome, miltefosine, and paromomycin - the project covers primary and secondary healthcare levels in the public, not-for-profit, and private sectors.
The infected culture was seeded onto 384-well plates and incubated in the presence of serially diluted miltefosine or amphotericin B, as positive control, and in the absence of drugs, as negative control.
A parenteral formulation of the aminoglycoside paromomycin (aminosidine) and the orally available alkylphospholipid miltefosine are also potential treatments for VL (Sundar 2003).
Clinical tests in India are proving encouraging for miltefosine and paromomycin, but these results have yet to be finalized for registration.
Within this ambitious, multi-faceted project, OneWorld Health will investigate the use of combination therapies with miltefosine, paromomycin and AmBisome[R] in the private sector in India to control and support VL elimination.
As positive controls, Glucantime was purchased from Aventis, and Miltefosine was kindly provided by /Eterna Zentaris Inc.