miltefosine

Action and Spectrum

Actions and Spectrum: 

• miltefosine is an antiparasitic drug primarily used to treat leishmaniasis, a parasitic infection caused by various Leishmania parasites. The mechanism of action of miltefosine has yet to be entirely understood. Still, it is thought to work by interfering with the parasite’s cell membrane integrity, leading to apoptosis (programmed cell death) of the parasite. 

• miltefosine has a broad spectrum of activity against various Leishmania species, including L. donovani, L. infantum, and L. braziliensis, which are responsible for visceral, cutaneous, and mucocutaneous forms of leishmaniasis, respectively. In addition to leishmaniasis, miltefosine has also shown activity against other parasitic infections, such as Chagas disease, caused by Trypanosoma cruzi, and amoebic dysentery caused by Entamoeba histolytica. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Cutaneous leishmaniasis 

Motion sickness (29.2%) 

Vomiting (4.5-27.5%) 

Diarrhea (15%) Dizziness (4.5-12.5%) 

Decreased appetite (10.8%) 

Headache (28.1%) 

Increased serum creatinine, 1.5-3 x baseline (25%) 

Abdominal pain (7.5-11.2%) 

Nausea (35.9-41.7%)  

Visceral leishmaniasis 

Decreased platelets <150,000 (62%) 

Decreased appetite (23.1%) 

Increased transaminases, <3 x ULN (94%) 

Vomiting (37.8%) 

Diarrhea (20.4%)  

1-10% 

Cutaneous leishmaniasis 

Lymphangitis (5.8%) 

Pruritus (4.5-5.8%) 

Somnolence (3.4%) 

Diarrhea (7.9%) 

Pyrexia (5.6%) 

Malaise (3.4%)  

Post-marketing reports 

Melena 

Agranulocytosis 

Peripheral edema 

Thrombocytopenia 

Jaundice 

Scrotal pain 

Epistaxis 

Decreased ejaculate volume 

Generalized edema 

Seizure 

Absent ejaculation 

Black Box Warning

Black box warning: 

• miltefosine is related to its potential to cause fetal harm. miltefosine is classified as Pregnancy Category D, meaning that it has been shown to pose a risk to the developing fetus based on human or animal data. Women who are pregnant or who may become pregnant should not take miltefosine unless the potential benefits outweigh the risks. 
• Another black box warning for miltefosine is related to its potential to cause severe gastrointestinal and liver toxicity. miltefosine has been associated with severe vomiting, diarrhea, and dehydration, which can lead to electrolyte imbalances and kidney damage.
• Additionally, miltefosine has been reported to cause liver damage, including elevations in liver enzymes and cases of liver failure. Patients taking miltefosine should be monitored closely for signs of these adverse effects, and treatment should be discontinued if they occur. 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: miltefosine is contraindicated in patients with known hypersensitivity to miltefosine or any of its components. 
• Pregnancy: miltefosine is contraindicated in pregnant women, as it has been associated with fetal harm. 
• Breastfeeding: miltefosine is contraindicated in breastfeeding women, as it can be excreted in breast milk and may harm the nursing infant. 
• Renal impairment: miltefosine should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as it can lead to accumulation of the drug and increased risk of adverse effects. 
• Hepatic impairment: miltefosine should not be used in patients with severe hepatic impairment, as it can cause liver damage and may exacerbate pre-existing liver disease. 
• Concomitant use with drugs that affect liver function: miltefosine should not be used concomitantly with drugs that affect liver function, such as rifampicin, as it can increase the risk of liver damage. 
• Children under 12: miltefosine is not recommended for use in children under 12, as safety and efficacy have not been established in this population. 

Caution: 

• Concomitant use with drugs that affect renal function: miltefosine should be used cautiously in patients taking other drugs that affect renal function, as it can increase the risk of kidney damage. 
• Neurological or psychiatric disorders: miltefosine should be used cautiously in patients with pre-existing neurological or psychiatric disorders, as it can exacerbate these conditions. 
• Elderly patients: miltefosine should be used with caution in elderly patients, as they may be more susceptible to the adverse effects of the drug. 
• Patients with electrolyte imbalances: miltefosine should be used cautiously in patients with pre-existing electrolyte imbalances, as it can exacerbate these conditions. 
• Patients with HIV infection: miltefosine should be used with caution in patients with HIV infection, as it can interact with antiretroviral medications and affect their efficacy. 
• Patients with impaired immune function: miltefosine should be used with caution in patients with impaired immune function, as it can increase the risk of infections. 
• Patients with gastrointestinal disorders: miltefosine should be used cautiously in patients with pre-existing gastrointestinal disorders, as it can exacerbate these conditions. 

Pregnancy / Lactation

Pregnancy consideration: miltefosine is contraindicated in pregnant women, as it has been associated with fetal harm. 

Lactation: miltefosine is contraindicated in breastfeeding women, as it can be excreted in breast milk and may harm the nursing infant. 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.   

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

miltefosine is a phosphocholine derivative that exhibits a broad spectrum of pharmacological activities. Its mechanism of action is not entirely understood, but it is believed to act through multiple mechanisms, including: 

• Inhibition of phosphatidylcholine synthesis: miltefosine inhibits the synthesis of phosphatidylcholine, a major component of cell membranes, disrupting the membrane structure and function. This can ultimately lead to cell death. 

• Inhibition of protein kinase C: miltefosine also inhibits the activity of protein kinase C, an enzyme that regulates many cellular processes, including cell proliferation, differentiation, and survival. This inhibition can lead to apoptosis or programmed cell death. 

• Interaction with DNA: miltefosine can also interact with DNA and interfere with its replication, leading to cell death. 

Pharmacodynamics: 

• The pharmacodynamics of miltefosine is not fully understood, but it is believed to exert its effects through multiple mechanisms of action. 

• Regarding its antimicrobial activity, miltefosine has been shown to inhibit the growth of various microorganisms, including protozoa, bacteria, and fungi. Its exact mechanism of action against these pathogens is not well characterized. Still, it is believed to involve disruption of cell membrane structure and function, inhibition of protein kinase C, and interference with DNA replication. 

Pharmacokinetics: 

Absorption 

The absolute bioavailability of miltefosine has not been determined. However, it is well absorbed after oral administration. 

Distribution 

miltefosine is highly protein bound, with more than 98% of the drug bound to plasma proteins. It has a large volume of distribution and is distributed throughout the body, including into the central nervous system. 

Metabolism 

miltefosine is metabolized by the enzyme phospholipase D to choline and hexadecanol. Choline is incorporated into tissues, while hexadecanol is oxidized to palmitic acid.miltefosine is not a substrate, inhibitor, or inducer of CYP450 enzymes. 

Elimination and Excretion 

miltefosine is primarily eliminated in the feces, with less than 0.2% of the administered dose excreted in the urine. It has a long half-life of approximately 150 hours, which allows for once-daily dosing. 

Adminstartion

Administration: 

Oral Administration: 

• Reduce Gastrointestinal side effects by taking medication with meals. 
• Do not chew or break the pill; instead, swallow it whole. 
• Advise the patient to finish the whole course of treatment. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: miltefosine 

Why do we use miltefosine? 

miltefosine is primarily used to treat leishmaniasis, a parasitic infection caused by the protozoan Leishmania spp. transmitted by the bite of infected sandflies. It is also used off-label to treat other infections, such as: 

• Visceral leishmaniasis (also known as kala-azar) is a severe form of leishmaniasis that affects internal organs such as the spleen, liver, and bone marrow. 
• Cutaneous leishmaniasis, is a less severe form of leishmaniasis that affects the skin. 
• Post-kala-azar dermal leishmaniasis, is a skin disorder that can occur after successful treatment of visceral leishmaniasis. 
• Mucosal leishmaniasis is a rare and severe form of leishmaniasis that affects the nose, mouth, and throat mucous membranes. 
• Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi that blood-sucking insects transmit. 
• Fungal infections, such as cryptococcosis and aspergillosis, resist other antifungal drugs.