Miltefosine: What is the Oral Drug for Visceral Leishmaniasis?

October 6, 2025 •

4 min read

Originally developed as an anticancer agent, miltefosine later emerged as the world's first effective oral drug for leishmaniasis, a neglected tropical disease. This was a significant breakthrough, offering a convenient alternative to traditional parenteral treatments for visceral leishmaniasis (VL). The drug, sold under the brand name Impavido in some regions, has demonstrated high cure rates, though its efficacy can vary by geographic location and parasite species.

Quick Summary

Miltefosine is the only recognized oral medication for visceral leishmaniasis. It works by disrupting the parasite's cell membranes and mitochondria. Though generally well-tolerated with common gastrointestinal side effects, it is teratogenic and its use requires careful management. Concerns over emerging drug resistance have increased the use of combination therapies to preserve its effectiveness.

Key Points

Sole Oral Agent: Miltefosine is the only recognized oral drug effective for treating visceral leishmaniasis, a significant advancement in treating this parasitic disease.
Mechanism of Action: It primarily works by disrupting the Leishmania parasite's cell membranes, interfering with mitochondrial function, and affecting calcium regulation.
Side Effects: Common adverse effects are gastrointestinal, including nausea, vomiting, and diarrhea, though they are often mild and temporary.
Teratogenic Risk: Miltefosine is contraindicated in pregnant women, and strict contraception is required for women of childbearing age due to its teratogenic potential.
Drug Resistance: Evidence of emerging miltefosine resistance, particularly in some regions of the Indian subcontinent, has been reported, leading to calls for better management and combination therapies.
Combination Therapy: To improve efficacy, reduce toxicity, and prevent resistance, miltefosine is often used in combination with other antileishmanial drugs like liposomal amphotericin B.

The Emergence of Miltefosine as a Treatment for VL

Miltefosine (brand name Impavido) is the cornerstone of oral treatment for visceral leishmaniasis (VL), also known as kala-azar. The journey of miltefosine from an investigational compound to a key leishmaniasis medication was a significant development in the fight against this neglected tropical disease. While initially studied as a potential anticancer drug, its potent antileishmanial activity was discovered in the 1980s. It was subsequently developed and registered for use, with FDA approval in 2014 for specific Leishmania species and patient demographics.

Mechanism of Action

Miltefosine's therapeutic effect is primarily attributed to its impact on the Leishmania parasite's cellular structure and function. As an alkylphosphocholine, it targets several vital processes within the parasite, ultimately leading to its death. Its multifaceted mechanism includes:

Membrane Disruption: Miltefosine is incorporated into the parasite's cell membrane, disrupting its integrity and affecting phospholipid biosynthesis. This impairs critical membrane-related functions essential for the parasite's survival.
Mitochondrial Inhibition: The drug interferes with the parasite's mitochondrial function, particularly inhibiting cytochrome c oxidase, which leads to reduced ATP levels.
Calcium Homeostasis: Miltefosine disrupts the parasite's intracellular calcium regulation, affecting organelles like the giant mitochondria and acidocalcisomes, and activating a specific calcium channel in the plasma membrane.
Apoptosis-like Cell Death: Studies have demonstrated that miltefosine can induce an apoptosis-like process in the parasite, leading to programmed cell death.

Clinical Efficacy and the Challenge of Resistance

Clinical trials, particularly in the Indian subcontinent (including India, Nepal, and Bangladesh), initially showed very high cure rates of 94–97% for adults and children treated with miltefosine. This led to its adoption as a first-line therapy in these regions. However, the landscape has changed with subsequent reports indicating increasing rates of treatment failure and relapse, raising concerns about the emergence of drug resistance. Achieving sufficient drug exposure is critical for treatment success, and factors like poor adherence or suboptimal dosing can contribute to resistance.

Side Effects and Safety Considerations of Miltefosine

One of the main advantages of miltefosine is its oral administration, making it a more convenient option than invasive parenteral therapies. However, it is not without side effects, which require careful management.

Common Adverse Effects

The most frequent adverse events associated with miltefosine treatment are gastrointestinal.

Gastrointestinal Issues: Patients commonly experience nausea, vomiting, diarrhea, stomach pain, and decreased appetite. These symptoms are usually mild to moderate, often occurring at the start of treatment, and typically resolve on their own. Taking the medication with food can help mitigate these effects.
Other Side Effects: Headaches, dizziness, and drowsiness are also reported.

Serious and Reproductive Risks

While less common, more serious side effects and safety considerations exist:

Embryotoxicity and Teratogenicity: Miltefosine is strictly contraindicated in pregnant women due to its potential to cause harm to the fetus. Women of childbearing age must use effective contraception during treatment and for an extended period afterward (often five months).
Liver and Kidney Function: Transient and mild elevation of serum aminotransferase (liver enzymes) and creatinine levels (kidney function) can occur. These usually resolve with time and do not typically necessitate treatment interruption.
Severe Skin Reactions: In rare cases, miltefosine can cause severe skin reactions, such as Stevens-Johnson syndrome, requiring immediate medical attention.

Miltefosine vs. Other Treatments for Visceral Leishmaniasis

Different treatment options for VL carry unique profiles regarding their administration, efficacy, safety, and suitability for different regions. Here is a comparison of miltefosine with other notable treatments.


Feature	Miltefosine (Oral)	Liposomal Amphotericin B (IV)	Pentavalent Antimonials (IV/IM)
Route of Administration	Oral capsules	Intravenous (IV) infusion	Intramuscular (IM) or Intravenous (IV)
Convenience	High (outpatient possible)	Requires hospitalization	Requires daily injections, hospital stay
Effectiveness	High initially, but declining in some regions due to resistance.	Very high and generally well-tolerated.	Effectiveness reduced in areas with emerging resistance.
Side Effects	Gastrointestinal issues (nausea, vomiting, diarrhea); teratogenic.	Chills, fever, kidney toxicity (less than conventional Amphotericin B).	Cardiotoxicity, pancreatitis, hepatotoxicity; resistance issues.
Duration of Therapy	28 days for monotherapy.	Shorter course (e.g., 5-7 days) in some regimens.	Long course (e.g., 28 days or more).
Cost	Varies widely by region; affordable in some endemic areas but expensive in others.	High cost, but effective in shorter courses.	Historically a mainstay, but compromised by resistance.

The Rise of Combination Therapy

To combat emerging drug resistance and improve outcomes, particularly in areas with higher rates of treatment failure, combination therapy is increasingly recommended. Combining miltefosine with another drug, such as liposomal amphotericin B (L-AmB), can offer several advantages:

Improved Efficacy: The combined action of two different drugs can increase the overall cure rate.
Reduced Resistance: Using drugs with different mechanisms of action can delay or prevent the development of resistance in the parasite population.
Lowered Toxicity: Combination therapy may allow for reduced doses or shorter treatment durations of one or both drugs, potentially leading to fewer or milder side effects.

Conclusion

Miltefosine remains a pivotal tool in the pharmacological arsenal against visceral leishmaniasis due to its convenient oral administration. Its introduction marked a significant step forward, moving away from complex and costly parenteral treatments. However, its continued efficacy is threatened by increasing resistance in key endemic areas, necessitating careful clinical practice, strict adherence to dosing regimens, and the strategic use of combination therapies. Proper deployment and patient monitoring are essential to preserve the effectiveness of this valuable oral drug for treating VL and managing its associated health risks globally. For more information, please see the Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for Leishmaniasis.

Frequently Asked Questions

Miltefosine disrupts the parasite's cellular functions by damaging its cell membrane and interfering with the energy production in its mitochondria. It also affects intracellular calcium levels, ultimately leading to programmed cell death.

The most significant advantage is its oral administration, which allows for outpatient treatment and avoids the need for a hospital stay and daily injections required by traditional therapies.

The most common side effects are gastrointestinal, such as nausea, vomiting, and diarrhea, and are typically mild to moderate. More serious issues like liver or kidney problems are less frequent and often reversible.

Miltefosine has demonstrated teratogenic effects in animal studies, meaning it can cause harm to a developing fetus. Women of childbearing potential must use reliable contraception during treatment and for several months afterward.

Miltefosine resistance is when the Leishmania parasite evolves to become less susceptible to the drug. This is a problem because it can lead to treatment failure and relapse, especially in high-prevalence areas like the Indian subcontinent, and threatens the long-term effectiveness of the drug.

Combination therapy, often with liposomal amphotericin B, is used to counteract drug resistance, improve cure rates, and potentially shorten treatment duration while reducing the risk of side effects from higher drug doses.

Yes, miltefosine is also used to treat certain types of cutaneous (skin) and mucosal leishmaniasis, in addition to visceral leishmaniasis, depending on the species and geographic location.