Miltefosine is the only oral drug approved to treat leishmaniasis, a parasitic disease that kills tens of thousands of people each year and disfigures many more. Originally developed as an anticancer compound in the 1990s, it was repurposed after researchers discovered it could wipe out Leishmania parasites, and it was first registered in India in 2002. A pivotal trial showed a cure rate of about 94% for visceral leishmaniasis, the deadliest form of the disease, making it a genuine breakthrough for regions where the only alternatives were injectable drugs with serious toxicity. But miltefosine comes with its own set of complications, from gastrointestinal side effects that affect the majority of patients to a strict prohibition on use during pregnancy, and emerging drug resistance is already a concern in some endemic areas.
What Miltefosine Treats
Miltefosine’s headline use is visceral leishmaniasis, sometimes called kala-azar, which is transmitted by sandfly bites and attacks the spleen, liver, and bone marrow. Left untreated, it is almost always fatal. In the phase III trial that led to the drug’s registration, 299 patients received miltefosine orally for 28 days. At the end of treatment every patient’s spleen was parasite-free, and six months later about 94% remained cured with no relapse.1PubMed. Oral miltefosine for Indian visceral leishmaniasis That cure rate held across both adults and children in subsequent studies, though later phase IV data from India and Bangladesh showed somewhat lower figures of around 72% to 82% under real-world conditions.2BMJ Global Health. Why miltefosine—a life-saving drug for leishmaniasis—is unavailable to people who need it the most
Miltefosine is also used for cutaneous leishmaniasis, the form of the disease that causes skin ulcers. Results here vary depending on the Leishmania species involved and the geographic region. In a Brazilian trial of cutaneous leishmaniasis caused by L. braziliensis, miltefosine produced a cure rate of 75% at six months, significantly outperforming the standard antimony-based treatment.3PubMed Central. Miltefosine in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil: A Randomized and Controlled Trial An Ethiopian pilot study painted a less encouraging picture: only about half of patients were cured at six months, and relapse rates were high, particularly at one site where 60% of patients relapsed.4PLOS Neglected Tropical Diseases. Miltefosine for the treatment of cutaneous leishmaniasis—A pilot study from Ethiopia The species of Leishmania matters enormously here. Miltefosine works well against some species and poorly against others, so treatment decisions in cutaneous disease depend heavily on where a patient was infected.
Post-kala-azar dermal leishmaniasis, a chronic skin condition that develops in some patients after visceral leishmaniasis has been treated, is another indication. Treatment courses for this condition tend to be longer, sometimes running six weeks or more rather than the standard four weeks.
How Miltefosine Kills Parasites
Miltefosine’s full mechanism is still being worked out, which is surprisingly common for antiparasitic drugs. What researchers do know is that it attacks Leishmania parasites on several fronts. The drug was originally designed to block the production of phosphatidylcholine, a building block of cell membranes, and it does inhibit that pathway. But its antiparasitic punch goes well beyond membrane disruption.5PubMed Central. Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular Ca2+ Homeostasis as a Rational Therapeutic Target in Leishmaniasis and Chagas Disease
One of the most important effects is the disruption of calcium balance inside the parasite. Leishmania species rely on specialized structures called acidocalcisomes to regulate their internal calcium levels. Miltefosine rapidly alkalinizes these structures, essentially breaking the parasite’s calcium thermostat. It also activates a calcium channel on the parasite’s outer membrane that responds to a fat-like molecule called sphingosine. The human version of that channel behaves differently, which helps explain why the drug can wreck the parasite’s calcium regulation while largely sparing human cells.6PubMed Central. Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca2+ Channel
Beyond its direct anti-parasite activity, miltefosine also nudges the immune system in a favorable direction. A systematic review found that the drug promotes a shift toward a Th1 immune response, characterized by increased levels of interferon-gamma and interleukin-12, which are the signals the body needs to fight intracellular parasites like Leishmania.7PubMed Central. Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation Separately, miltefosine disrupts lipid rafts on macrophage surfaces, blunting certain inflammatory pathways and reducing the production of the inflammatory molecule IL-1β by roughly 75% in cell experiments.8Scientific Reports. Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release This dual role, directly killing the parasite while recalibrating the immune response, likely contributes to its clinical effectiveness.
Side Effects and Tolerability
The biggest downside of miltefosine is gastrointestinal distress. Nausea, vomiting, diarrhea, and abdominal pain are common enough that patients should expect them. In an early dose-finding trial, gut-related side effects showed up in about 62% of patients, though they were mild to moderate and nobody had to stop treatment because of them.9PubMed. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis A meta-analysis of post-kala-azar dermal leishmaniasis treatment found that roughly 20% of patients reported adverse events, with gastrointestinal symptoms dominating the list and vomiting being the most frequently noted complaint across all included studies.10PubMed Central. The safety and efficacy of miltefosine in the long-term treatment of post-kala-azar dermal leishmaniasis in South Asia – A review and meta-analysis The discrepancy in those numbers partly reflects differences in how adverse events are captured and in treatment duration: longer courses used for dermal leishmaniasis expose patients to more cumulative drug.
Less common but clinically important are effects on the liver and kidneys. Liver enzyme elevations have been reported in roughly a quarter of patients in some trials, usually mild and reversible. Kidney function changes also occur. One early clinical study described reversible kidney toxicity in about 29% of patients; in most cases it was mild, but one patient on a high dose experienced a sharp spike in creatinine that required stopping the drug. Levels returned to normal within a week.11Therapeutics and Clinical Risk Management. Miltefosine in the treatment of leishmaniasis: Clinical evidence for informed clinical risk management A pharmacovigilance study from Bihar, India confirmed that rises in liver enzymes and creatinine are among the adverse events clinicians should monitor.12PubMed Central. Pharmacovigilance of Miltefosine in Treatment of Visceral Leishmaniasis in Endemic Areas of Bihar, India
Why Miltefosine Stays in the Body So Long
Miltefosine has unusually slow elimination. Pharmacokinetic studies in cutaneous leishmaniasis patients found a terminal half-life of about 31 days, meaning the drug is still detectable in the blood five to six months after the last dose.13PubMed Central. Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients This sluggish clearance is driven by extensive binding to blood proteins, slow metabolism, and very little excretion through the kidneys.14PubMed Central. Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach
This long half-life has two practical consequences. The first is positive: the drug continues working at therapeutic concentrations long after the treatment course ends, giving a prolonged window of parasite killing. The second is a concern: those lingering concentrations may fall into a range where the drug is present but not at high enough levels to efficiently kill parasites, creating conditions that could favor resistance. It also means that women of childbearing age must continue contraception for months after their last dose, a requirement that varies by treatment length.
Pregnancy and Contraception Requirements
Miltefosine is teratogenic, meaning it can cause birth defects. This is not a theoretical concern or a caution based on limited data; it has been clearly established in animal studies and is the single most important safety restriction on the drug.15Journal of Antimicrobial Chemotherapy. Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine Because miltefosine lingers in the body for months, the required duration of contraception after treatment is not a quick matter. Modeling studies have attempted to define exactly how long women need to maintain contraceptive cover for different regimen lengths. For standard 28-day regimens, the modeling suggests at least four months of contraception from treatment start is necessary. Shorter 14-day regimens may only need three months, while extended 42-day courses used for post-kala-azar dermal leishmaniasis may require five months.16medRxiv. Female contraceptive cover duration for miltefosine-containing regimens for the treatment of women with leishmaniasis
In endemic areas where access to reliable contraception can be difficult, this requirement creates a real barrier to prescribing miltefosine to women of reproductive age. Some programs have explored pairing the drug with long-acting injectable contraceptives administered at the start of treatment. The modeling data suggest a single dose of depot medroxyprogesterone acetate given at treatment initiation could cover the needed window for the shortest regimens. For longer courses, the logistics become harder to guarantee.
The Resistance Problem
Drug resistance is a growing shadow over miltefosine’s future. In the laboratory, Leishmania parasites develop resistance through a straightforward strategy: they reduce the amount of drug that gets inside the cell. This happens in two ways. One is increased drug pumping out of the cell, driven by overproduction of a particular transport protein. The other is decreased drug uptake, achieved when the parasite’s miltefosine transporter or its partner protein becomes inactive. Knocking out either one of these uptake proteins is enough to confer resistance.17PubMed. Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use
The clinical implications are real. The declining cure rates seen in later phase IV studies in India and Bangladesh, compared to the original trial figures, may partly reflect resistance emerging in the field. Miltefosine’s long half-life, which exposes parasites to sub-therapeutic drug levels for months, creates textbook conditions for resistance selection. This has driven interest in combination therapies and shorter-course regimens that might reduce that vulnerability window.
Use in Children
Visceral leishmaniasis disproportionately affects children, so pediatric dosing of miltefosine matters enormously. A challenge is that the standard adult dosing approach, based simply on body weight, tends to underdose children because their bodies handle fat-soluble drugs differently. Researchers have developed weight-band-based dosing schedules using body composition modeling to ensure children reach the same drug exposure as adults. These simplified schedules assign specific milligram doses to weight bands: for instance, 50 mg for children between 10 and 15 kg, scaling up to 80 mg for those approaching 30 kg.18PubMed Central. Weight-band-based simplification of oral allometric miltefosine dosing in paediatric patients with visceral leishmaniasis
In a phase II trial of this adjusted dosing in East African children, the drug was tolerable. All 30 children experienced at least one adverse event during treatment, but the most common were anemia and upper respiratory infection, which are common in this patient population regardless of treatment. Drug-related events included low white blood cell counts in about 20% and vomiting in about 17% of patients. No child had to discontinue treatment.19Clinical Infectious Diseases. Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial
Uses Beyond Leishmaniasis
Miltefosine has found a second life as a treatment for infections caused by free-living amoebae, particularly Acanthamoeba. Acanthamoeba keratitis is a painful eye infection most commonly associated with contact lens wear and exposure to contaminated water. Standard treatment involves weeks to months of topical antiseptic eye drops, and a significant fraction of cases prove resistant to these conventional therapies. For those refractory cases, oral miltefosine has emerged as a salvage option.
A review of 15 patients with Acanthamoeba keratitis that had failed to respond to standard antiseptics found that after adding oral miltefosine, 11 of 15 retained useful vision of counting fingers or better, and all were considered infection-free at their last follow-up.20PubMed. Oral Miltefosine as Salvage Therapy for Refractory Acanthamoeba Keratitis Animal experiments have explored topical miltefosine for this indication, with hamster studies showing cure rates well above those achieved by conventional antiseptics: 85% of miltefosine-treated eyes were graded as fully clear by the end of treatment.21PubMed. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters Combination approaches pairing miltefosine with other antiseptics showed even better outcomes in follow-up rodent studies.22PubMed Central. Oral miltefosine for refractory Acanthamoeba keratitis
Miltefosine is also part of the recommended drug combination for primary amoebic meningoencephalitis caused by Naegleria fowleri, a nearly always fatal brain infection acquired from warm freshwater. Survivors are extraordinarily rare, and those who have survived typically received aggressive multi-drug regimens that included miltefosine. The U.S. Centers for Disease Control and Prevention maintains an emergency supply of the drug for these cases.
Availability and Access Challenges
For a drug considered essential by the World Health Organization, miltefosine is remarkably hard to get. The drug was developed through a public-private partnership between WHO’s tropical disease research program and a pharmaceutical company, but the access provisions built into that original agreement have not been effectively enforced. The result has been recurring shortages, supply chain failures, and, in some instances, distribution of substandard product that led to treatment failures and deaths.23PubMed Central. Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most
The drug’s shelf life has been a recurring headache. Miltefosine degrades in tropical heat, and maintaining cold-chain storage across rural health infrastructure in South Asia and East Africa is a tall order. When degraded product is administered, patients receive less active drug than intended, which means lower cure rates and, potentially, selection for resistant parasites. The combination of affordability barriers, limited manufacturing capacity, and supply fragility means that in the places where visceral leishmaniasis kills the most people, the one oral drug that can treat it is often unavailable.
Veterinary Use in Canine Leishmaniasis
Dogs are the primary reservoir for Leishmania infantum, the species responsible for visceral leishmaniasis in southern Europe, Latin America, and parts of the Middle East. Treating infected dogs has both an animal welfare and a public health rationale, since reducing the parasite load in dogs can interrupt transmission to humans via sandflies.
In a multicenter trial, 96 dogs were treated with miltefosine at 2 mg per kilogram daily for 28 days. Clinical scores improved by an average of about 61% by day 56, and veterinarians judged the drug at least as effective as other available treatments in roughly 83% of cases.24PubMed. Clinical efficacy and tolerance of miltefosine in the treatment of canine leishmaniosis The drug is marketed for veterinary use in several countries under the brand name Milteforan.
However, clinical improvement in dogs does not always mean parasitological cure. A detailed study of two naturally infected dogs found that even after two full treatment cycles, the parasite load remained elevated in both animals, even though one became symptom-free. The other worsened clinically. A treated dog that looks healthy but still carries a high parasite burden can continue to serve as a source of infection for sandflies, which poses an ongoing public health risk.25PubMed Central. Therapeutic success and failure in using miltefosine to treat dogs naturally infected with Leishmania infantum This gap between symptom relief and actual parasite clearance is an important limitation that complicates the use of canine treatment as a disease-control strategy.
Topical Formulations and Combination Therapies
Because miltefosine’s gastrointestinal side effects and teratogenicity stem from systemic exposure, there is strong motivation to develop formulations that deliver the drug directly to the skin for cutaneous leishmaniasis. Several research groups have experimented with liposomal creams designed to push miltefosine through the outer skin layer and into the tissue where parasites reside. In mouse models of cutaneous disease, liposomal miltefosine at higher concentrations significantly reduced both lesion size and parasite burden compared to untreated controls, with the best results at 2% and 4% formulations.26PubMed. Development of topical liposomes containing miltefosine for the treatment of Leishmania major infection in susceptible BALB/c mice Other groups have tested different dispersion and carrier systems to optimize how much drug penetrates the skin barrier.27PubMed. Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis None of these topical approaches has yet reached clinical use in humans, but the concept of keeping the drug local rather than systemic would, if it works, sidestep the main safety concerns that limit oral miltefosine.
On the combination therapy front, researchers are exploring fixed-dose formulations that pair miltefosine with amphotericin B, the powerful injectable antifungal that is the other first-line drug for visceral leishmaniasis. One experimental approach packages both drugs into oral granules, with amphotericin B in the core and a miltefosine coating, aiming to make an all-oral combination that could reduce both treatment duration and the likelihood of resistance emerging.28PubMed Central. Targeted Oral Fixed-Dose Combination of Amphotericin B-Miltefosine for Visceral Leishmaniasis The idea of an oral amphotericin B would itself be a major advance, since the drug currently requires intravenous infusion, typically in a hospital setting. Whether these formulations will succeed in clinical trials remains to be seen, but the approach recognizes that miltefosine alone, with its resistance vulnerabilities and safety constraints, probably cannot carry the burden of leishmaniasis treatment indefinitely.
Miltefosine and Cancer Research
The story of miltefosine comes full circle with renewed interest in its anticancer properties. The drug was originally developed to target cancer cells, and recent work has revisited that angle with more modern tools. One line of research found that miltefosine disrupts lipid rafts on the surface of colorectal cancer stem cells. These stem-like cells are often the reason tumors resist chemotherapy and recur after treatment. In lab experiments, miltefosine specifically killed these resistant stem cells by shutting down a checkpoint protein that normally allows cells to pause and repair DNA damage before dividing. Without that checkpoint, cancer stem cells were forced into division with extensive unrepaired damage, leading to catastrophic cell death.29PubMed Central. Lipid raft-disrupting miltefosine preferentially induces the death of colorectal cancer stem-like cells This mechanism is distinct from how miltefosine kills parasites, though the shared thread is the drug’s affinity for disrupting membrane structures. Whether these laboratory findings will translate into clinical oncology applications is uncertain, but the work illustrates how a single drug’s mechanism can open doors across very different diseases.