A Comprehensive Monograph on Lumefantrine: Pharmacology, Clinical Efficacy, and Therapeutic Role in Malaria Management

Executive Summary

Lumefantrine is a synthetic, highly lipophilic antimalarial agent belonging to the aryl amino alcohol class. It is a cornerstone of global malaria treatment, exclusively used in a fixed-dose combination with the artemisinin derivative, artemether. This combination therapy, recommended as a first-line treatment for uncomplicated Plasmodium falciparum malaria by the World Health Organization (WHO), leverages a powerful synergy between its two components. Artemether provides a rapid reduction in parasite biomass and swift symptomatic relief, while lumefantrine, with its significantly longer elimination half-life, eradicates residual parasites, thereby preventing recrudescence. The primary mechanism of action for lumefantrine is believed to be the inhibition of hemozoin formation within the parasite's food vacuole, leading to the accumulation of toxic heme and subsequent parasite death.

Clinically, the artemether-lumefantrine regimen has demonstrated consistently high efficacy, with 28-day PCR-corrected cure rates exceeding 95% in diverse patient populations and geographical regions, including areas with chloroquine resistance. Its favorable safety profile makes it suitable for a wide range of patients, including children as young as two months and pregnant women in all trimesters. However, its therapeutic success is critically dependent on its pharmacokinetic profile, which is characterized by poor aqueous solubility and a profound reliance on co-administration with fatty food for adequate oral absorption. This presents a significant clinical challenge, particularly in acutely ill, anorexic patients.

The development of lumefantrine, from its origins in China's Project 523 to its global deployment as the first WHO-prequalified fixed-dose artemisinin-based combination therapy (ACT), represents a paradigm of public-private partnership in global health. Despite its success, its long-term utility is threatened by systemic challenges, including the proliferation of substandard and counterfeit medicines and the ever-present risk of emerging parasite resistance. Future strategies focus on developing novel formulations to improve bioavailability and deploying lumefantrine as a partner drug in next-generation combination therapies to preserve its efficacy for years to come.

Section 1: Drug Identification and Physicochemical Properties

1.1 Nomenclature and Chemical Identifiers

Establishing a precise and unambiguous identity for a pharmaceutical agent is fundamental to scientific communication and regulatory oversight. Lumefantrine is identified by a variety of names and registry numbers across chemical, pharmacological, and clinical domains. Its generic name is Lumefantrine.[1] Historically and in scientific literature, it is also frequently referred to by synonyms such as Benflumetol and its developmental code, CPG-56695.[2] The formal chemical name, defined by the International Union of Pure and Applied Chemistry (IUPAC), is 2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]fluoren-4-yl]ethanol, which precisely describes its molecular architecture.[5]

To facilitate cross-referencing across global databases, lumefantrine is assigned several unique identifiers. The most critical of these is its Chemical Abstracts Service (CAS) Registry Number, 82186-77-4.[2] In pharmacological and drug development contexts, it is cataloged under DrugBank Accession Number DB06708.[1] A consolidated list of these primary identifiers is presented in Table 1.

Table 1: Key Chemical and Physical Identifiers for Lumefantrine

Identifier Type	Value	Source(s)
Generic Name	Lumefantrine	1
IUPAC Name	2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]fluoren-4-yl]ethanol	5
CAS Number	82186-77-4	3
DrugBank ID	DB06708	1
UNII	F38R0JR742	5
Molecular Formula	C30​H32​Cl3​NO	1
Average Molecular Weight	528.94 g/mol	1

1.2 Molecular Structure and Chemical Classification

Lumefantrine is a synthetic, racemic small molecule with the chemical formula C30​H32​Cl3​NO and an average molecular weight of 528.94 g/mol.[1] Structurally, it is a fluorene derivative, belonging to the broader chemical class of aryl amino alcohols.[5] This classification is significant as it places lumefantrine in the same family as other well-known antimalarials, including quinine, mefloquine, and halofantrine, which share a common mechanistic theme of interfering with heme metabolism in the malaria parasite.[6]

The molecule's core is a 9-(p-chlorobenzylidene)-9H-fluorene scaffold. This core is heavily substituted, featuring chlorine atoms at positions 2 and 7, and a 2-(dibutylamino)-1-hydroxyethyl side chain at position 4.[5] The key functional groups present in the structure—a tertiary amine, a secondary alcohol, and multiple monochlorobenzene rings—are critical determinants of its physicochemical properties, biological activity, and metabolic fate.[5] The complex, multi-ring structure and halogen substitutions contribute to its pronounced lipophilicity, a characteristic that fundamentally governs its entire clinical and pharmacological profile.

1.3 Physical and Chemical Properties

The physical and chemical properties of lumefantrine directly influence its formulation, stability, and pharmacokinetic behavior. It presents as a yellow crystalline powder or solid.[3] Its melting point is reported within a range of 129°C to 138°C, reflecting slight variations in purity and measurement methodology across different sources.[3]

The most defining physicochemical characteristic of lumefantrine is its solubility profile. It is highly lipophilic, being soluble in dimethyl sulfoxide (DMSO) and chloroform, slightly soluble in acetone, and practically insoluble in both alcohol and water.[3] This poor aqueous solubility is the direct cause of its challenging oral absorption characteristics. The molecule's high lipophilicity dictates that its bioavailability is profoundly dependent on the presence of lipids during administration, a factor that has major implications for its clinical use, especially in acutely ill malaria patients who are often anorexic.[6] This connection between basic chemistry and clinical reality is a central theme in understanding the therapeutic application of lumefantrine; the very nature of the molecule creates a therapeutic paradox where its effectiveness can be compromised by the symptoms of the disease it is intended to treat. Due to its chemical nature, lumefantrine requires specific storage conditions, typically in a refrigerator at 2-8°C or at a cool room temperature below 15°C, protected from light, to ensure its stability.[4]

Section 2: Preclinical and Clinical Pharmacology

2.1 Mechanism of Action

The therapeutic effect of lumefantrine is rooted in its activity against the erythrocytic stages of the Plasmodium parasite, particularly P. falciparum. Its mechanism, while not definitively elucidated, is understood through a primary pathway common to its chemical class, supplemented by secondary actions and a critical synergistic partnership with artemether.

2.1.1 Primary Antimalarial Activity: Inhibition of Hemozoin Formation

The principal mechanism of action for lumefantrine is believed to be its interference with the parasite's heme detoxification pathway.[1] During its intra-erythrocytic life cycle, the malaria parasite digests large amounts of host hemoglobin within its acidic food vacuole to obtain essential amino acids. This process releases substantial quantities of free heme (ferriprotoporphyrin IX), which is highly toxic to the parasite as it can generate reactive oxygen species and destabilize membranes. To protect itself, the parasite rapidly detoxifies the heme by polymerizing it into an insoluble, chemically inert crystalline pigment known as hemozoin (malaria pigment).[12]

Lumefantrine, like other aryl amino alcohols, is thought to disrupt this vital detoxification process. It is proposed that lumefantrine accumulates in the parasite's food vacuole and forms a complex with hemin, thereby preventing its incorporation into the growing hemozoin crystal.[1] This inhibition leads to a buildup of toxic, monomeric heme, which ultimately causes oxidative damage to parasite membranes and other essential components, leading to cell lysis and death.[12]

2.1.2 Secondary Mechanisms and Molecular Targets

Evidence suggests that lumefantrine's antimalarial activity may not be limited to hemozoin inhibition alone. Some studies indicate that it can also inhibit nucleic acid and protein synthesis within the parasite, representing an additional mode of disrupting parasite viability.[1] Furthermore, lumefantrine has been shown to bind to the human sodium/potassium-transporting ATPase subunit alpha-1, though the clinical significance of this off-target interaction in humans remains unclear.[1] The observation that lumefantrine exhibits activity against quiescent (dormant) parasite forms further supports the hypothesis that it may target additional pathways beyond the highly active process of hemoglobin digestion and hemozoin formation.[12]

2.1.3 The Synergistic Partnership with Artemether

In clinical practice, lumefantrine is never used as a monotherapy but is always co-formulated with artemether, an artemisinin derivative.[1] This combination is not merely additive but profoundly synergistic, operating on both pharmacokinetic and pharmacodynamic levels.

The initial rationale for this partnership was based on complementary pharmacokinetics. Artemether is characterized by a rapid onset of action and a very short elimination half-life of approximately 2-3 hours.[15] It is rapidly absorbed and converted to its active metabolite, dihydroartemisinin (DHA), which effects a swift and substantial reduction in the total parasite biomass, leading to rapid resolution of fever and other clinical symptoms.[1] However, due to its rapid clearance, artemether monotherapy is associated with a high rate of recrudescence (relapse of the original infection).[13] This is where lumefantrine plays its crucial role. With its much longer elimination half-life of 3-6 days, lumefantrine persists at therapeutic concentrations in the blood long after artemether has been cleared.[1] This sustained exposure acts to eliminate the residual parasites that survived the initial artemether assault, thereby preventing recrudescence and achieving a definitive cure.[16]

More recent research has uncovered a deeper, more sophisticated pharmacodynamic synergy that is particularly relevant in the era of emerging drug resistance. Artemisinin resistance is phenotypically characterized by delayed parasite clearance, which is caused by reduced parasite susceptibility specifically during the early ring stage of the parasite's life cycle.[19] Crucially, studies have demonstrated that lumefantrine potentiates the killing activity of artemisinins against these resistant parasites, with isobologram analysis confirming true synergism during this specific early ring-stage resistance window.[19] This finding transforms the understanding of lumefantrine's role from that of a passive "mop-up" agent to an active partner that helps overcome the primary resistance mechanism of its companion drug. This unexpected synergy makes the artemether-lumefantrine combination more robust against resistance than originally conceived and provides a powerful model for the design of future ACTs.

2.2 Pharmacodynamics

The pharmacodynamic profile of lumefantrine is characterized by a clear dose-response relationship and a notable effect on cardiac repolarization.

2.2.1 Dose-Response Relationship

The clinical outcome of artemether-lumefantrine therapy is directly linked to the systemic exposure of each component, with each drug playing a distinct role. Clinical studies have established that exposure to artemether and its active metabolite, DHA, is the primary determinant of the initial parasite clearance time (PCT).[10] In contrast, the systemic exposure to lumefantrine, typically quantified by the area under the plasma concentration-time curve (AUC), is the principal determinant of the ultimate cure rate and prevention of recrudescence.[6] This clear distinction reinforces the specialized functions of each drug within the combination: artemether for the initial knockdown of parasites and lumefantrine for the definitive cure.

2.2.2 Cardiovascular Effects: QT Interval Prolongation

A significant pharmacodynamic property of lumefantrine is its potential to prolong the QT interval on the electrocardiogram (ECG), an effect it shares with other members of the aryl amino alcohol class.[1] The QT interval represents the time taken for ventricular depolarization and repolarization. Its prolongation can increase the risk of a life-threatening ventricular tachyarrhythmia known as Torsades de Pointes. The mechanism for this effect is understood to be the blockade of the rapidly activating delayed-rectifier potassium channel (IKr), encoded by the hERG gene, which is a critical component of cardiac repolarization.[3] While the degree of QT prolongation observed with therapeutic doses of lumefantrine is generally transient and mild, and rarely associated with adverse clinical events, this effect constitutes a significant risk management consideration.[3] Caution is strongly advised, and use should be avoided in patients with pre-existing risk factors such as congenital long QT syndrome, a history of cardiac arrhythmias, or uncorrected electrolyte imbalances (hypokalemia or hypomagnesemia).[21] The risk is amplified when lumefantrine is co-administered with other drugs known to prolong the QT interval.[1]

2.3 Pharmacokinetics

The pharmacokinetic profile of lumefantrine is complex and marked by high variability, primarily driven by its lipophilicity. Its absorption, distribution, metabolism, and elimination (ADME) properties are critical to its therapeutic efficacy and safety.

2.3.1 Absorption and the Critical Role of Food and Fat Intake

Lumefantrine exhibits slow, erratic, and incomplete oral absorption.[3] This is a direct consequence of its high lipophilicity and poor aqueous solubility. Its oral bioavailability is critically and profoundly dependent on co-administration with food, especially fat. In the fasted state, absorption is minimal. However, administration with a high-fat meal can increase the bioavailability of lumefantrine by as much as 16-fold.[10] This food effect is the single most important factor governing lumefantrine exposure and, by extension, its clinical efficacy.

This creates a significant clinical challenge, as acute malaria is often accompanied by anorexia, nausea, and vomiting, which limit a patient's ability to consume food.[10] The entire therapeutic success of the drug hinges on overcoming this barrier. Fortunately, studies have shown that even a small amount of fat, such as that contained in 36 mL of soya milk (approximately 1.2-1.6 g of fat), is sufficient to achieve adequate absorption.[10] As patients recover from the acute phase of malaria and their appetite returns, the absorption of subsequent doses of lumefantrine improves, leading to an accumulation of the drug over the three-day treatment course.[6] Following oral administration with food, peak plasma concentrations (

Cmax​) are typically reached in 3 to 6 hours.[3]

2.3.2 Distribution and Protein Binding

Once absorbed, lumefantrine is extensively distributed throughout the body, consistent with its lipophilic nature, resulting in a large apparent volume of distribution.[6] It is highly bound to human serum proteins, with a binding fraction exceeding 99.7%.[1] This high degree of protein binding limits the amount of free, pharmacologically active drug but also contributes to its long residence time in the body.

2.3.3 Metabolism via Cytochrome P450 Isoenzymes

Lumefantrine undergoes extensive hepatic metabolism, primarily mediated by the cytochrome P450 3A4 (CYP3A4) isoenzyme.[1] The cytochrome P450 2D6 (CYP2D6) isoenzyme also plays a minor role in its metabolism.[14] The main metabolic pathway is N-debutylation, which produces the major plasma metabolite, desbutyl-lumefantrine.[1] In vitro studies have shown that this metabolite possesses 5- to 8-fold greater antimalarial activity than the parent compound, lumefantrine.[3] However, its systemic exposure in vivo is substantially lower (ranging from <1% to 10%) than that of the parent drug, so its overall contribution to the clinical effect is considered minor.[26] The reliance on CYP3A4 for metabolism makes lumefantrine susceptible to significant drug-drug interactions.

2.3.4 Elimination and Half-Life

The elimination of lumefantrine and its metabolites is slow. The terminal elimination half-life (t1/2​) is a key feature of its pharmacokinetic profile, averaging approximately 3 to 6 days in patients with malaria and potentially extending up to 6 days in healthy volunteers.[1] This long half-life is fundamental to its therapeutic role, as it ensures sustained drug concentrations sufficient to eradicate any slow-growing or residual parasites that survive the initial, rapid onslaught of artemether, thereby preventing recrudescence.[16]

2.3.5 Pharmacokinetic Variability in Special Populations

The pharmacokinetics of lumefantrine can be altered in specific patient populations, necessitating careful consideration of dosing and monitoring.

• Pediatrics: When dosed according to body weight, the overall pharmacokinetic profile of lumefantrine in children is generally comparable to that in adults.[18] However, a growing body of evidence suggests that young children, particularly those under 5 years of age and weighing less than 15 kg, may exhibit lower systemic exposures and higher apparent clearance rates.[26] This can lead to an increased risk of treatment failure, suggesting that the current weight-based dosing bands may be suboptimal for this vulnerable population. Population pharmacokinetic modeling in children under 5 has shown that both age and Body Mass Index (BMI) are significant covariates influencing lumefantrine clearance, highlighting the complexity of dosing in this group.[26]
• Pregnancy: The physiological changes during pregnancy can alter the disposition of many drugs. Studies investigating the pharmacokinetics of lumefantrine in pregnant women during their second and third trimesters have yielded inconclusive results.[25] While one study found no significant difference in overall drug exposure (AUC) compared to non-pregnant adults, it did identify a statistically significant shortening of the terminal elimination half-life in pregnant women.[25] A shorter half-life could translate to a reduced post-treatment prophylactic period, potentially increasing the risk of reinfection in high-transmission settings.[25]

Section 3: Clinical Efficacy and Therapeutic Application

3.1 Approved Indications and Place in Therapy

The fixed-dose combination of artemether and lumefantrine is a cornerstone of modern malaria chemotherapy. Its primary indication is for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum.[1] This indication is broad, covering both adults and pediatric patients from two months of age, provided they have a body weight of at least 5 kg.[21] A key aspect of its utility is its proven efficacy in geographical regions where resistance of

P. falciparum to older antimalarials, such as chloroquine, is widespread.[1] The combination may also be used empirically for the treatment of uncomplicated malaria when the causative

Plasmodium species has not been definitively identified, ensuring coverage against the most virulent species, P. falciparum.[1]

It is critical to recognize the specific limitations of its use. Artemether-lumefantrine is explicitly not approved for the prevention (prophylaxis) of malaria.[21] Furthermore, it is not indicated for the initial treatment of severe or complicated malaria, which requires immediate parenteral therapy with agents like intravenous artesunate.[21] However, it does have a role as an oral completion therapy once a patient with severe malaria has been stabilized with parenteral treatment and is able to tolerate oral medication.[23]

3.2 Evidence from Clinical Trials

The clinical efficacy of artemether-lumefantrine is supported by a vast body of evidence from numerous clinical trials conducted across different continents and in diverse patient populations.

3.2.1 Pivotal Trials in Uncomplicated P. falciparum Malaria

The standard six-dose regimen of artemether-lumefantrine has been rigorously evaluated in pivotal Phase 3 and 4 trials. These studies have consistently demonstrated high rates of therapeutic success. The primary efficacy endpoint in these trials is typically the 28-day or 42-day parasitological cure rate, corrected by polymerase chain reaction (PCR) analysis to distinguish between true treatment failure (recrudescence) and new infection (reinfection).[16] Across studies conducted in Africa, Asia, and for non-immune travelers, the 28-day PCR-corrected cure rates in the evaluable patient populations consistently exceed 95%.[16]

In addition to high cure rates, these trials have also shown that the therapy leads to rapid clinical and parasitological improvement. Secondary endpoints such as fever clearance time (FCT) and parasite clearance time (PCT) are typically rapid. For example, in trials involving infants and children in Africa, the median FCT was approximately 8 hours, and the median PCT was between 24 and 35 hours, underscoring the rapid action of the artemether component.[16] Phase 4 trials conducted in real-world settings in countries like Tanzania, the Democratic Republic of the Congo, and Burkina Faso have confirmed this high level of effectiveness at the community level.[32]

3.2.2 Trials in Special Populations and Emerging Research

The evidence base extends to specific populations and novel applications. Clinical trials have specifically evaluated its use in children, leading to the development and approval of a dispersible formulation to improve adherence.[33] A notable trial (NCT00495508) compared artemether-lumefantrine to quinine for the treatment of uncomplicated malaria during pregnancy, contributing to the evidence supporting its use in this group.[32]

The therapeutic landscape for lumefantrine continues to evolve. It is currently being investigated in a Phase 2 trial (NCT04675931) as part of a combination therapy for severe malaria, which could potentially expand its indications in the future.[34] Furthermore, lumefantrine is a key component in the development of next-generation antimalarials. A novel combination of ganaplacide (KAF156) with a new lumefantrine solid dispersion formulation (SDF) is under investigation.[35] This new formulation aims to enhance the bioavailability of lumefantrine, potentially allowing for a shorter and simpler dosing regimen while maintaining high efficacy against both sensitive and artemisinin-resistant parasites.[36]

3.3 Comparative Efficacy Analysis

The widespread adoption and robust efficacy of artemether-lumefantrine (AL) have established it as a benchmark treatment, making it the standard comparator arm in clinical trials for new antimalarial therapies. This unique position has been earned through its status as the first WHO-prequalified, fixed-dose ACT and its extensive real-world use, particularly in Africa.[37] Consequently, trials for newer ACTs, such as artesunate-mefloquine (AS-MQ), dihydroartemisinin-piperaquine (DP), and pyronaridine-artesunate, have all been designed to demonstrate non-inferiority or superiority against AL.[37] This role as the "gold standard" comparator underscores its established and trusted place in malaria therapy.

• AL vs. Artesunate-Mefloquine (AS-MQ): A large, multicenter, non-inferiority trial conducted in over 900 children under five in Africa directly compared AL with a fixed-dose formulation of AS-MQ.[37] The study found that AS-MQ was non-inferior to AL, with 63-day PCR-corrected cure rates of 90.9% for AS-MQ and 89.7% for AL. The safety profiles of the two treatments were comparable, with similar low rates of early vomiting and neurological adverse events.[37] A key difference noted was the potential for AS-MQ to provide a longer period of post-treatment prophylaxis against new infections, which is attributable to the significantly longer elimination half-life of mefloquine compared to lumefantrine.[37]
• AL vs. Other ACTs: A systematic review and meta-analysis comparing the safety of AL to other ACTs in children concluded that AL is as safe as artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP).[41] The analysis revealed some differences in the tolerability profiles; for instance, AL was associated with a significantly lower risk of vomiting compared to ASAQ.[41] Conversely, studies have shown that DP is superior to AL in preventing new malaria infections in the weeks following treatment, again due to the longer half-life of its partner drug, piperaquine.[31] This highlights a critical therapeutic trade-off: while AL is highly effective for curing the acute infection and is generally well-tolerated, ACTs with longer-acting partner drugs may offer a greater benefit in terms of preventing reinfection in high-transmission settings. This is a crucial consideration for national malaria control programs when selecting a first-line therapy.

3.4 Role in Global Malaria Treatment Guidelines (WHO)

The World Health Organization (WHO) guidelines for the treatment of malaria form the basis of national policies in most endemic countries. Artemisinin-based Combination Therapy (ACT) is the universally recommended first-line treatment for uncomplicated P. falciparum malaria.[42]

Artemether-lumefantrine holds a prominent place within these guidelines. It was the very first fixed-dose ACT to receive WHO pre-qualification, a process that certifies a drug's quality, safety, and efficacy, making it eligible for procurement by international aid organizations.[17] It is one of the six currently recommended ACTs for uncomplicated

P. falciparum malaria, alongside options like artesunate-amodiaquine, artesunate-mefloquine, and dihydroartemisinin-piperaquine.[43]

The WHO guidelines specify the standard 3-day, six-dose regimen and strongly emphasize the importance of administering each dose with food or a fatty drink to ensure adequate absorption and therapeutic efficacy.[23] The guidelines also provide specific recommendations for special populations. For pregnant women with uncomplicated

P. falciparum malaria, AL is recommended for treatment during the second and third trimesters. Following a review of safety data, the WHO updated its guidelines in November 2022 to also recommend AL as a treatment option during the first trimester, recognizing that the benefits of treating malaria in this vulnerable period outweigh the potential risks.[43]

Section 4: Safety, Tolerability, and Risk Management

4.1 Common and Serious Adverse Events

Artemether-lumefantrine is regarded as a well-tolerated antimalarial therapy. The vast majority of adverse events (AEs) reported in extensive clinical trials and post-marketing surveillance are of mild to moderate severity.[38] A significant challenge in assessing its safety profile is that many of the commonly reported AEs—such as headache, fever, dizziness, and gastrointestinal disturbances—are also cardinal symptoms of the underlying malaria infection, making it difficult to definitively attribute causality to the drug.[38]

In adult populations, the most frequently reported AEs include headache, dizziness, anorexia (loss of appetite), and asthenia (weakness or lack of energy).[1] In pediatric patients, the safety profile is similar, with the most common AEs being pyrexia (fever), cough, vomiting, anorexia, and headache.[1] A comprehensive systematic review focusing on children identified cough as the single most common AE, followed by other common events such as coryza (runny nose), vomiting, anaemia, and diarrhoea.[41]

While serious adverse events (SAEs) are infrequent, several are of clinical importance. The potential for QT interval prolongation is the most significant known risk, though it rarely leads to clinically apparent cardiac arrhythmias.[1] Rare but serious hypersensitivity reactions have been documented, including cases of urticaria (hives), angioedema (swelling of the deeper layers of the skin), and bullous eruptions.[1] Asymptomatic enlargement of the spleen (splenomegaly) and liver (hepatomegaly) has also been observed in a subset of patients during clinical trials.[1]

Comparative safety data provide additional context. A meta-analysis in children found that while AL was associated with a higher risk of body weakness compared to artesunate-mefloquine, it carried a significantly lower risk of vomiting than both artesunate-amodiaquine and the combination of chlorproguanil-dapsone-artesunate.[41] The risk of SAEs was also found to be significantly lower with AL compared to the chlorproguanil-dapsone-artesunate combination.[41]

4.2 Drug-Drug Interactions

The safety profile of lumefantrine is heavily influenced by its metabolic pathway and its intrinsic pharmacodynamic effects, leading to several clinically significant drug-drug interactions. The risk profile is not idiosyncratic but is largely predictable based on these two pharmacological characteristics. This allows for a proactive risk management strategy centered on careful medication review and patient screening.

4.2.1 Interactions via CYP3A4 Metabolism

Lumefantrine is both a substrate and a weak inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for the metabolism of a vast number of drugs.[1] This creates a high potential for pharmacokinetic interactions.

• Strong CYP3A4 Inducers: Co-administration with strong inducers of CYP3A4, such as the antibiotic rifampin, anticonvulsants like carbamazepine and phenytoin, and the herbal supplement St. John's wort, is contraindicated.[29] These agents can dramatically accelerate the metabolism of lumefantrine, leading to a significant decrease in its plasma concentrations and a high risk of therapeutic failure.[29]
• Strong CYP3A4 Inhibitors: Conversely, co-administration with strong inhibitors of CYP3A4, such as certain protease inhibitors (e.g., amprenavir) and azole antifungals (e.g., ketoconazole), can impair the metabolism of lumefantrine.[1] This leads to increased plasma concentrations, which may elevate the risk of toxicity, most notably an increased risk of QT interval prolongation.[1]

4.2.2 Additive QTc-Prolonging Effects

Due to its inherent effect on cardiac repolarization, lumefantrine should be avoided or used with extreme caution with other medications known to prolong the QT interval. The co-administration of such drugs can have an additive pharmacodynamic effect, substantially increasing the risk of serious cardiac arrhythmias. This class of interacting drugs is broad and includes Class IA and Class III antiarrhythmics (e.g., quinidine, amiodarone), certain antipsychotics (e.g., chlorpromazine), macrolide antibiotics (e.g., clarithromycin), fluoroquinolones, and other antimalarials with known cardiac effects like halofantrine and quinine.[1]

4.2.3 Other Clinically Relevant Interactions

• Hormonal Contraceptives: Lumefantrine has the potential to reduce the efficacy of hormonal contraceptives (e.g., oral pills, patches, rings). Patients of childbearing potential should be counseled to use an effective, non-hormonal backup method of contraception during and for a period after treatment.[48]
• Grapefruit Juice: Grapefruit and its juice are known inhibitors of intestinal CYP3A4. Consumption during treatment with artemether-lumefantrine should be avoided, as it may increase the systemic exposure of both components.[21]

A summary of the most critical drug-drug interactions is provided in Table 2 for clinical reference.

Table 2: Clinically Significant Drug-Drug Interactions with Artemether-Lumefantrine

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Effect	Management Recommendation	Source(s)
Strong CYP3A4 Inducers (e.g., Rifampin, Carbamazepine, Phenytoin, St. John's wort)	Induction of CYP3A4 metabolism	Significantly decreased plasma concentrations of lumefantrine and artemether, leading to loss of antimalarial efficacy.	Contraindicated.	29
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Protease Inhibitors)	Inhibition of CYP3A4 metabolism	Increased plasma concentrations of lumefantrine and artemether, increasing the risk of toxicity, particularly QT prolongation.	Avoid co-administration. If unavoidable, monitor closely for adverse effects, including ECG monitoring.	1
QTc-Prolonging Agents (e.g., Amiodarone, Quinine, Macrolides, Fluoroquinolones, Antipsychotics)	Additive pharmacodynamic effect on cardiac repolarization	Increased risk of significant QT interval prolongation and Torsades de Pointes.	Avoid co-administration.	1
Hormonal Contraceptives	Potential induction of metabolizing enzymes	Decreased effectiveness of the contraceptive, leading to a risk of unintended pregnancy.	Advise patient to use an additional, non-hormonal method of contraception during therapy.	48
Other Antimalarials (e.g., Mefloquine, Halofantrine)	Potential for additive toxicity (e.g., QTc prolongation) and altered metabolism	Increased risk of adverse events.	Avoid sequential use with mefloquine without a thorough risk assessment. Halofantrine should not be used.	1

4.3 Contraindications, Warnings, and Precautions

Based on its pharmacological profile, the use of artemether-lumefantrine is subject to specific contraindications and warnings.

• Contraindications: The primary contraindications are a known history of hypersensitivity to artemether, lumefantrine, or any of the excipients in the formulation, and the concurrent use of strong CYP3A4 inducers.[29]
• Warnings and Precautions: The main warning pertains to the risk of QT interval prolongation. The drug should be avoided in patients with congenital long QT syndrome, a family history of the condition, or any other clinical condition known to prolong the QTc interval. This includes patients with a history of symptomatic cardiac arrhythmias, clinically relevant bradycardia (slow heart rate), severe cardiac disease, and those with uncorrected electrolyte disturbances such as hypokalemia (low potassium) or hypomagnesemia (low magnesium).[21] Caution is also warranted in patients with severe hepatic or renal impairment, as pharmacokinetic data in these populations are limited.[21] Finally, due to the critical importance of food for absorption, patients who are unable to eat or tolerate food must be monitored closely for potential treatment failure.[21]

4.4 Safety Profile in Special Populations

• Pregnancy: Historically, there have been concerns about the use of artemisinins in the first trimester based on animal data suggesting a risk of fetal loss.[51] However, accumulating clinical safety data and the high risk posed by malaria to both mother and fetus have shifted this risk-benefit assessment. Clinical studies have not shown clinically relevant differences in pregnancy outcomes for women exposed to AL compared to older regimens like sulphadoxine-pyrimethamine.[38] Consequently, the WHO now recommends AL for the treatment of uncomplicated P. falciparum malaria in all trimesters of pregnancy.[43]
• Lactation: It is not known whether lumefantrine is excreted in human milk. Due to a lack of definitive data, caution is advised when administering the drug to a nursing woman.[23]
• Pediatrics: The artemether-lumefantrine combination has been extensively studied in children and is approved for use in infants as young as two months of age with a body weight of 5 kg or more.[22] The development of a sweet-tasting, dispersible tablet formulation in 2009 was a major advancement, significantly improving the ease of administration and likely adherence in this critical patient group.[33]

Section 5: Dosage, Administration, and Formulations

5.1 Standard Dosing Regimen for Artemether-Lumefantrine

The standard therapeutic course for artemether-lumefantrine is a fixed, six-dose regimen administered over a period of three days.[21] This dosing schedule has been optimized through extensive clinical trials to ensure maximum efficacy. The regimen is designed to provide sustained exposure to the fast-acting artemether over at least two full asexual parasite life cycles (approximately 48 hours each), while simultaneously allowing the slow-acting lumefantrine to accumulate to concentrations sufficient to prevent recrudescence.[10]

The specific timing of the doses is critical for achieving this therapeutic goal. An initial dose is administered at the time of diagnosis (hour 0). This is followed by a second dose 8 hours later. For the subsequent two days, one dose is administered twice daily, typically in the morning and evening.[23] This front-loaded schedule ensures high initial drug levels to rapidly control the infection.

5.2 Weight-Based Pediatric Dosing

In pediatric patients, the dosage is not fixed but is carefully calculated based on body weight to account for differences in drug distribution and metabolism, ensuring that children receive an equivalent therapeutic exposure to adults. The number of tablets per dose is adjusted according to predefined weight bands, as outlined by the WHO and regulatory agencies like the FDA.[21] The standard 20 mg artemether / 120 mg lumefantrine tablet is used for these calculations. The dosing schedule is summarized in Table 3.

Table 3: Weight-Based Dosing Schedule for Artemether-Lumefantrine Combination Therapy

Patient Body Weight (kg)	Tablets per Dose (20mg/120mg)	Total Tablets per 3-Day Course	Source(s)
5 to < 15 kg	1 tablet	6 tablets	21
15 to < 25 kg	2 tablets	12 tablets	21
25 to < 35 kg	3 tablets	18 tablets	21
≥ 35 kg	4 tablets	24 tablets	21

5.3 Administration Guidelines and Patient Counseling

Proper administration is paramount to the success of artemether-lumefantrine therapy, primarily due to the pharmacokinetic challenges posed by lumefantrine. Patient and caregiver counseling on the following points is essential:

• Administration with Food: Every dose must be taken with food or a drink containing fat, such as milk, infant formula, pudding, or porridge.[21] This is not an optional recommendation; it is a requirement for achieving adequate drug absorption and ensuring a clinical cure.[10]
• Administration to Patients with Swallowing Difficulties: For infants, young children, or any patient unable to swallow tablets whole, the tablets can be crushed immediately before administration and mixed with a small amount of water (1-2 teaspoons) or soft food.[29]
• Management of Vomiting: If the patient vomits within one to two hours of taking a dose, the full dose should be re-administered.[23] If the repeat dose is also vomited, it indicates a potential failure of oral therapy, and the patient should be given an alternative antimalarial treatment.[50]

5.4 Available Formulations

The evolution of artemether-lumefantrine formulations provides a clear example of how drug delivery can be adapted to overcome clinical challenges and meet the needs of specific patient populations. This progression demonstrates a critical lesson in global health: pharmacological innovation must be paired with practical, user-centered formulation development to achieve real-world impact.

• Fixed-Dose Combination Tablets: The most common formulation is a fixed-dose tablet containing 20 mg of artemether and 120 mg of lumefantrine.[10] An 80 mg / 480 mg strength tablet is also available, which simplifies dosing for adults and larger children requiring four of the lower-strength tablets per dose.[23]
• Dispersible Tablets: Recognizing the difficulty of administering crushed tablets to children, a pediatric dispersible formulation was developed and launched in 2009.[33] These tablets have a sweet taste and are designed to disperse quickly in a small amount of water, ensuring more accurate dosing and improving adherence in the most vulnerable patient group.[33]
• Next-Generation Formulations: The focus on formulation science continues. A new, lower-dose formulation specifically designed for infants and newborns weighing less than 5 kg has recently been approved by Swissmedic, addressing a previously unmet need in this highly vulnerable population.[33] Furthermore, research is actively underway on a solid dispersion formulation (SDF) of lumefantrine.[35] This advanced formulation technique aims to improve the dissolution and absorption of the poorly soluble lumefantrine, potentially overcoming its dependence on fatty food and allowing for simpler, more reliable dosing regimens in future combination therapies.[36]

Section 6: Developmental History and Regulatory Status

6.1 Discovery within China's Project 523

The origins of lumefantrine are inextricably linked to one of the most ambitious drug discovery programs of the 20th century. In response to a request from North Vietnam for aid in combating rampant malaria during the Vietnam War, Chinese leader Mao Zedong launched a massive, secret military research initiative on May 23, 1967.[53] This program, known as "Project 523," involved over 500 scientists from dozens of institutions across China.[55]

The project's most famous achievement was the rediscovery and isolation of artemisinin from the traditional medicinal herb Artemisia annua (sweet wormwood) by Tu Youyou and her team, a discovery for which she was awarded a share of the 2015 Nobel Prize in Physiology or Medicine.[56] Concurrently, other teams within Project 523 were tasked with synthesizing novel antimalarial compounds. It was within this parallel effort that a new series of quinoline derivatives was created, including the compound that would later be named lumefantrine (initially known as benflumetol).[14] The strategic insight to combine the fast-acting artemisinin derivatives with these new, longer-acting synthetic compounds was conceived early on within the project, laying the groundwork for modern Artemisinin-based Combination Therapy (ACT).[53]

6.2 Key Milestones in Clinical Development

Following the end of the Cultural Revolution and the opening of China to the West in the 1980s, the discoveries of Project 523 began to attract international attention.[53] The Swiss pharmaceutical company Novartis (then Ciba-Geigy) recognized the potential of combining artemether with lumefantrine. This collaboration led to the development of the first stable, quality-assured, fixed-dose ACT. The combination came into medical use in 1992 and was first launched under the brand name Coartem® in 1999.[33]

A pivotal moment in its history occurred in 2001, when artemether-lumefantrine became the first fixed-dose ACT to meet the stringent pre-qualification criteria of the World Health Organization for efficacy, safety, and quality.[33] This pre-qualification made it eligible for procurement by major international donors like the Global Fund, paving the way for its widespread adoption in malaria-endemic countries. In partnership with the non-profit product development partnership Medicines for Malaria Venture (MMV), Novartis launched a pediatric dispersible formulation in 2009, a major innovation to improve treatment in children.[33] This trajectory—from a secret military project to a commercially developed product, and finally to a globally subsidized public health tool—illustrates a paradigm shift in drug development, requiring a hybrid model of public-private partnership to tackle diseases of poverty.

6.3 Global Regulatory Approvals

Artemether-lumefantrine has received approval from the world's most stringent regulatory authorities and is now registered in over 80 countries.[33]

• U.S. Food and Drug Administration (FDA): On April 7, 2009, the FDA approved Coartem® for the treatment of acute, uncomplicated P. falciparum malaria. This was a landmark event, as it was the first ACT to be approved for use in the United States.[28] The initial approval was for patients weighing at least 5 kg, which was later expanded to include infants from 2 months of age.[22]
• European Medicines Agency (EMA): The combination is also approved for use in the European Union, where it is often marketed as Riamet®.[33] The EMA's Committee for Medicinal Products for Human Use (CHMP) has reviewed paediatric investigation plans for the drug, and it serves as a standard comparator in the regulatory submissions for new antimalarials in Europe.[37] In 2010, the EMA granted an orphan designation for a powder for oral suspension formulation of beta-artemether/lumefantrine, recognizing its potential benefit for patients with difficulty swallowing tablets.[60]
• Swissmedic: The Swiss agency for therapeutic products approved the combination (as Riamet®). More recently, in a significant development in July 2025, Swissmedic approved a novel formulation, "Coartem Baby," specifically developed and dosed for the treatment of malaria in infants and newborns weighing less than 5 kg.[33]

6.4 Brand Names and Generic Status

The most widely recognized brand names for the artemether-lumefantrine combination are Coartem® and Riamet®, both marketed by Novartis.[1] In the United States, there is currently no FDA-approved, therapeutically equivalent generic version of Coartem® available.[61] However, in many malaria-endemic countries, numerous other branded generic versions are commercially available.[45] The proliferation of these alternative brands has raised significant public health concerns regarding their quality, as studies have shown that a substantial proportion of these products may be substandard, containing incorrect amounts of the active pharmaceutical ingredients, which can lead to treatment failure and foster the development of drug resistance.[62]

Section 7: Concluding Analysis and Future Perspectives

7.1 Summary of Lumefantrine's Clinical Value

Lumefantrine, as the long-acting partner in the artemether-lumefantrine combination, represents a triumph of modern pharmacotherapy and global public health collaboration. Its role is indispensable. By providing a sustained parasiticidal effect that complements the rapid but short-lived action of artemether, it ensures a definitive cure and prevents the recrudescence that plagued early artemisinin monotherapies. The resulting fixed-dose ACT is highly effective against multidrug-resistant P. falciparum, generally well-tolerated across a wide age spectrum, and has become the most widely deployed antimalarial treatment in the world. The continuous innovation in its formulation, from standard tablets to dispersible pediatric versions and now infant-specific doses, has further cemented its role in protecting the most vulnerable populations and has undoubtedly saved millions of lives.

7.2 Challenges: Bioavailability, Adherence, and Counterfeit Drugs

Despite its profound success, the long-term utility of lumefantrine is shadowed by persistent and complex challenges. These threats are not primarily rooted in the molecule's intrinsic pharmacology, which is well-understood, but rather in systemic issues related to its clinical use and supply chain integrity.

• Bioavailability: The Achilles' heel of lumefantrine remains its poor, fat-dependent oral absorption.[10] This creates a high risk of sub-therapeutic drug exposure and subsequent treatment failure, particularly in acutely ill, anorexic, or malnourished patients who cannot consume the requisite fatty food.[27] This is a fundamental vulnerability that requires constant clinical vigilance and patient education.
• Adherence: The six-dose, three-day regimen, while pharmacokinetically optimized, can be challenging for patients and caregivers to complete perfectly, especially in resource-limited settings. Incomplete adherence can compromise efficacy and contribute to the selection of drug-resistant parasites.
• Counterfeit and Substandard Drugs: The global success and high demand for artemether-lumefantrine have made it a lucrative target for counterfeiters. The widespread circulation of poor-quality and falsified medicines in many endemic regions poses a grave, dual threat. It leads directly to treatment failures and deaths, and by exposing parasite populations to sub-lethal drug concentrations, it creates an ideal environment for the selection and spread of drug resistance.[45]

7.3 The Evolving Landscape: Resistance and Next-Generation Combinations

The future of lumefantrine will be defined by the continuous evolutionary battle against the malaria parasite and by ongoing innovation in pharmaceutical science.

• The Threat of Resistance: While the artemether-lumefantrine combination remains highly effective in most regions, the emergence and spread of artemisinin resistance in Southeast Asia is a major global health threat.[55] The discovery that lumefantrine can synergistically enhance artemisinin activity against resistant parasites is a crucial advantage.[19] However, the potential for the parasite to develop resistance to lumefantrine itself necessitates vigilant surveillance and proactive strategies to preserve its efficacy.
• Future Perspectives: Lumefantrine is poised to remain a vital component of the antimalarial arsenal for the foreseeable future. Its established safety and efficacy profile make it an attractive partner drug for novel antimalarial compounds. The most promising development is the investigation of a new combination of ganaplacide (KAF156) with an advanced lumefantrine solid dispersion formulation (SDF).[35] This next-generation therapy aims to address the key challenges of the current regimen by enhancing lumefantrine's bioavailability, offering a simpler (potentially single-day) dosing schedule, and providing a new mechanism of action to combat resistant parasites. This ongoing research underscores lumefantrine's enduring value and its adaptability as a cornerstone in the next wave of antimalarial therapies.

Ultimately, preserving the immense public health value of lumefantrine depends on a multi-pronged strategy. This includes continued pharmacological innovation to overcome its bioavailability limitations, robust public health programs to ensure adherence, and strengthened regulatory and law enforcement systems to secure the global supply chain against the existential threat of counterfeit drugs. The fight to maintain lumefantrine's efficacy is a fight on biological, clinical, and logistical fronts.

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