MALOFF TABLETS

Indications

• Uncomplicated malaria caused by Plasmodium falciparum
• Malaria treatment in combination with lumefantrine

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Refer to specific guidelines; typically, artemether is administered in a combination therapy regimen with lumefantrine.

Mechanism of action

Artemether interacts with ferriprotoporphyrin IX (heme) in the acidic vacuole of malaria parasites, leading to the generation of cytotoxic radical species. This interaction involves the activation of the drug by reduced heme or ferrous iron, resulting in the formation of oxygen-centered radicals that subsequently convert into carbon-centered radicals. These radicals are toxic to the parasites, thereby inhibiting their growth and reproduction.

Pharmacodynamics

Artemether is rapidly metabolized to its active metabolite, dihydroartemisinin. It primarily targets the erythrocytic stages of Plasmodium falciparum by inhibiting nucleic acid and protein synthesis. The drug has a rapid onset of action, providing quick symptomatic relief by significantly reducing the number of circulating malarial parasites. In combination therapy with lumefantrine, artemether enhances overall treatment effectiveness and contributes to a higher clinical cure rate.

Pharmacokinetics

Artemether is absorbed quickly, with a rapid onset of action. It is metabolized in the liver to dihydroartemisinin, which is the active form responsible for its antimalarial effects. The drug is eliminated from the body relatively quickly, while lumefantrine, which has a longer half-life, aids in clearing any residual parasites. This pharmacokinetic profile supports the use of artemether in combination therapies for malaria.

Adverse effects

• nausea
• vomiting
• dizziness
• headache
• fatigue
• abdominal pain
• anemia
• QT prolongation

Interactions

• mitotane+artemether with lumefantrine: Severe (decreases exposure)
• mitotane+artemether: Severe (decreases exposure)
• rifampicin+artemether: Severe (decreases exposure)
• grapefruit juice+artemether: Unknown (increases exposure)
• efavirenz+artemether: Unknown (decreases concentration)
• etravirine+artemether: Unknown (decreases exposure)

Precautions

• Monitor for signs of hypersensitivity reactions
• Use with caution in patients with pre-existing QT prolongation
• Assess liver function before use, as hepatic impairment may alter drug metabolism

Pregnancy

Artemether is categorized as pregnancy category C. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Artemether is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• artemether/lumefantrine combination tablets
• artemether oral solution

Indications

• Uncomplicated Plasmodium falciparum malaria
• Prevention of malaria in at-risk populations

Dosage

Children: Refer to the BNF for Children for specific dosage recommendations.

Adults: Refer to the BNF for specific dosage recommendations.

Mechanism of action

Lumefantrine acts by forming complexes with heme, a byproduct of hemoglobin degradation in the malaria parasite. This interaction interferes with the detoxification of heme, leading to the accumulation of toxic heme in the parasite, ultimately resulting in its death.

Pharmacodynamics

Lumefantrine has a rapid onset of action, particularly when used in combination therapy. It exhibits a concentration-dependent effect on the malaria parasites, with its efficacy enhanced when administered alongside artemether. The combination helps to reduce the likelihood of resistance development and increases the overall effectiveness of treatment.

Pharmacokinetics

Lumefantrine is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 6 to 8 hours after oral administration. It is highly lipophilic, leading to accumulation in body tissues. The drug is extensively metabolized in the liver via cytochrome P450 enzymes, particularly CYP3A4, and has a long half-life, allowing for sustained therapeutic levels. The elimination half-life ranges from 3 to 6 days, facilitating once or twice daily dosing in combination regimens.

Contra-indications

• Hypersensitivity to lumefantrine or any of its components
• Severe hepatic impairment
• Certain arrhythmias (e.g., congenital long QT syndrome)

Adverse effects

• Headache
• Dizziness
• Nausea
• Vomiting
• Diarrhea
• Fatigue
• Abdominal pain
• Palpitations
• QT interval prolongation

Interactions

• Concomitant use with other drugs that prolong the QT interval (e.g., certain antiarrhythmics, antipsychotics)
• May interact with CYP3A4 inducers (e.g., rifampicin, St John's wort) which can decrease lumefantrine levels
• May interact with CYP3A4 inhibitors (e.g., ketoconazole) which can increase lumefantrine levels

Precautions

• Monitor for signs of arrhythmia, especially in patients with pre-existing heart conditions
• Use with caution in patients with a history of seizures
• Assess for potential drug interactions before initiation

Pregnancy

Lumefantrine is categorized as pregnancy category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Limited data suggests that lumefantrine is excreted in breast milk. Caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature, away from moisture and direct sunlight. Keep out of reach of children.

Formulations

• Film-coated tablets
• Combination with artemether (as artemether-lumefantrine)

Mechanism of action

Involves an interaction with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals. Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Two theories have been put forward for the mode of antimalarial action of the artemisinin antimalarials, in accodance with the known properties of peroxides with medicinal activity. The first assumes that the artemisinins must be activated by contact with either reduced haem (ferrous haem, Fe(ll)PPIX) or non-haem ferrous iron (exogenous iron), causing cleavage of the peroxide to generate oxygen-centered radicals (alkoxy radicals') which are then presumed to be converted into carbon-centered radicals by transfer of proximate hydrogen atoms from the periphery of the peroxide molecule. These carbon-centered radicals are then thought to alkylate sensitive, yet unspecified, biomolecules in the parasite. A second theory argues for a process in which the intact artemisinin binds to a site within a vital protein in the parasite. The act of binding causes the peroxide to be converted to hydroperoxide or similar open peroxide, which in accordance with known properties of such compounds, generates one or more active chemical entities, either oxidizing agents or oxygen transfer agents per se, or oxygen-centered free radicals. This would be associated with the binding process. In such a way, the artemisinins might act as (irreversibile) inhibitors. Iron may, or may not, be associated with the activation process. No specific biological target in the parasite has yet been identified in support of this theory, but it may be membrane-bound proteins. A 2025 systematic review notes Artemether's pharmacological activity is antimalarial.

Pharmacodynamics

In the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin. The drug works against the erythrocytic stages of <i>P. falciparum</i> by inhibiting nucleic acid and protein synthesis. Artemether is administered in combination with lumefantrine for improved efficacy. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thought that artemether provides rapid symptomatic relief by reducing the number of malarial parasites. Lumefantrine has a much longer half life and is believed to clear residual parasites.