EURARTESIM FILM COATED TABLETS

Indications

• Uncomplicated malaria caused by Plasmodium falciparum
• Malaria in combination with other antimalarial medications

Dosage

Children: Refer to BNF for Children for age-appropriate dosing recommendations.

Adults: Refer to BNF for specific dosing guidelines based on the severity of malaria and combination therapy used. Commonly used doses may vary.

Mechanism of action

Dihydroartemisinin acts by binding to haem within the Plasmodium falciparum parasite. It is believed to bind to haem produced during the parasite's haem biosynthesis pathway in the early ring stage, and later to haem released from haemoglobin digestion. This binding triggers a reductive scission of the endoperoxide bridge, leading to the generation of a reactive oxygen species. This species further leads to the formation of a reactive carbon radical, which alkylates multiple protein targets within the parasite, contributing to its antimalarial activity. Notably, it irreversibly inhibits the sarco/endoplasmic reticulum Ca2+ ATPase pump of Plasmodium falciparum.

Pharmacodynamics

Dihydroartemisinin forms a reactive carbon radical intermediate that is instrumental in killing Plasmodium falciparum through the alkylation of diverse proteins. This mechanism is thought to disrupt various cellular functions within the parasite, ultimately leading to its death.

Pharmacokinetics

Dihydroartemisinin is rapidly absorbed following oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. It is extensively metabolized in the liver, primarily through cytochrome P450 enzymes, leading to the formation of several metabolites. The elimination half-life is relatively short, ranging from 1 to 3 hours. The drug is primarily excreted in urine and bile, making it effective for short-term treatment but necessitating multiple doses for sustained efficacy.

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Dizziness
• Headache
• Fatigue
• Abdominal pain

Precautions

• Use with caution in patients with a history of hypersensitivity to artemisinin derivatives.
• Monitor for signs of malaria treatment failure, especially in cases of severe malaria.
• Assess liver function prior to and during treatment, as hepatic impairment can affect drug metabolism.

Pregnancy

Dihydroartemisinin is classified as category C. Animal studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in pregnant women. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Dihydroartemisinin is excreted in breast milk. Caution should be exercised when administering to nursing mothers. The effects on the infant are unknown.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Oral tablets
• Injectable solution

Indications

• Plasmodium falciparum malaria
• Uncomplicated malaria
• Treatment of malaria in combination with other antimalarials

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing information.

Adults: Refer to the BNF for specific dosing information based on the treatment regimen and patient condition.

Mechanism of action

The mechanism of piperaquine inhibition of the haem detoxification pathway is unknown but is expected to be similar to that of other antimalarial agents. It is thought to interfere with the parasite's ability to detoxify haem, leading to toxic accumulation within the parasite, thereby inhibiting its growth and replication.

Pharmacodynamics

Piperaquine exhibits a mechanism of action that inhibits the Plasmodium falciparum parasite's haem detoxification pathway. This action is crucial in preventing the survival of the parasite within the host, leading to a reduction in parasitemia and clinical symptoms associated with malaria.

Pharmacokinetics

Piperaquine displays a relatively long half-life, allowing for once-daily dosing in treatment regimens. It is well absorbed following oral administration, with peak plasma concentrations achieved within several hours. The drug is extensively distributed in body tissues, and its elimination involves hepatic metabolism and renal excretion. The pharmacokinetics may be influenced by various drug interactions.

Interactions

• grapefruit juice: Severe (increases concentration)
• mitotane: Severe (decreases concentration)
• St John's Wort: Severe (decreases concentration)
• rifampicin: Severe (decreases concentration)
• dronedarone: Unknown (increases concentration)
• cobicistat: Unknown (increases concentration)
• crizotinib: Unknown (increases concentration)
• idelalisib: Unknown (increases concentration)
• imatinib: Unknown (increases concentration)
• letermovir: Unknown (increases concentration)

Pregnancy

Data on the use of piperaquine in pregnancy are limited. Consult local guidelines for the management of malaria in pregnant women.

Breast-feeding

Piperaquine is excreted in breast milk; caution should be exercised when administering to breastfeeding women.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Piperaquine phosphate tablet

Dosage

Children: Refer to relevant safety guidelines, as specific dosing information for clinical use is not provided in the BNF.

Adults: Refer to relevant safety guidelines, as specific dosing information for clinical use is not provided in the BNF.

Mechanism of action

Tetrachloride is a non-polar solvent that dissolves a wide range of organic compounds. It disrupts cellular membranes and can interfere with metabolic processes by forming reactive intermediates, leading to cellular damage. The mechanism may also involve the induction of oxidative stress and mitochondrial dysfunction.

Pharmacodynamics

The pharmacodynamic effects of tetrachloride are primarily linked to its role as a solvent and its cytotoxic properties. It can cause cellular damage, particularly in the liver, through lipid peroxidation and disruption of cellular integrity. Its effects may vary based on exposure duration, concentration, and route of administration, leading to acute or chronic toxicity.

Pharmacokinetics

Tetrachloride is absorbed through the respiratory tract, gastrointestinal tract, and skin. Once in the bloodstream, it distributes widely throughout body tissues, particularly in adipose tissue and the liver, where it undergoes biotransformation via cytochrome P450 enzymes. The elimination half-life can vary, but it is primarily excreted through the urine as metabolites. Accumulation may occur with prolonged exposure, leading to increased toxicity.

Pregnancy

There is insufficient data on the safety of tetrachloride in pregnancy. Caution is advised.

Breast-feeding

Caution is advised as the effects on nursing infants are not well-studied.

Storage

Store in a cool, dry place away from direct sunlight and heat sources. Keep in tightly closed containers.

Dosage

Children: Refer to specific drug information for paediatric dosing guidelines, as this will depend on the active compound and its therapeutic use.

Adults: Refer to specific drug information for adult dosing guidelines, as this will depend on the active compound and its therapeutic use.

Mechanism of action

The mechanism of action will depend on the specific active compound that is in the tetrahydrate form. Generally, tetrahydrates can improve the bioavailability of a drug by facilitating its dissolution in bodily fluids, which can enhance absorption in the gastrointestinal tract.

Pharmacodynamics

Pharmacodynamics will vary based on the specific drug in the tetrahydrate form. However, it generally involves the interaction of the drug with specific receptors or enzymes in the body, influencing physiological and biochemical processes. Tetrahydrate forms may affect the pharmacokinetics of the drug, altering its efficacy and safety profile.

Pharmacokinetics

Pharmacokinetics of a tetrahydrate form will depend on the parent compound. Typically, factors such as absorption, distribution, metabolism, and excretion can be influenced by the hydration state of the drug. Hydrates may have different solubility and stability profiles, which can impact the rate and extent of drug absorption.

Dosage

Children: Refer to specific guidelines or clinical recommendations for appropriate dosing.

Adults: Refer to specific guidelines or clinical recommendations for appropriate dosing.

Mechanism of action

Tetraphosphate acts as a phosphate donor in biochemical reactions, participating in the transfer of phosphate groups to other molecules. This mechanism is essential in the regulation of metabolic pathways and energy production within cells.

Pharmacodynamics

As a polyphosphate, tetraphosphate influences cellular processes by modulating the availability of phosphate. The compound is involved in energy metabolism, particularly in the synthesis and hydrolysis of ATP, and may also impact nucleic acid metabolism and signaling pathways that rely on phosphate.

Pharmacokinetics

The pharmacokinetics of tetraphosphate are not well-documented; however, it is generally assumed that, like other phosphate compounds, it may be absorbed and utilized in various tissues, with renal excretion being a likely route for elimination.

Indications

• pH stabilization in pharmaceutical formulations
• solubilization of poorly soluble drugs
• buffering agent in injectable preparations

Dosage

Children: Refer to specific product guidelines for paediatric dosing as it may vary based on formulation.

Adults: Refer to specific product guidelines for adult dosing as it may vary based on formulation.

Mechanism of action

Tetrasodium functions primarily as a buffering agent, helping to maintain the pH of pharmaceutical preparations. This stabilization is crucial in ensuring the solubility and bioavailability of active pharmaceutical ingredients, thereby enhancing their therapeutic effects.

Pharmacodynamics

The pharmacodynamic properties of tetrasodium relate to its ability to modulate pH levels in a solution. By maintaining optimal pH conditions, tetrasodium aids in preserving the stability and efficacy of various drugs, improving their overall therapeutic action.

Pharmacokinetics

Tetrasodium is generally not absorbed systemically when used in pharmaceutical formulations, as its primary role is localized within the preparation. Its pharmacokinetic profile is largely influenced by its solubility and stability in solution, which can affect the release and absorption of the active ingredients it is combined with.

Mechanism of action

Artemisinins, including Artenimol which is a major active metabolite of many artemisinins, are thought to act via a common mechanism. While the exact mechanism of action is not certain, theories exist as to how artemisinins produce their antimalarial effect. Artemisinins are believed to bind to haem within the *P. falciparum* parasite. The source of this haem varies with the life stage of the parasite. When the parasite is in the early ring stage artemisinins are believed to bind haem produced by the parasite's haem biosynthesis pathway. In later stages artemisinins likely bind to haem released by haemoglobin digestion. Once bound to haem, artemisinins are thought to undergo activation involving ferrous iron via reductive scission which splits the endoperoxide bridge to produce a reactive oxygen. This reactive oxygen is thought to undergo a subsequent intramolecular hydrogen abstraction to produce a reactive carbon radical. The carbon radical is believed to be the source of the drugs potent activity against *P. falciparum* by alkylating a wide array of protein targets. The nature and magnitude of the effect on specific protein function as a result of this alkylation is unknown. One target which has been the focus of research is the sarco/endoplasmic reticulum Ca2+ ATPase pump of *P. falciparum*. Artemisinins have been found to irreversably bind to and inhibit this protein at a binding site similar to that of Thapsigargin. The mechanism is likely the same as for other proteins, namely alkylation via the carbon radical intermediate. Artemisinins appear to preferentially collect in infected erythrocytes, concentrating the drug by several hundred-fold compared to uninfected cells. This may play a role in why little alkylation is seen in uninfected erythrocytes. A 2025 systematic review notes Dihydroartemisinine's pharmacological activities as being antimalarial and anticancer, and that it has shown promise in improving nonalcoholic steatohepatitis (NASH) by reducing  liver fat, inflammation, and fibrosis via Inhibition of  lipogenesis (SREBP-1c, FASN, SCD1) and promotion of  lipolysis (PGC1α, CPT-1a).

Pharmacodynamics

Artenimol is thought to form a reactive carbon radical intermediate which kills *P. falciparum* through alkylation of a wide array of proteins.

Mechanism of action

The mechanism of piperaquine inhibition of the haem detoxification pathway is unknown but is expected to be similar to that of [DB00608].

Pharmacodynamics

Piperaquine inhibits the P. Falciparum parasite's haem detoxification pathway.