Antimalarial (artemisinin-based combination, ACT)
Dihydroartemisinin + piperaquine is a combined antimalarial medicine (ACT), used to treat uncomplicated Plasmodium falciparum malaria in adults and children. It prolongs the QT interval of the heart, so it must not be combined with other drugs that have the same effect.
Also known as: Eurartesim
Clarithromycin prolongs QT and inhibits CYP3A4 (which metabolises Piperaquine) — high risk of arrhythmias.
Piperaquine is partly metabolised by CYP3A4; clarithromycin inhibits this enzyme and can raise its concentrations, and both prolong the QT interval — the torsades de pointes risk is additive and potentially severe. During antimalarial treatment with dihydroartemisinin+piperaquine, prefer an antibiotic without QT effects; if the combination is unavoidable, monitor the ECG and electrolytes.
Dihydroartemisinin+piperaquine + clarithromycin: clarithromycin raises piperaquine levels and both prolong the QT. Avoid the combination.
Additive QT prolongation + enzymatic inhibition raising Piperaquine exposure.
ECG (QTc) and electrolytes.
Palpitations, syncope.
Avoid the association; consider an alternative antibiotic.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Clarithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d836ae7e-fdbf-4dcb-a90d-ede1dcbc3e67
Carbamazepine (an inducer) lowers Piperaquine and Dihydroartemisinin levels — risk of treatment failure.
Carbamazepine induces CYP3A4, an important pathway in dihydroartemisinin and piperaquine metabolism; antimalarial levels can fall below the therapeutic threshold, compromising cure. In addition, piperaquine prolongs the QT — in epileptic patients treated with carbamazepine, prefer an alternative antimalarial (e.g. atovaquone+proguanil, which is also less CYP3A4-dependent) and monitor the clinical and parasitological response if the combination is unavoidable.
Carbamazepine + dihydroartemisinin+piperaquine: carbamazepine induces antimalarial metabolism, with risk of subtherapeutic levels. Avoid if possible.
Enzymatic induction (CYP3A4) accelerating metabolism of the ACT components.
Clinical and parasitological response.
Persistent or recurrent fever.
Consider an alternative ACT and confirm parasitological cure.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2
Both prolong QT — combining adds no benefit and increases arrhythmic risk.
Piperaquine (the dihydroartemisinin-piperaquine component, Eurartesim) prolongs the QT interval in a dose-dependent way and the EMA EPAR contraindicates co-administration with other QT-prolonging drugs; the mefloquine label, in turn, documents QTc prolongation and advises against drugs that alter cardiac conduction. Combining these antimalarials is not used in practice (they are alternatives to each other), but overlap can occur in patients with therapeutic failure or severe malaria, especially with hypokalaemia, hypomagnesaemia, bradycardia or cardiac disease. Avoid; if unavoidable, monitor the ECG and electrolytes before and during therapy and correct hypokalaemia/hypomagnesaemia.
Dihydroartemisinin-piperaquine + mefloquine: additive QT. Avoid the combination (EMA contraindicates QT-prolonging drugs); ECG if unavoidable.
Additive QT prolongation.
ECG and neurological surveillance.
Palpitations, dizziness, seizures.
Avoid; use a single antimalarial regimen.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Mefloquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09716a24-d7da-42b2-af29-c03a1b6670bd
Risk of additive QT prolongation; not combined in clinical practice.
Piperaquine (the dihydroartemisinin-piperaquine component, Eurartesim) prolongs the QT interval in a dose-dependent way and the EMA EPAR contraindicates co-administration with other QT-prolonging drugs, including quinine, chloroquine and amodiaquine; the quinine label, in turn, documents consistent, dose-dependent QT prolongation with potentially fatal ventricular arrhythmias (torsade de pointes, ventricular fibrillation), recommending avoiding other QT-prolonging drugs. The combination is not used in antimalarial practice (quinine is an alternative to the artemisinin derivatives), but overlap can occur in patients with therapeutic failure or severe malaria, especially with hypokalaemia, hypomagnesaemia, bradycardia or cardiac disease. Avoid; if unavoidable, monitor the ECG and electrolytes before and during therapy and correct hypokalaemia/hypomagnesaemia.
Quinine + dihydroartemisinin-piperaquine: additive QT (piperaquine prolongs the QT). Avoid the combination; ECG if unavoidable.
Additive effect on cardiac repolarisation.
ECG (QTc) and signs of toxicity.
Palpitations, tinnitus, syncope.
Avoid; choose a single regimen.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Quinine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f32f05c-a215-40be-b951-e41a7b54a8a0
Additive QT prolongation (Piperaquine + Ciprofloxacin) — risk of ventricular arrhythmias.
Piperaquine (component of the dihydroartemisinin+piperaquine combination used in malaria) significantly prolongs the QT interval, and ciprofloxacin adds the fluoroquinolone class effect. The combination increases the risk of torsade de pointes, especially in patients with long QT, hypokalaemia or taking other QT-prolonging drugs. The European EPAR for Eurartesim recommends caution with QT-prolonging drugs. If the combination is unavoidable, monitor the ECG and electrolytes and avoid other risk factors.
Ciprofloxacin + dihydroartemisinin+piperaquine: additive risk of QT prolongation. Avoid or monitor the ECG.
Additive effect on cardiac repolarisation.
ECG (QTc) and electrolytes.
Palpitations, syncope.
Caution in at-risk patients; ECG if symptoms.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Ciprofloxacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14c3bc33-201d-492e-9aee-a4d84c813a3d
Piperaquine prolongs QT; combining with Amiodarone raises the risk of ventricular arrhythmias (e.g. torsades de pointes).
Piperaquine markedly prolongs the QT interval (hERG blockade) and has been associated with torsades de pointes, especially in combination with other QT-prolonging drugs such as amiodarone. The risk is higher with a prolonged baseline QT, hypokalaemia, hypomagnesaemia or heart disease. In patients on chronic amiodarone, prefer an antimalarial without QT effects. If the combination is unavoidable, monitor the ECG and electrolytes and avoid other risk factors.
Dihydroartemisinin+piperaquine + amiodarone: additive QT prolongation (piperaquine). Avoid the combination or monitor the ECG.
Additive effect on cardiac repolarisation.
ECG (QTc), potassium and magnesium.
Syncope, palpitations, seizures.
Avoid; if unavoidable, strict cardiac monitoring (ECG and electrolytes).
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim ; DailyMed/FDA (NIH/NLM) — approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d
Alcohol may potentiate central nervous system effects during treatment; limit intake.
Limit alcohol intake during treatment.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim
Taking with food increases piperaquine absorption; it is recommended to take with food to reduce variability.
Take with food, preferably at the same daily meal.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim
Dihydroartemisinin and piperaquine are metabolised in the liver; in severe liver disease exposure may increase and requires caution.
Use with caution in severe liver disease.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim
Piperaquine significantly prolongs the QT interval; the arrhythmia risk increases in patients with QT prolongation or with QT-prolonging drugs.
Avoid in known QT prolongation or with QT-prolonging drugs; monitor ECG.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim
Dihydroartemisinin + piperaquine is recommended by WHO for malaria in pregnancy in the 2nd and 3rd trimesters; data in the 1st trimester are limited.
Use in the 2nd and 3rd trimesters; in the 1st trimester, consider only if the benefit outweighs the risk.
Excreted into breast milk in small amounts; compatible with breastfeeding under supervision.
Possible CYP3A4 induction by artemisinin derivatives — consider an additional contraceptive method if a hormonal contraceptive is used.
EMA — EPAR Eurartesim (dihydroartemisinin + piperaquine): https://www.ema.europa.eu/en/medicines/human/EPAR/eurartesim
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Fixed-dose combination antimalarial (artenimol/dihydroartemisinin and piperaquine). Artenimol is very rapidly absorbed (Tmax 1 to 2 hours); piperaquine, highly lipophilic, is slowly absorbed (Tmax about 5 hours) and accumulates in plasma (accumulation factor about 3). Associated with QTc prolongation — administer with water, at least 3 hours after the last food intake.
Artenimol has antimalarial activity attributed to the endoperoxide moiety; piperaquine is a long-acting blood schizonticide. Artenimol is an inhibitor of CYP1A2; piperaquine inhibits CYP3A4 (also in a time-dependent way) and, to a lesser extent, CYP2C19, while it stimulates CYP2E1.
Artenimol: Tmax about 1 to 2 hours; piperaquine: Tmax about 5 hours. A high-fat meal increases artenimol exposure by 43% and piperaquine exposure about 3-fold, with a greater effect on the QT interval — hence the recommendation to take it while fasting (water, 3 hours before and after the dose).
Artenimol is principally converted to a glucuronide (UGT1A9 and UGT2B7), with no cytochrome P450-mediated metabolism. Piperaquine is metabolised mainly by CYP3A4 and, to a lesser extent, CYP2C9 and CYP2C19; main metabolites: a carboxylic acid cleavage product and a mono-N-oxide. Artenimol is eliminated mainly by metabolism (glucuroconjugation).
Elimination half-life of artenimol of about 1 hour; half-life of piperaquine of about 22 days in adults (about 20 days in children), with accumulation after multiple dosing. Piperaquine is >99% bound to plasma proteins; artenimol 44 to 93%.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
