EURARTESIM Film-coated tablet Ref.[10713] Active ingredients: Artenimol Artenimol and Piperaquine Piperaquine

Eurartesim should not be used to treat severe falciparum malaria (see section 4.3) and, due to insufficient data, should not be used to treat malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale.

The long half-life of piperaquine (about 22 days) should be kept in mind in the event that another antimalarial agent is started due to treatment failure or a new malaria infection (see below and sections 4.3 and 4.5).

Piperaquine is a mild inhibitor of CYP3A4. Caution is recommended when co-administering Eurartesim with medicinal products exhibiting variable patterns of inhibition, induction or competition for CYP3A4 as the therapeutic and/or toxic effects of some co-administered medicinal products could be altered.

Piperaquine is also a substrate of CYP3A4. A moderate increase of piperaquine plasma concentrations (<2-fold) was observed when co-administered with strong CYP3A4 inhibitors, resulting in a potential exacerbation of the effect on QTc prolongation (see section 4.5).

Exposure to piperaquine may also be increased when co-administered with mild or moderate CYP3A4-inhibitors (e.g. oral contraceptives). Therefore, caution should be applied when co-administering Eurartesim with any CYP3A4-inhibitor and ECG monitoring should be considered.

Due to the lack of multiple dose PK data for piperaquine, administration of any strong CYP3A4-inhibitors should be discouraged after initiation (i.e. the first dose) of Eurartesim (see sections 4.5 and 5.2).

Eurartesim should not be used during the 1st trimester of pregnancy in situations where other suitable and effective antimalarials are available (see section 4.6).

In the absence of carcinogenicity study data, and due to lack of clinical experience with repeated courses of treatment in humans, no more than two courses of Eurartesim should be given in a 12-month period (see sections 4.2 and 5.3).

Effects on cardiac repolarization

In clinical trials with Eurartesim limited ECGs were obtained during treatment. These showed that QTc prolongation occurred more frequently and to a larger extent in association with Eurartesim therapy than with the comparators (see section 5.1 for details of the comparators). Analysis of cardiac adverse events in clinical trials showed that these were reported more frequently in Eurartesim treated patients than in those treated with comparator antimalarial (see section 4.8). Before the third dose of Eurartesim, in one of the two Phase III studies 3/767 patients (0.4%) were reported to have a QTcF value of >500 ms versus none in the comparator group.

The potential for Eurartesim to prolong the QTc interval was investigated in parallel groups of healthy volunteers who took each dose with high (~1000 Kcal) or low (~400 Kcal) fat/calorie meals or in fasting conditions. Compared to placebo, the maximum mean increases in QTcF on Day 3 of dosing with Eurartesim were 45.2, 35.5 and 21.0 msec under respective dosing conditions. The QTcF prolongation observed under fasting conditions lasted between 4 and 11 hours after the last dose was administered on Day 3. The mean QTcF prolongation compared to placebo decreased to 11.8 msec at 24 hours and to 7.5 msec at 48 hours. No healthy subject dosed in fasting conditions showed a QTcF greater than 480 msec or an increase over baseline greater than 60 msec. The number of subjects with QTcF greater than 480 msec after dosing with low fat meals was 3/64, while 10/64 had QTcF values over this threshold after dosing with high fat meals. No subject had a QTcF value greater than 500 msec in any of the dosing conditions.

An ECG should be obtained as early as possible during treatment with Eurartesim and ECG monitoring should be applied in patients who may have a higher risk of developing arrhythmia in association with QTc prolongation (see below).

When clinically appropriate, consideration should be given to obtaining an ECG from all patients before the last of the three daily doses is taken and approximately 4-6 hours after the last dose, since the risk of QTc interval prolongation may be greatest during this period (see section 5.2). QTc intervals of more than 500 ms are associated with a pronounced risk for potentially life-threatening ventricular tachyarrhythmias. Therefore, ECG monitoring during the following 24-48 hours should be applied for patients found to have a prolongation to this extent. These patients should not receive another dose of Eurartesim and alternative antimalarial therapy should be instituted.

Compared to adult males, female patients and elderly patients have longer QTc intervals. Therefore, they may be more sensitive to the effects of QTc-prolonging medications such as Eurartesim so that special caution is required.

Delayed Haemolytic Anaemia

Delayed haemolytic anaemia has been observed up to one month following use of IV artesunate and oral artemisinin-based combination treatment (ACT) including reports involving Eurartesim. Risk factors may include young age (children under 5 years old) and previous treatment with IV artesunate.

Patients and caregivers should be advised to be vigilant for signs and symptoms of post-treatment haemolysis such as pallor, jaundice, dark-coloured urine, fever, fatigue, shortness of breath, dizziness and confusion.

Paediatric population

Special precaution is advised in young children when vomiting, as they are likely to develop electrolyte disturbances. These may increase the QTc-prolonging effect of Eurartesim (see section 4.3).

Hepatic and renal impairment

Eurartesim has not been evaluated in patients with moderate or severe renal or hepatic insufficiency (see section 4.2). Due to the potential for higher plasma concentrations of piperaquine to occur, caution is advised if Eurartesim is administered to patients with jaundice and/or with moderate or severe renal or hepatic insufficiency, and ECG and blood potassium monitoring are advised.

Geographical drug resistance

Drug resistance patterns of P. falciparum may vary geographically. Increased resistance in P. falciparum against artemisinins and/or piperaquine has been reported, predominantly in South-East Asia. In the event of proven or suspected recrudescent malaria infections after treatment with artenimol/piperaquine patients should be treated with a different antimalarial.

Eurartesim is contraindicated in patients already taking other medicinal products that are known to prolong the QTc interval due to the risk of a pharmacodynamic interaction leading to an additive effect on the QTc interval (see section 4.3 and 4.4).

A limited number of drug-drug pharmacokinetic interaction studies with Eurartesim have been performed in healthy adult subjects. Therefore the assessment of the potential for drug-drug interactions to occur is based on either in vivo or in vitro studies.

Effect of Eurartesim on co-administered medicinal products

Piperaquine is metabolised by, and is an inhibitor of CYP3A4. The concurrent administration of oral Eurartesim with 7.5 mg oral midazolam, a CYP3A4 probe substrate, led to a modest increase (≤2-fold) in midazolam and its metabolites exposures in healthy adult subjects. This inhibitory effect was no longer evident one week after last administration of Eurartesim. Therefore, particular attention should be paid when medicinal products that have a narrow therapeutic index (e.g. antiretroviral medicinal products and cyclosporine) are co-administered with Eurartesim.

From in vitro data, piperaquine undergoes a low level of metabolism by CYP2C19, and is also an inhibitor of this enzyme. There is the potential for reducing the rate of metabolism of other substrates of this enzyme, such as omeprazole, with consequent increase of their plasma concentration, and therefore, of their toxicity.

Piperaquine has the potential to increase the rate of metabolism for CYP2E1 substrates resulting in a decrease in the plasma concentrations of substrates such as paracetamol or theophylline, and the anaesthetic gases enflurane, halothane and isoflurane. The main consequence of this interaction could be a reduction of efficacy of the co-administered medicinal products.

Artenimol administration may result in a slight decrease in CYP1A2 activity. Caution is therefore, advised when Eurartesim is administered concomitantly with medicinal products metabolised by this enzyme that have a narrow therapeutic index, such as theophylline. Any effects are unlikely to persist beyond 24 hours after the last intake of artenimol.

Effect of co-administered medicinal products on Eurartesim

Piperaquine is metabolised by CYP3A4 in vitro. The concurrent administration of a single dose of oral clarithromycin, (a strong CYP3A4 inhibitor probe) with a single dose of oral Eurartesim led to a modest increase (≤2-fold) in piperaquine exposure in healthy adult subjects. This increase in exposure to the antimalarial combination may result in an exacerbation of the effect on QTc (see section 4.4). Therefore, particular caution is required if Eurartesim is administered to patients taking potent CYP3A4 inhibitors (e.g. some HIV-protease inhibitors atazanavir, darunavir, indinavir, lopinavir, ritonavir], or verapamil and ECG monitoring should be considered due to the risk of higher plasma concentrations of piperaquine (see section 4.4).

Enzyme inducing medicinal products such as rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort (Hypericum perforatum) are likely to lead to reduced piperaquine plasma concentrations. The concentration of artenimol may also be reduced. Concomitant treatment with such medicinal products is not recommended.

Paediatric population

Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Oral contraceptives

When co-administered to healthy women, Eurartesim exerted only a minimum effect on an estrogen/progestinic combination oral contraceptive treatment increasing the ethynilestradiol rate of absorption (expressed by geometric mean C_max) of about 28% but not significantly changing the exposure to ethynilestradiol and levonorgestrel and not influencing contraception activity as demonstrated by the similar plasma concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and progesterone observed after oral contraceptive treatment with or without concomitant Eurartesim administration.

Food interaction

Absorption of piperaquine is increased in the presence of fatty food (see sections 4.4 and 5.2) which may increase its effect on QTc interval. Therefore, Eurartesim should be taken with water only as described in section 4.2. Eurartesim should not be taken with grapefruit juice as it is likely to lead to increased piperaquine plasma concentrations.

Pregnancy

There are only limited (n=3) amount of data from the use of artenimol/piperaquine during the 1^st trimester of pregnancy.

Based on animal data, Eurartesim is suspected to cause serious birth defects when administered during the first trimester of pregnancy (see sections 4.4 and 5.3). Reproductive studies with artemisinin derivatives have demonstrated teratogenic potential with an increased risk during early gestation (see section 5.3). Piperaquine was not teratogenic in the rat or rabbit.

Therefore Eurartesim should not be used during the 1^st trimester of pregnancy in situations where other suitable and effective anti-malarials are available (see section 4.4).

A large amount of data (more than 3000 exposed outcomes) from the use of artenimol/piperaquine during the 2^nd and 3^rd trimester indicate no fetotoxicity. In perinatal and postnatal studies in rats, piperaquine was associated with delivery complications. However, there was no delay in neonatal development following exposure in utero or via milk (see section 5.3).

Consequently, if Eurartesim is more suitable for a pregnant woman than other artemisinin-based combination therapies with a higher range of experience (or sulfadoxine–pyrimethamine), Eurartesim may be used in the 2^nd and 3^rd trimester.

Breast-feeding

Animal data suggest excretion of piperaquine into breast milk but no data are available in humans. Women taking Eurartesim should not breast-feed during their treatment.

Fertility

There are no specific data relating to the effects of piperaquine on fertility, however, to date no adverse events have been reported during clinical use. Moreover, data obtained in animal studies show that fertility is unaffected by artenimol in both females and males.

Adverse event data collected in clinical trials suggest that Eurartesim has no influence on the ability to drive and operate machines once the patient has recovered from the acute infection.

Summary of the safety profile

The safety of Eurartesim has been evaluated in two phase III open-label studies involving 1,239 paediatric patients up to 18 years and 566 adult patients >18 years treated with Eurartesim.

In a randomised trial in which 767 adults and children with uncomplicated P. falciparum malaria were exposed to Eurartesim, 25% of subjects were judged to have experienced an adverse drug reaction (ADR). No single type of ADR occurred at an incidence of ≥5%. The most frequent ADRs observed at an incidence ≥1.0% were: Headache (3.9%), Electrocardiogram QTc Prolonged (3.4%), P. falciparum infection (3.0%), Anaemia (2.8%), Eosinophilia (1.7%), Haemoglobin decreased (1.7%), Sinus tachycardia (1.7%), Asthenia (1.6%), Haematocrit [decreased] (1.6%), Pyrexia (1.5%), Red Blood Cell Count decreased (1.4%). A total of 6 (0.8%) subjects had serious ADRs in the study.

In a second randomised trial, 1,038 children, aged between 6 months and 5 years, were exposed to Eurartesim and 71% were judged to have experienced an ADR. The following ADRs were observed at an incidence of ≥5.0%: Cough (32%), Pyrexia (22.4%), Influenza (16.0%), P. falciparum infection (14.1%), Diarrhoea (9.4%), Vomiting (5.5%) and Anorexia (5.2%). A total of 15 (1.5%) subjects had serious ADRs in the study.

Tabulated list of adverse reactions

In the tables below, ADRs are listed under system organ class (SOC), and ranked by headings of frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness, using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). The table in this section is for adult patients only. A corresponding table for paediatric patients is presented in the specific section below.

Frequency of ADRs in adult patients participating in clinical studies with Eurartesim and postmarketing data:

Description of selected adverse reactions

The ADRs noted for Eurartesim were generally mild in severity, and the majority were non-serious. Reactions such as cough, pyrexia, headache, P. falciparum infection, anaemia, asthenia, anorexia and the observed changes in blood cell parameters are consistent with those expected in patients with acute malaria. The effect on prolongation of the QTc interval was observed on Day 2, and had resolved by Day 7 (the next time point at which ECGs were performed).

Paediatric population

A tabular overview of the frequency of the ADRs in paediatric patients is given below. The majority of paediatric experience is derived from African children aged 6 months to 5 years.

Frequency of ADRs in paediatric patients participating in clinical studies with Eurartesim:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.