Eurartesim · 4.8 Undesirable effects · 2

HOS-095636 · has-adverse-reaction-information · PDF-Seite 23

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), 23 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 post- marketing data: Very SOC Common Uncommon Not known Common Respiratory tract Infections and P. falciparum infection infestations infection

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HOS-095630 · has-adverse-reaction-information · PDF-Seite 8

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 8 (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 post- marketing data: Very SOC Common Uncommon Not known Common Respiratory tract Infections and P. falciparum infection infestations infection

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HOS-095626 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. - Severe malaria according to WHO definition. - Family history of sudden death or of congenital prolongation of the QTc interval. - Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval. - History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. - Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction. - Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. - Taking medicinal products that are known to prolong the QTc interval. These include (but are not limited to): • Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol). • Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive medicinal products. • Certain antimicrobial medicinal products, including medicinal products of the following classes: − macrolides (e.g. erythromycin, clarithromycin), − fluoroquinolones (e.g. moxifloxacin, sparfloxacin), − imidazole and triazole antifungal medicinal products, − and also pentamidine and saquinavir. • Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine). • Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide. - Recent treatment with medicinal products known to prolong the QTc interval that may still be circulating at the time that Eurartesim is commenced (e.g. mefloquine, halofantrine, lumefantrine, chloroquine, quinine and other antimalarial medicinal products) taking into account their elimination half-life.

HOS-095632 · has-contraindication-information · PDF-Seite 19

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. - Severe malaria according to WHO definition. - Family history of sudden death or of congenital prolongation of the QTc interval. - Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval. - History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. - Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction. - Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. - Taking medicinal products that are known to prolong the QTc interval. These include (but are not limited to): • Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol). • Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive medicinal products. • Certain antimicrobialmedicinal products, including medicinal products of the following classes: − macrolides (e.g. erythromycin, clarithromycin), − fluoroquinolones (e.g. moxifloxacin, sparfloxacin), − imidazole and triazole antifungal medicinal products, − and also pentamidine and saquinavir. • Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine). • Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide. - Recent treatment with medicinal products known to prolong the QTc interval that may still be circulating at the time that Eurartesim is commenced (e.g. mefloquine, halofantrine, lumefantrine, chloroquine, quinine and other antimalarial medicinal products) taking into account their elimination half-life.

HOS-095625 · has-indication-information · PDF-Seite 2

Eurartesim is indicated for the treatment of uncomplicated Plasmodium falciparum malaria in adults, adolescents, children and infants 6 months and over and weighing 5 kg or more. Consideration should be given to official guidance on the appropriate use of antimalarial medicinal products, including information on the prevalence of resistance to artenimol/piperaquine in the geographical region where the infection was acquired (see section 4.4).

HOS-095631 · has-indication-information · PDF-Seite 17

Eurartesim is indicated for the treatment of uncomplicated Plasmodium falciparum malaria in adults, adolescents, children and infants 6 months and over and weighing 5 kg or more. Consideration should be given to official guidance on the appropriate use of antimalarial medicinal products, including information on the prevalence of resistance to artenimol/piperaquine in the geographical region where the infection was acquired (see section 4.4).

HOS-095634 · has-interaction-information · PDF-Seite 21

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. 21 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

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HOS-095628 · has-interaction-information · PDF-Seite 6

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 sections 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 6 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

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HOS-095635 · has-pregnancy-information · PDF-Seite 23

Pregnancy There are only limited (n=3) amount of data from the use of artenimol/piperaquine during the 1st 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 1st 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 2nd and 3rd 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 2nd and 3rd 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.

HOS-095629 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are only limited (n=3) amount of data from the use of artenimol/piperaquine during the 1st trimester of pregnancy. Based on animal data, Eurartesim is suspected to cause serious birth defects when administered during 7 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 1st 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 2nd and 3rd 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 2nd and 3 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.

HOS-095633 · has-warning-information · PDF-Seite 19

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. 19 The long half-life of piperaquine (about 22 days) should be kept in mind in the event that another anti- malarial 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 Eurarte

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HOS-095627 · has-warning-information · PDF-Seite 4

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 anti- malarial 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 4 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

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