Artenimol and Piperaquine

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 piperaquine/artenimol combination 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.

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 is a mild inhibitor of CYP3A4. Caution is recommended when co-administering piperaquine/artenimol 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 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 piperaquine/artenimol 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. Therefore, particular caution is required if piperaquine/artenimol 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.

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 piperaquine/artenimol 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 piperaquine/artenimol.

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.

Piperaquine/artenimol has not been evaluated in subjects with moderate or severe renal insufficiency. Therefore, caution is advised when administering piperaquine/artenimol to these patients.

Piperaquine/artenimol has not been evaluated in subjects with moderate or severe hepatic insufficiency. Therefore, caution is advised when administering piperaquine/artenimol to these patients.

When co-administered to healthy women, piperaquine/artenimol 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 piperaquine/artenimol administration.

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, artenimol/piperaquine combination is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with artemisinin derivatives have demonstrated teratogenic potential with an increased risk during early gestation. Piperaquine was not teratogenic in the rat or rabbit.

Therefore artenimol/piperaquine combination should not be used during the 1^st trimester of pregnancy in situations where other suitable and effective anti-malarials are available.

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.

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

Animal data suggest excretion of piperaquine into breast milk but no data are available in humans. Women taking artenimol/piperaquine combination 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 artenimol/piperaquine combiantion 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 artenimol/piperaquine 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 artenimol/piperaquine.

In a randomised trial in which 767 adults and children with uncomplicated P. falciparum malaria were exposed to artenimol/piperaquine, 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 artenimol/piperaquine 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 artenimol/piperaquine and postmarketing data:

Description of selected adverse reactions

The ADRs noted for artenimol/piperaquine 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 artenimol/piperaquine: