Artecef 50/Artecef 150 (ARTECEF BV) WHOPAR part 4 09/2008, version 1.0 MA027/028 SUMMARY OF PRODUCT CHARACTERISTICS. Page 1 of 7

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1 SUMMARY OF PRODUCT CHARACTERISTICS Page 1 of 7

2 1. NAME OF THE MEDICINAL PRODUCT Artecef 50, Solution for intramuscular injection Artecef 150, Solution for intramuscular injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Artecef 50: Each ampoule contains 50 mg of Artemotil in sesame oil Artecef 150: Each ampoule contains 150 mg of Artemotil in sesame oil For excipients see PHARMACEUTICAL FORM Solution for intramuscular injection Amber glass ampoule of 1 ml with coloured rings on the neck and with breakring. Ampoules are packed in trays in a carton of 10 ampoules or packed in a polystyrene box of 100 ampoules for inhospital-use. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Artecef 50 and Artecef 150 are used for the treatment of severe Plasmodium falciparum (Falciparum) malaria infections. Clinical efficacy of Artemotil in infections caused by P. falciparum strains resistant to other antimalarials has not been established. Artecef 50 and Artecef 150 are not effective against P. vivax malaria. It is recommended to follow WHO-guidelines in the choice and prescription of anti-malaria agents. 4.2 Posology and method of administration Intramuscular use Intramuscular injection of: 4.8 mg Artemotil per kg body weight as start dose, followed by 1.6 mg per kg body weight after 6, 24, 48 and 72 hours. The start dose must be evenly divided and injected in both anterior thighs. The follow-up doses must be injected in alternating thighs. A repetition of the treatment of the same patient within two weeks following on the initial dose must be avoided. Follow-up treatment with a suitable anti-malaria remedy after treatment with Artemotil is advised, in particular with very weak hyperparasitaemic patients (see also section 4.4). Page 2 of 7

3 One must strictly adhere to the following dosing scheme: Dosing scheme of Artecef 50 and Artecef 150 Statement of ml Artemotil in sesame oil solution in relation to the body weight of the patient*. Time (hours): Artemotil mg.kg Body weight 50 mg ampoule green - red - yellow < 5 kg 0.6 ml 0.2 ml 0.2 ml 0.2 ml 0.2 ml 5-10 kg 0.9 ml 0.3 ml 0.3 ml 0.3 ml 0.3 ml kg 1.5 ml 0.5 ml 0.5 ml 0.5 ml 0.5 ml Time (hours): Artemotil mg.kg mg ampoule red - white - blue kg 0.6 ml 0.2 ml 0.2 ml 0.2 ml 0.2 ml kg 0.9 ml 0.3 ml 0.3 ml 0.3 ml 0.3 ml kg 1.2 ml 0.4 ml 0.4 ml 0.4 ml 0.4 ml kg 1.5 ml 0.5 ml 0.5 ml 0.5 ml 0.5 ml kg 1.8 ml 0.6 ml 0.6 ml 0.6 ml 0.6 ml * Use a new ampoule and a new needle for each injection and take good care of a safe disposal of the used ampoule and needle. Renal or hepatic Impairment: Artemotil has not been studied in patients with a decreased renal or liver function. Caution is recommended when treatment of Artemotil is indicated. 4.3 Contraindications Artecef is contraindicated in patients with hypersensitivity to Artemotil and / or sesame oil. 4.4 Special warnings and special precautions for use The product must be used via the intramuscular route only. In general, severe Falciparum malaria infections require supportive treatment like: glucose-salt infusion and paracetamol, which should be administered intravenously or via the rectal route. Following on the resolution of the critical phase of the Falciparum malaria infection, it is advised to once a week perform parasite readings in the blood of the patient, during four weeks. In case of reinfection or recrudescence of the original infection caused by P. falciparum, the patient should be treated with a different anti-malarial drug. When combined infections with P. vivax are proven or suspected, different anti-malarial treatments are necessary. Combinations of Artemotil with other anti-malarial drugs have not been tested. Pharmacokinetic or clinical studies in patients with pre-existing renal or liver failure concerning the use of Artemotil have not been undertaken. In general, Artemotil shows no tendency to QTc-interval prolongation at the recommended dose regimens. QTc-interval prolongation may incidentally occur in patients with pre-existing abnormal ECG (high U-waves and old infarctions). Until the clinical consequences of the observed QTc prolongations are clarified, Artemotil should not be used in adults. During animal studies a potential of Artemisia derivatives for neurotoxicity has been observed. No significant toxicity has been reported in humans, however, may not be excluded. No maximum tolerable dosehas been defined in volunteers or patients. Page 3 of 7

4 4.5 Interaction with other medicinal products and other forms of interaction Pre-clinical parasitological studies have shown that additive effects may occur when Artemotil is combined with mefloquine. Besides, pre-clinical parasitological studies have shown potentiation when Artemotil was combined with quinine. To date there is no clinical information available. Pharmacokinetic in vivo interaction studies have not been conducted. In vitro studies suggest that Artemotil is metabolised by cytochrome P450 3A4 to dihydroartemisinin. Drugs with a strong inhibition effect on CYP3A4, like HIV-protease inhibitors or ketonazole, could influence this metabolism, resulting in higher Artemotil plasma concentrations when given concomitantly. Drugs with strong induction effect on CYP3A4, like carbamazepine and phenobarbital, could result in lower Artemotil plasma concentrations when given concomitantly. 4.6 Pregnancy and lactation There is no clinical information available on the use of Artemotil during pregnancy. Pre-clinical studies revealed embryotoxic effects, but no teratogenic potential. Until more data become available, Artemotil should not be used during pregnancy. There are no data available with regard to excretion of Artemotil in human milk. It is recommended to stop breast feeding during two weeks starting from the first dose of the Artemotil treatment regimen. 4.7 Effects on ability to drive and use machines There are no data available with regard to the effects on the ability to drive and to use machines. 4.8 Undesirable effects After administration of Artemotil, the following side effects have been reported: General: asthenia, anorexia, fever, headache, pain at the injection site, upper respiratory tract infections, pneumonia and coughing. Cardiovascular system : QTc-interval prolongation may incidentally occur in patients with preexisting abnormal ECG (high U-waves and old infarcts). Central and peripheral nerve system : dizziness. Gastro-intestinal system : diarrhea, headache and nausea. Skin : pruritus. Bone and soft tissue : myalgia. 4.9 Overdose There have been no cases reported of an overdose, and there are no clinical data available on the symptoms and the possible effects of an overdose of Artemotil. When an overdose exceeds the dose of the complete course, the remaining injections must not be administered. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Page 4 of 7

5 Artemotil is a blood schizontocide for Plasmodium falciparum (Falciparum) malaria. ATC-code: P51AX (agent against infection by protozoa). Artecef 50 and Artecef 150 are not effective against P. vivax malaria. Artemotil is active against P. falciparum parasites from the very early blood stages until the early gametocytes. In in vitro studies, Artemotil has also been shown to be effective against parasite strains which were resistant against chloroquine, mefloquine, halofantrine, quinine, pyrimethamine, cycloguanil and amodiaquine. Clinical efficacy in infections caused by P. falciparum strains resistant to other anti-malarials has not been confirmed in clinical studies. The efficacy in the treatment of severe malaria has been investigated in two studies with children. Criteria for efficacy were survival rate (primary), coma resolution time (if applicable) and the time until parasite clearance from blood and fever clearance time. In a small double-blind controlled study in Thailand in children with severe but not (yet) cerebral malaria all children (62 on Artemotil and 63 on artemether) survived with parasite and fever clearance within 1 to 4 days. The efficacy of Artemotil was at least equivalent to the efficacy of artemether in this study. In a small supportive open controlled study in Zambia and Cameroon with 193 comatose children with cerebral malaria, 100 were treated with Artemotil and 93 children with quinine. Survival was 82%. Coma resolution for the surviving children was within 4 hours to 8 days and parasite and fever clearance were within 1 to 7 days. With respect to survival rate, coma resolution time and parasite clearance time the efficacy of Artemotil was at least equivalent to standard quinine treatment (survival rate 72%). However, fever clearance was faster during quinine treatment. Part of the patients in both groups in this study received follow-up treatment with an oral anti-malaria remedy after treatment with Artemotil or quinine. In 5 small studies with adult patients, positive indications were observed regarding efficacy, however the studies concerned were uncontrolled or open studies. Therefore therapy should be primarily for treatment of severe Plasmodium falciparum (Falciparum) malaria infections. 5.2 Pharmacokinetic properties After intramuscular injection of the solution in sesame oil, a slow release takes place of Artemotil into the systemic circulation. Peak concentrations in plasma are generally attained between 3 and 12 hours following the injection. Plasma half-life is determined by the slow release from the injection site, and varies depending on muscle tone and activity between around one to two days. It follows that due to this slow release, plasma levels tend to accumulate during the treatment course. The physicochemical properties of Artemotil exclude intravenous administration. It is therefore not possible to determine the biological availability, the clearing and the distribution volume. Plasma protein binding of Artemotil amounts to 98 to 99%. Prior to excretion, the majority of Artemotil is metabolised. The most important route is an oxidative de-alkylation by CYP3A4 to dihydroartemisin and biliary excretion of glucuronidated dihydroartemisinin with the faeces. A minor part (20-30%) can be excreted as dihydroartemisinin glucuronidine in urine. Dihydroartemisinin has a stronger anti-malarial activity than Artemotil, however plasma concentrations after intramuscular injections a typically less that 10% in comparison to Artemotil and the contribution to the therapeutic effect therefore seems to be of less importance. 5.3 Preclinical safety data See also under Special warnings and special precautions for use and under Pregnancy and lactation. During pre-clinical safety studies degenerative neurotoxic effects have been observed at cumulative doses above 100 mg Artemotil per kg body weight. During clinical treatment the cumulative dose of Artemotil is 11.2 mg per kg body weight. During clinical studies in volunteers and patients, neurotoxicity has not been observed. Page 5 of 7

6 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sesame oil 6.2 Incompatibilities In the absence of incompatibility studies, this medical product must not be mixed with other medicinal products. 6.3 Shelf life Shelf-life is 5 years. The expiry date is indicated on the label of the ampoule and on the outer package by EXP: MM (month).jjjj (Year). 6.4 Special precautions for storage Do not store above 25 C. Do not refrigerate or freeze. The product must preferably be stored in the original package in order to protect from direct sun light. This package is specially designed to guarantee safe transport and storage. The doctor must always check if the ampoule contains crystals. If crystals are observed then the ampoule must not be used. 6.5 Nature and contents of container The solution of Artemotil in sesame oil is contained in a transparent amber coloured glass ampoule of hydrolytic class I. The ampoule has a break ring. The neck of the ampoule has a coloured code to indicate its strength: green - red - yellow for the 50 mg ampoule, and red - white - blue for the 150 mg ampoule. Artecef 50 or Artecef 150 are supplied: - in a polystyrene packaging of 100 ampoules of 1 ml, or - in a carton pack of 10 ampoules of 1 ml, together with graduated syringes and needles. 6.6 Instructions for use and handling and disposal Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER / SUPPLIER ARTECEF BV, Schepenveld 41 / P.O. Box 1262, 3890 BB Zeewolde, The Netherlands. Tel: Fax: info@artecef.com 8. WHO REFERENCE NUMBERS (PREQUALIFICATION PROGRAMME) MA027 / MA028 Page 6 of 7

7 9. DATE OF FIRST PREQUALIFICATION/RENEWAL OF PREQUALIFICATION March DATE OF REVISION OF THE TEXT September 2008 Page 7 of 7