Artesunate 50 mg tablets (Guilin), MA044 WHOPAR part 4 02/2009, version 1.0 Section 3 & 6 updated : June 2017 SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS

2 1. NAME OF THE MEDICINAL PRODUCT Artesunate 50 mg tablets* 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains artesunate 50 mg For a full list of excipients, see section PHARMACEUTICAL FORM White round tablets debossed with AS on one side and a score line on the other side. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indication Artesunate 50 mg tablets is indicated for the treatment of uncomplicated cases of malaria due to Plasmodium falciparum strains which are susceptible to artesunate. The most recent official guidelines on the appropriate use of antimalarial agents and local information on the prevalence of resistance to antimalarial drugs must be taken into consideration for deciding on the appropriateness of therapy with Artesunate 50 mg tablets. Official guidance will normally include WHO ( and public health authorities guidelines. According to current WHO recommendations, artesunate should be used in combination therapy with amodiaquine, sulfadoxine+pyrimethamine, or mefloquine (see also section 4.2). 4.2 Posology and method of administration Oral use. Artemisinin-based combination therapy (ACT) In combination therapy in adults and children, artesunate should be given at 4 mg/kg body weight once daily for three days (range 2-10 mg/kg; 200 mg per day in adults) Artesunate dosing scheme in combination therapy (treatment duration 3 days) Age No of tablets per day (dose) 1-6 years 1 tablet (50 mg/day) 7-13 years 2 tablets (100 mg/day) > 13 years 4 tablets (200 mg/day) * Trade names are not prequalified by WHO. This is under local DRA responsibility. Throughout this WHOPAR the proprietary name is given as an example only.

3 Monotherapy (not usually recommended) In case of allergy, intolerance or contraindication to combination agents, artesunate can be used as monotherapy: in adults a total dose of mg should be given during five to seven days of treatment, and in children a total dose of 12 mg/kg BW should be given during five to seven days of treatment (see table below). Example for artesunate dosing scheme in monotherapy (treatment duration 5-7 days) Age No of tablets per day (dose) Day 1 Subsequent days 7-13 years 1 tablet twice daily (50 mg x 2) 1 tablet daily (50 mg x 1) > 13 years 2 tablets twice daily (100 mg x 2) 1 tablet twice daily (50 mg x 2) Artesunate 50 mg tablets should not be taken with a high-fat meal (see section 5.2). The tablets should be swallowed with water. Should vomiting occur within half an hour after dosing, a repeated dose of Artesunate 50 mg tablets should be taken. In case of further vomiting, treatment for severe malaria should be considered. If a dose has been missed, it should be taken as soon as possible and the next regular dose when it is due. In the once daily regimen the interval between two doses should be at least 8 hours. Renal/hepatic impairment No dose adjustment is needed for hepatically or renally impaired patients. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings and precautions for use In patients with a previous rash or urticarial reaction to artesunate, rechallenge should be avoided, since this has been associated with recurrence and occasionally with the development of severe anaphylactic reactions (see section 4.3). Artesunate has not been evaluated for the treatment of complicated malaria and is therefore not recommended. Artesunate has not been evaluated in the treatment of malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale and is therefore not recommended. There is insufficient evidence to support the use of Artesunate for prevention of malaria. Artesunate has not been studied specifically in patients with thalassaemia, sickle cell anaemia or G6PD-deficiency. Co-administration of artesunate in combination with amodiaquine, and efavirenz, should be avoided, since this combination has been noted to cause marked hepatotoxicity.

4 4.5 Interaction with other medicinal products and other forms of interaction No clinically important pharmacokinetic interactions with sulfadoxine/pyrimethamine or atovaquone/proguanil have been identified. Single dose data have shown that the co-administration of artesunate and amodiaquine leads to a 47% decrease in the Cmax of dihydroartemisinin, the main active metabolite of artesunate, and a 17% decrease of its AUC 0-inf, relative to what is seen when artesunate is administered alone. This is clinically relevant, only when the combination is used in the presence of amodiaquine resistance, as this interaction might then further compromise the activity of the regimen. 4.6 Pregancy and lactation Pregnancy: The limited data available on exposure during pregnancy does not indicate any adverse effects of artesunate on the health of the foetus/newborn child. However, information is inadequate for determining the fetal risk of artesunate treatment during pregnancy. Artesunate should only be used during pregnancy, especially in the first trimester, when the benefit is considered to outweigh the potential risks, and alternative drugs are not available. Lactation: The amounts of antimalarials in breast milk are small. Therefore, lactating women can receive artemisinin-based combination therapies (including artesunate) for malaria treatment. 4.7 Effects on the ability to drive and use machines Patients receiving Artesunate 50 mg tablets should be warned that dizziness may occur, in which case they should not drive or use machines. 4.8 Undesirable effects The adverse events are ranked under body-system and frequency using the following convention: very common: 1/10; common : 1/100 to <1/10; uncommon : 1/1000 to < 1/100; rare : 1/10,000 to < 1/1000; very rare : < 1/10,000; not known (frequency cannot be estimated from the available data). Blood and lymphatic disorders Uncommon: Neutropenia, low reticulocyte count. Cardiac disorders Uncommon: Bradycardia Not known: AV-block, possible QT-prolongation. Gastro-intestinal disorders Uncommon: Mild gastrointestinal disturbances. Hepato-biliary disorders Uncommon: Elevated liver enzymes. Neurological Disorders Not known: Dizziness, tinnitus. Skin disorders: Not known: Rash, urticaria.

5 General disorders Rare: hypersensitivity (allergic) reactions. 4.9 Overdose No cases of overdose have been reported. If overdose occurs, the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Antimalarial (ATC code: P01BE03). Artesunate is a hemisuccinate derivative of dihydroartemisinin, which is obtained by the reduction of artemisinin, a sesquiterpene lactone endoperoxide, extracted from a plant used in traditional Chinese medicine, known as sweet or annual wormwood (Artemisia annua). The mechanism of action of artesunate has been widely studied and appears well established. The artesunate endoperoxide bridge is split by haeme within the infected erythrocyte, generating singlet oxygen. Parasite proteins, particularly in membranous structures, are thus alkylated, leading to parasite death. In-vitro experiments in P. falciparum have shown that artemisinin derivatives are active against a broad spectrum of the life cycle of the parasite, from the relatively inactive ring stage to late schizontes. The schizonticidal and gametocytocidal activities of artesunate, administered orally have been demonstrated in vivo on chloroquine-sensitive strains of Plasmodium (P. berghei in mice and P. knowlesi in monkeys) and on chloroquine-resistant strains (P. berghei in mice). In-vitro, artesunate appears to be inactive against extra-erythrocyte forms, sporozoites, liver schizontes or merozoites. When administered orally, artesunate consistently acts more quickly than orally administered chloroquine and intravenous quinine in all animal models studied, regardless of the strain or dose tested. In macaques (the animal model most similar to humans) infected with a chloroquine-resistant strain of P. knowlesi, cure was obtained with the same dose of artesunate and quinine. Limited clinical data with the innovator and other artesunate-containing products do not indicate a relevant difference in the efficacy and safety profile of the drug, when the tablets are crushed in patients unable to swallow the tablets whole. 5.2 Pharmacokinetic properties Absorption and bioavailability After oral administration artesunate is rapidly absorbed. Most of the artesunate is promptly biotransformed, mainly through plasma esterases, into the active metabolite dihydroartemisinin (DHA). Following single dose Artesunate 50 mg tablets administration in healthy volunteers, the mean (CV) artesunate Cmax value was 1.94 µg/ml, respectively and the corresponding value for AUC was 3.55 μg.h/ml. The median (range) artesunate tmax value was min. No pharmacokinetic data are available on crushing of Artesunate 50 mg tablets (see also section 5.1).

6 Distribution DHA (dihydroartemisinin) has been shown to substantially accumulate in P. falciparum-infected erythrocytes. In man, artesunate is poorly protein bound. Metabolism Artesunate is extensively hydrolysed by plasma esterases and perhaps also by CYP2A6. Its main metabolite, DHA is presumed to account for most of the in vivo antimalarial activity. DHA is metabolised thorugh glucuronidation. Elimination Artesunate has a plasma half-life of 3-29 minutes. The active metabolite DHA has a plasma half-life of 40 to 95 minutes. Food effect When an artesunate amodiaquine fixed dose combination was taken with a high fat meal in healthy volunteers, the Cmax and AUC(0-t) of artesunate decreased by 66% and 13% respectively, compared to fasting. The Cmax and AUC(0-t) of the active metabolite dihydroartemisinin (DHA) decreased by 48% and 5% respectively with a high-fat meal, compared to fasting (see section 4.2). 5.3 Preclinical safety data - General toxicity: Artesunate s toxicity appears in rat and dog after repeated oral administration of doses 50 and 82.5mg/kg/day, respectively, i.e and 20.6 times the proposed therapeutic dose in man. In both species, toxicity is expressed as bone marrow changes (hypoplasia in both myeloid and erythroid populations with some regeneration at lower doses as expressed by increases in reticulocytes which then decrease at the severely toxic doses), liver and renal lesions (rat only) in addition to lymphoid hypoplasia in the dog only (decrease in circulating lymphocytes). - Genotoxicity: Artesunate: in vitro tests (Ames test) and in vivo tests (micronucleus in mice) did not show any mutagenic potential. - Carcinogenesis: No studies of the carcinogenic potential of Artesunate 50 mg tablets have been conducted. - Toxicity to reproduction : Embryofoetal development studies recently published in rats and rabbits showed a low incidence of cardiovascular malformation and syndrome of skeletal defects at doses close to embryolethal doses. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day. In these same studies the compound showed evidence of embryotoxicity from the dose of 6 mg/kg/day. - Safety pharmacology studies Artesunate depresses all the major body functions (gastro-intestinal, respiratory and cardiovascular systems) at very high doses in rat and cat, i.e. generally after intravenous administration of doses exceeding 300 mg/kg, which is the equivalent of about 75 times the recommended clinical dose administered orally. Renal function appears to be affected at relatively lower doses (from 12 mg/kg followed by infusion of mg/min for one hour in the rat).

7 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline Cellulose, Corn Starch, Dextrin, Sucrose, Sodium Starch Glycolate (CMS-Na), Magnesium Stearate 6.2 Incompatibilities Not applicable 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store below 30 C. Store in the original package. 6.5 Nature and contents of container PVC/Aluminium blister cards containing 12 tablets. The blisters are further packaged in cardboard boxes. 6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirements. 7. SUPPLIER Guilin Pharmaceutical Co. Ltd No 17, Shanghai Road, Guilin, Guanxi People s Republic of China Tel.: Fax: glpharma@public.glptt.gx.cn 8. WHO REFERENCE NUMBER (PREQUALIFICATION PROGRAMME) MA DATE OF PREQUALIFICATION 21 December DATE OF REVISION OF THE TEXT February Section 3 & 6 updated in June 2017.

8 References: General: Guidelines for the Treatment of Malaria, World Health Organization, 2006 ( Dosing recommendations: Taylor WR et al. Bulletin of the World Health Organization 2006;84: Drug interactions: Minzi OM et al, Eur J Clin Pharmacol 2007 ;May 63(5): Van Vugt M et al, Eur J Clin Pharmacol 1999 ;Aug 55(6): German P et al, Clin Inf Dis 2007;44: Undesirable effects: White NJ, Lancet Inf Dis 2007;Aug 7(8): Crushing of tablets: Ashley EA et al. Tropical Medicine & International Health 2006;11(11):