Arthemed and Arthemed Junior Artemether and Lumefantrine Tablets

ARTHEMED & ARTHEMED®JUNIOR

(Artemether & Lumefantrine Tablets)

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

 

Composition

Each coated tablet contains:

1) Arthemed® (Artemether 80mg & Lumefantrine 480mg)

2) Arthemed® (Artemether 20mg & Lumefantrine 120mg)

3) Arthemed® Junior (Artemether 20mg & Lumefantrine 120mg)

 

Pharmacology

Arthemed® comprises a fixed ratio of 1:6 parts of artemether and lumefantrine respectively. The site of antiparasitic action of both components is the food vacuole of the malaria parasite, where they are thought to interfere with the conversion of haem (a toxic intermediate produced during haemoglobin breakdown) to the non toxic haemozoin malaria pigments. Lumefantrine is thought to interfere with the polymerisation process, while artemether generates reactive metabolites as a result of the interaction between its peroxide bridge and haem iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic action and protein synthesis within the malaria parasite. The antimalarial activity of the combination of the lumefantrine and artemether in Artemed® is greater than that of either substances alone. In a double-blind comparative study in China, the 28-day cure rate of Arthemed® when given at 4 doses was 100%, compared with 92% for lumefantrine and 55% for artemether when given as monotherapy.

 

Pharmacokinetics

Pharmacokinetics characterisation of Arthemed® is limited by the lack of an intravenous formulation and the very high inter and intra subject variability of artemether and lumefantrine plasma concentration and derived pharmacokinetics parameters (AUC, Cmax).

 

Absorption

Artemether is absorbed fairly rapidly with peak plasma concentration reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentration of about 6-8 hours after dosage. Food enhances the absorption of both artemether and lumefantrine: in healthy volunteers the relative bioavailability of artemether was increased more than two-folds, and that of lumefantrine sixteen- fold compared with fasted condition when Arthemed® was taken after a high-fat meal.

Food has also been shown to increase the absorption of lumetantrine in patients with malaria, although to a leser extent (approximately two-fold), most probably due to the lower fat content of the food ingested by acutely ill patients. The food interaction data indicates that absorption of lumefantrine under fasted condition is very poor (assuming 100% absorption after a high-fat meal, the amount absorbed under fasted condition would be <10% of the dose). Patients should therefore be encouraged to take the medication with a normal diet as soon as food can be tolerated.

 

Distribution

Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.9% respectively). Dihydroartemisinin is also bound to
human serum proteins (47-76%).

 

Metabolism

Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolise artemether to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly through the isoenzyme CYP3A415. This metabolite has also been detected in humans in viva. The artemether/dihydroartemisinin AUC ratio is 1:2 after a single dose and 0:3 after 6 doses given over 3 days. In viva data indicate that artemisinins have some capacity to induce cytochrome isoenzymes CYP2C19 and CYP3A4. Dihydroartemisinin is further converted to inactive metabolites.

Lumefantrine is N-debutylated mainly by CYP3A4 in human liver microsomes. In animals such as dogs and cats, in vivo studies show that glucuronidation of lumefantrine takes place directly and after oxidative biotransformation. In humans, the kinetic profile of the metabolite desbutyl-lumefantrine, for which the in vitro antiparasitic effect is 5 to 8 fold higher than lumefantrine, has not been documented. In vitro lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.

 

Elimination

Artemether and dihydroartemisinin are rapidly cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated very slowly with a terminal half-life of 2-3 days in healthy volunteers and 4-6 days in patients with Falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of Arthemed®.

No urinary excretion data are available for humans. In rats and dogs unchanged artemether has not been detected in faeces and urine due to its rapid and high- pass metabolism, but several metabolites (unidentified) have been detected in both faeces and urine.

Lumefantrine is eliminated via the bile in rats and dogs, with excretion primarily in the faeces. After oral dosing in rats and dogs qualitative and quantitative recovery of metabolites in bile and faeces was relatively low; most of the dose being recovered as parent drug.

 

Indications

Arthemed® is indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria in patients.

 

Dosage and Administration

To increase absorption, Arthemed® should be taken with food. If patients are unable to tolerate food, Arthemed® should be administered, but the systemic exposure maybe reduced. Patients who vomit within 1 hour of taking the medication should repeat the dose.

 

Arthemed® dosage schedule

Patients Total Tablets Day 1 Day 1 Day 2 Day 2 Day 3 Day 3
    0-Hour Morning 8-Hours 24-Hours Morning 36-Hours Evening 48-hours Morning 60-Hours Evening
Adult 6 1 1 1 1 1 1

 

Arthemed® Junior (Artemether 20 & Lumefantrine 120mg) dosage schedule Adults
For patients of 12years of age and 35kg body weight, a course of treatment comprises six doses of four tablets (i.e. Total of 24 tablets, given over a period of 60 Hours) as follows:
The first dose of four tablets, given at the time of initial diagnosis, should be followed by five further doses of four tablets given at 8, 24, 36, 48, and 60 hours thereafter .

 

Children

Patients weight in kg Total Tablets Day 1 Day 1 Day 2 Day 2 Day 3 Day 3
    0-Hour Morning 8-Hours 24-Hours Morning 36-Hours Evening 48-hours Morning 60-Hours Evening
5-14kg 6 1 1 1 1 1 1
15-24kg 12 2 2 2 2 2 2
25-34kg 18 3 3 3 3 3 3
≥35kg (Adults & Children 24 4 4 4 4 4 4

 

Elderly

Although no studies have been carried out in the elderly, no special precautions or dosage adjustments are considered necessary in such patients.

 

Renal or hepatic impairment

Caution is advised when administering Arthemed® to patients with severe renal or hepatic problems. In these patients, ECG and blood potassium monitoring is advised.

 

Contraindications

Arthemed® is contraindicated in:

– Patients with known hypersensitivity to the active substance or to any of the excipients.

– Patients with complicated malaria.

– Patients who are taking any drug which inhibits the cytochrome enzyme CYP3A4 (e.g. erythromycin, ketoconazole, itraconazole, cimetidine, HIV protease inhibitors).

 

Drug interactions

In patients previously treated with halofantrine, Arthemed® should be dosed at least one month after the last halofantrine dose. Due to the limited data on safety and efficacy, Arthemed® should not be given concurrently with any, other antimalarial agents to prolong the QT interval. Caution is advised when administering Arthemed® to patients in whom there may still be detectable concentrations of these drugs in the plasma following prior treatments.

 

Pregnancy and Lactation

Pregnancy

There are no adequate data from the use of artemether and lumefantrine in pregnant women.

Reproductive studies in rats and rabbits have shown matemo, feto and embryotoxicity with artemether. No evidence of teratogenicity for the combination or for the individual components of lumefantrine and artenether has been reported. Arthemed® treatment should only be considered if the expcted benefit to the mother outweighs the risk to the fetus.

 

Lactation

Animal data suggest excretion into breast milk, but no data is available in human. Arthemed® should not be taken by breastfeeding women. Due to the long elimination half-life of lumefantrine (4 to 6 days), it is recommended that breastfeeding should not resume until at least one week after the last dose of Arthemed®.

 

Overdosage

In cases of suspected overosage symptomatic and supportive therapy should be given as appropriate, which include ECG and blood potassium monitoring.

 

Storage

Store below 30°C in a dry place.

Protect from light.

Keep out of reach of children.

 

Presentation

Blister of 6 tablets. 1 blister in a carton along with pack insert.

Blister of 12 tablets. 2 blisters in a carton along with pack insert.

Blister of 24 tablets. 4 blisters in a carton along with pack insert.

 

Manufactured by

Fidson Healthcare Plc

Km 38, Lagos-Abeokuta Expressway,

Sango-Ota, Ogun State, Nigeria.

customercare@fidson.com

www.fidson.com

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