Mercator Artemether Tablets
Artemether 80mg + Lumefantrine 480mg Tablets
PHARMACEUTICAL FORM: Tablet
(3R,5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)-Decahydro-10-methoxy 3.6.9-trimethyl-3, 12-epoxy-12H-pyrano (4,3-j)-1,2-benzodioxepin (=artemether) and (1R,S)-2-Dibutylamino-1-(2,7 - dichloro-9-(Z) (4-chlorobenzylidene)-9H-fluoren-4-yl) (=lumefantrine)
Artemether is a sesquiterpene lactone derived from the naturally occurring substance artemesinin. Lumefantrine is a synthentic racemic fluorine mixture..
Each tablet contains 80mg Artemether and 480mg Lumefantrine.
Mercator Artemether Tablets is a combination of artemether and lumefantrine which acts as blood schizontocides. It is indicated for the treatment of adults and children with acute, uncomplicated infections due to Plasmodium falciprum or mixed infection including P. Falciprum and strains from multi drug resistant areas. Mercator Artemether Tablets is recommended for use as a standby emergency treatment for travelers to area where the Parasite is resistant to other drugs.
DOSAGE AND ADMINISTRATION
One tablet to be taken at the time of initial diagnosis, again after 8hrs , then 1 tablet twice daily (morning and evening) on each of the following two days.(Total course comprises 6 tablets)
Absorption is enhanced when taken with milk or fat containing food.
Mercator Artemether Tablets is contraindicated in:
-Patients with known hypersensitivity to either of the components
-Pregnant and lactating women
-Patients with severe malaria
PRECAUTIONS FOR USE
Mercator Artemether Tablets is not recommended for prophylaxis.
Although the likelihood of Mercator Artemether Tablets interactions with other drugs is minimal in view of its short duration of administration and wide therapeutic index, three specific pharmacokinetic and pharmacodynamic drug-drug interaction studies with ketoconazole (a patient CYP3A4 inhibitor), mefloquine and quinine have been conducted in healthy volunteers.
INTERACTION WITH ANTIMALARIA
As patients to be treated with Mercator Artemether Tablets may have recently been treated with other antimalaria, interactions with mefloquine and quinine were studied in healthy volunteers. The sequential oral administration of mefloquine prior to Mercator Artemether Tablets had no effect on plasma concentrations of artemether or the artemether/dihydroartemisinin, but there was a significant (around 30-0%) reduction in plasma levels (Cmax and AUC) of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Based on this study, patients should be encouraged to eat at dosing times to compensate for this decrease in bioavailability.
The concurrent i.v. administration of quinine (10mg/kg BW) with Mercator Artemether Tablets had no effect on plasma concentrations of lumefantirne or quinine. Plasma concentrations of artemether and DHA appeared to be lower in this study, administration of Mercator Artemether Tablets to 14 subjects had no effect on QTc interval, infusion of quinine alone in 14 other subjects caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine. This effect was slightly, but significantly greater when quinine was infused after Mercator Artemether Tablets in 14 additional subjects. It would thus appear that the inherent risk of QTc prolongation associated with i.v. quinine was enhanced by prior administration of Mercator Artemether Tablets.
In a clinical trial in Thailand some patients received Mercator Artemether Tablets following treatment failures with mefloquine or quinine. One hundred and twenty-one patients received Mercator Artemether Tablets without any previous antimalaria treatment whereas 34 and 9 patients has measurable quinine or mefloquine, respectively, at enrolment. These patients showed similar safety and pharmacokinetic profiles of Mercator Artemether Tablets to patients who had no detectable levels of other antimalarias. In the different clinical trials, a symptomatic prolongation of QTc intervals by > 30ms, with an actual QTc >450ms in males and > 470ms in females, was observed in approximately 5% of patients treated with various dose regimens of Mercator Artemether Tablets. It is possible that these changes were disease-related. No correlation was found between QTc prolongation and peak plasma concentration in individual patients
When Mercator Artemether Tablets is given sequentially to mefloquine or quinine, close monitoring of foof intake (for mefloquine)or ECG (for quinine) is necessary in addition, because data on safety and efficacy are limited. Mercator Artemether Tablets should not be given concurrently with antimalarias other than mefloquine or quinine in patients previously treated with halofantrine. Mercator Artemether Tablets should be administered at least one month after the last halofantrine dose.
If a patient deteriorates while taking Mercator Artemether Tablets, alternative treatment for malaria should be started without delay. In such cases, monitoring of the ECG is recommended and steps should be taken to correct any electrolyte disturbances.
INTERACTION WITH CONCOMITANT TREATMENT OTHER THAN ANTIMALARIALS
No safety issues that could be attributed to drug interactions arose during clinical studies with Mercator Artemether Tablets in which most patients received antipyretic medication, antibiotics and fluid electrolyte replacement.
INTERACTION WITH A CYP450 3A4 INHIBITOR (KETOCONAZOLE)
The concurrent oral administration of ketoconazole with Mercator Artemether Tablets led to a modest increase(<2-fold) in artemether, DHA, and lumefantrine exposure in healthy subjects. This increase in exposure to the antimalaria combination was not associated with increased side effects or changes in electrocardiographic parameters. Based on this study, dose adjustment of Mercator Artemether Tablets is considered unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.
INTERACTION WITH CYP450 ENZYMES
Whereas in-vitro studies with artemether at therapeutic concentrations revealed no significant interactions with cytochrome P450 enzymes, the artemisinins have some capacity to induce the production of the cytochrome enzymeCYP2C19 and perhaps also CYP3A4.
It is possible that iso-enzymeproduction could after the therapeutic effects of drugs that are predominantly metabolized by these enzymes.
Lumefantrine was found to inhibit CYP2D6 in vitro. This may be of particular clinical relevance for compounds with a low therapeutic index. Co-administration of Mercator Artemether Tablets with drugs that are metabolized by this iso enzyme (e.g neuroleptics and tricylic antidepressant) is contraindicated.
The following adverse effects have been reported, dizziness and fatigue, patients receiving Mercator Artemether Tablets should not drive or use machines, anorexia, nausea, vomiting, abdominal pain, palpitations, myalgia, sleep disorders, arthragia, headache and rash.
In children and adults treated with this combinations the frequency and degree of QTC prolongations was lower compared with other antimalarials. Stiches show no indication of cardiotoxicity.
Mercator Artemether Tablets 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 though to interfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to the non-toxic haemozoin, malaria pigment. Lumefantrine is thought to interfere with the polymerization process,
while artemether generates reactive metabolites as a result of the interaction between the peroxide bridge and haem iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid, and protein synthesis within the malaria parasite. Data from in-vitro and in-vivo studies show that Mercator Artemether Tablets did not induce resistance.
The antimalarial activity of the combination of lumefantrine and artemether in Mercator Artemether Tablets is greater than that of either substance alone. In a double-blind comparative study in China (n=157), the 28-day cure rate of Hatherley when given as 4 doses was 94% compared with 90% for lumefantrine and 46% for artemether when given as monotherapy (intention to treat analysis, ITT).
In areas where multi-drug-resistant strains of falciparum malaria are common and in the resident population, 28-day cure rates with the 6-dose regimen (given over 60-96 h) were 87% and 90% for Mercator Artemether Tablets versus 94% and 96% for mefloquine/artesunate (ITT). Patients of European origin were not included in trials with the six-dose regimen. However, as efficacy and safety were similar in European and Thai patients following a four-dose regimen, similar efficacy and safety profiles with the six-dose regimen would be expected in both populations. In 319 patients in whom gamelocytes were present, the median time to gamelocyte clearance with Mercator Artemether Tablets was 96 h. Mercator Artemether Tablets was associated with more rapid gamecolyte clearance than any comparator other than mefloquine/artesunate.
Mercator Artemether Tablets is active against blood stages of Plasmodium vivax, but is not active against hypnozoites, therefore, sequential treatment with primaquine should be used to achieve hypnozoite eradication (see section SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
Pharmacokinetics characterization of Mercator Artemether Tablets is limited by the lack of an intravenous formulation, and the very high inter and intra-subject variability of artemether and lumefantrine plasma concentrations and derived pharmacokinetic parameters (AUC, Cmax).
Artemether is absorbed fairly rapidly with peak plasma concentrations 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 about 2 hours after dosing. Food enhances the absorption of both artemether and lumefantrine in healthy volunteers, the relative bioavailability of artemether was increased more than two-fold and that of lumefantrine sixteen-fold compared with fasted conditions while Mercator Artemether Tablets was taken after a high-fat meal. Food has also been shown to increase the absorption of lumefantrine in patients with malaria, although to a lesser extent (approximately two-fold), most probably due to the lower fat content of the food ingested by acutely ill patients. The food interaction data indicate that absorption of lumefantrine under fasted conditions is very poor (assuming 100% absorption after a high-fat meal, the amount absorbed) under fasted conditions 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.
Artemether and lumefantrine are both highly bound to human serum proteins in vitro (97.9% and 99.95 respectively)
Dihydroartemisinin is also bound to human serum proteins (47%-76%) protein binding to human plasma protein in linear.
Artemether is rapidly and extensively metabolized (substantial first-pass metabolism both in vitro and in humans). Human liver microsomes metabolized artemether to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly through the enzyme CYP3A4/5. The pharmacokinetics of this metabolite has also been described in humans in vivo. The artemether/dihydroartemisinin AUC ratio is 12 after a single dose and 0.3 after 6 doses given over 3 days. In vivo data indicate that artemisinins have omecapacity to induce cytochrome iso enzymes CYP2C19 and CYP3A4 (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE AND INTERACTIONS)
Lumefantrine is N-debutylated, mainly by CYP3M in human liver microsomes in vivo in animals (dogs and rats) glucuronidation of lumefantrine takes place directly and after oxidative biotrans formation. In vitro lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE AND INTERACTIONS)
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 Mercator Artemether Tablets.
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-first-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 gods, qualitative and quantitative recovery of metabolites in bile and faeces was relatively low, most of the dole being recovered as parent drug.
Protect from heat; Store below 25ºC
Mercator Artemether Tablets should not be used after the date marked "EXP" on the box.
INSTRUCTIONS FOR USE AND HANDLING
Note: Mercator Artemether Tablets should be kept out of the reach and sight of children.
Mercator Artemether Tablets 80/480mg tablet is available in a box of 6 tablets.
Mercator's Other popular Antimalarial products according to the WHO guidelines include:
1. Arteether Injection
2 Artemether + Lumefantrine Powder for Suspension
3. Artemether + Lumefantrine Tablets
4. Artemether Injection
5. Artemisinin + Piperaquine Tablets
6. Artesunate + Amodiaquine Tablets
7. Artesunate + Mefloquine Tablets
8. Artesunate + Sulfadoxine + Pyrimethamine Tablets
9. Chloroquine Phosphate Injection
10. Dihydroartemisinin + Piperaquine Phosphate + Trimethoprim Powder for Suspension
11. Dihydroartemisinin + Piperaquine Phosphate + Trimethoprim Tablets
12. Dihydroartemisinin + Piperaquine Phosphate Powder for Suspension
13 Dihydroartemisinin + Piperaquine Phosphate Tablets
14. Quinine Dihydrochloride Injection
15. Sulfadoxine + Pyrimethamine Tablets