Description

COMPOSITION:

Each 5ml when reconstituted contains 15mg Artemether and 90mg Lumefantrine.

DESCRIPTION:

Artemether is a sesquiterpene lactone derived from the naturally occurring substance artemisinin.

Lumefantrine is a synthetic racemic fluorene mixture.

PHARMACODYNAMICS:

COMAX DPS comprises a fixed ratio of 1:6 parts of Artemether and Lumefantrine, respectively. The site of anti-parasitic 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 pigment. Lumefantrine is thought to interfere with the polymerization 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 acid and protein synthesis within the malarial parasite. Data from in-vitro and in-vivo studies show that the combination of Artemether and Lumefantrine did not induce resistance and that the anti-malarial activity is greater than that of either substance alone. In patients in whom gametocytes were present, the median time for gametocyte clearance is 96 hours.

PHARMACOKINETICS:

Artemether is absorbed fairly rapidly with peak plasma concentrations about 2 hours after administration. For Lumefantrine, a highly lipophilic compound, there is a lag-time of up to 2 hours with peak concentrations at about 6-8 hours after administration. Food enhances absorption of both Artemether and Lumefantrine. Patients should therefore be encouraged to take COMAX DPS with a normal diet as soon as food can be tolerated.

Artemether and Lumefantrine are both highly bound to human serum proteins in-vitro, 95.4% and 99.7% respectively. Dihydroartemisinin is also bound to serum proteins (45-76%). Protein binding to human plasma proteins is linear.
Artemether is rapidly and extensively metabolized with substantial first-pass metabolism by liver microsomes to the biologically active dihydroartemisinin (demethylation), mostly through enzyme CYP3A4/5.

The Artemether/ Diihydroartemisinin ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. Lumefantrine is N-debutylated mainly by CYP3A4 in liver microsomes. In-vitro, Lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.

Artemether and Dihydroartemisinin are rapidly cleared from plasma with an elimination half-life of about 2hours. Lumefantrine is eliminated slowly with terminal half-life of 2-3 days in healthy volunteers and 4-6 days in falciparum malaria patients. Sex and weight appear to have no clinically relevant effects on the pharmacokinetics of Co-Max. No urinary excretion data are available for humans. In rats and dogs, metabolites of Artemether are found in both faeces and urine while excretion of Lumefantrine is primarily in faeces, most of it as the parent drug.

INDICATIONS:
It is indicated for the treatment of adults and children with acute, uncomplicated infections due to Plasmodium falciparum or mixed infections including P. falciparum. Because COMAX DPS is effective against both drug-sensitive and drug-resistant P. falciparum, it is also recommended for malaria infections acquired in areas where the parasites may be resistant to other antimalarials.

For travellers (non-immune subjects), prescribers are advised to issue COMAX DPS for self-administration with guidance regarding the appropriate use.

CONTRAINDICATIONS:

COMAX DPS is contraindicated in:

• Patients that are hypersensitive to the active substances or any of the excipients.
• Patients with severe malaria according to WHO definition.
• Patients with a family history of congenital elongation of QTc interval, cardiac arrhythmias, clinically relevant bradycardia or with severe cardiac disease and in known disturbances of electrolyte balance e.g. hypokalaemia or hypomagnesaemia.
• Patients taking any drug which is metabolized by the cytochrome enzyme CYP2D6 e.g. Fleicanide, Metoprolol, Imipramine, Amitryptiline, Clomipramine.
• Patients taking drugs that prolong QT interval such as antiarrhythmics of  classes