Each Tablet contains Artemether 80mg Lumefantrine 480mg
DESCRIPTION AND PHARMACEUTICAL FORM
(3R, 5aS, 6R, 8aS, 9R, 10S, 12aR)-Dechdro-10-methoxy 3,6,9-trimethy 1-3, 12-epoxy-12-epoxy-12Hpyrano [4,3-j]- 1,2-benzodioxpin (=artemether)
and [1R,S]-2-Dbutylamini-1-[2,7-dichloro-9–] (Z) (4-chlorobenzylidene)-9H-flouren-4-yl) (Lumefantrine).
Artemether is a sesquiterpene lactone derived from the naturally occurring substances artemisinin.
Lumefantrine is a synthetic racemic flourine mixture.
CLARTEM-DS 80/480 is a combination of artemether and lumefantrine, which act as a blood schizontocide. It is indicated for the treatment of adults and children with acute, uncomplicated infections due to Plasmodium falciparium or mixed infection including P. Falciparium and strains from multi drug resistant areas.
CLARTEM-DS 80/480 is recommended for use as a standby emergency treatment for travellers to areas where the parasite is resistant to other drugs.
DOSAGE AND ADMINISTRATION IN ADULTS
CLARTEM-DS 80/480 should be taken with high fat food or drinks such as milk. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorptions of artemether and lumefantrine. On the event of vomiting within 1 hour of administration, a repeat dose should be taken.
|Weight in Kg||Total Tablets||Dosage Regimen|
|35 kg and above||Day 1||Day 2||Day 3|
|0 hr||8 hr||20 hr||32 hr||44 hr||56 hr|
Second dose to be taken strictly after 8 hours of first dose.
Better taken with high-fat food or drinks such as milk.
There is no information on overdoses of CLARTEM-DS 80/480 higher than the doses recommended for treatment. In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.
CLARTEM-DS 80/480 is contraindicated in:
-Hypersensitivity to artemether, lumefantrine or any of the excipients of CLARTEM-DS 80/480.
-Patients with severe malaria according to WHO definition.
-First trimester of pregnancy.
-Patients with a family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
-Patients with known disturbances of electrolyte imbalance e.g. hypo Kaleamia or hypomagnesaemia.
-Patients taking any drug, which is metabolised by the cytochrome enzyme CYP206 (e.g Hecainde, metaprolol, imipramine, amitriptyline, clomipranaine)
-Patients taking drugs that are known to prolong the QTc interval such as antiarrhythics of classes IA and III, neuroleptics, and antidepressive agents.
Although the likelihood of CLARTEM-DS 80/480 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 potent CYP3A4 inhibitor), mefloquine and quinine have been conducted in healthy volunteers.
Interactions with antimalarials
As patients to be treated with CLARTEM-DS 80/480 may have recently been treated with other antimalarial. Interactions with mefloquine and quinine were studied in healthy volunteers. The sequential oral administration of mefloquine prior to CLARTEM-DS 80/480 had no effect on plasma concentration of artemether or the artemeter/ dihydroartemisinin ratio but there was a significant (about 30-40%) reduction on plasma levels (Cmax and AUC) of lumefantrine, possibly due to lower absorption secondary to a mefloquine induced decrease in bile production. Patients should be encouraged to eat at dosing times to compensate for this decrease in bioavailability. The concurrent i.v. administration of quinine. (10 mg/kg BW) with CLARTEM-DS 80/480 had no effect on plasma concentrations of lumefantrine or quinine. Plasma concentration of artemether and DHA appeared to be lower in this study, administration of CLARTEM-DS 80/480 to 14 subjects had no effects 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 CLARTEM-DS 80/480 in 14 additional subjects. It would thus appear that the inherent risk of QTc prolongation associates i.v. quinine was enhanced by prior administration of CLARTEM-DS 80/480.
When CLARTEM-DS 80/480 is given sequentially to mefloquine or quinine, close monitoring of food intake (for mefloquine) or ECG (for quinine) is necessary in addition, because data on safety and efficacy are limited. CLARTEM-DS 80/480 should not be given concurrently with antimalarial other than mefloquine or quinine in patients previously treated with halofantrine. CLARTEM-DS 80/480 should be administered at least one month after the last halofantrine dose.
If a patient deteriorates while taking CLARTEM-DS 80/480, 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 CLARTEM-DS 80/480, 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 CLARTEM-DS 80/480 led to a modest increase (<2-fold) in artemether, DHA, and lumefantrine exposure in healthy subjects. The increase in exposure to the antimalarial combination was not associated with increased side effects or changes in electrocardiographic parameters. Base on this study, dose adjustment of CLARTEM-DS 80/480 is considered unnecessary in falciparium 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 concentration revealed no significant interactions with cytochrome p450 enzymes, the artemisinins have some capacity to induce the production of the cytochrome enzyme CYP2C19, and perhaps also CYP3A4. It is possible that iso-enzyme production could alter the therapeutic effects of drugs that are predominantly metabolised by these enzymes.
Lumefantrine was found to inhibit CYP2D6 in-vitro. This may be particular clinical relevance for compounds with a low therapeutic index. Co-administration of CLARTEM-DS 80/480 with drugs that are metabolised by this iso-enzmes (e.g neuroleptics and tricyclic antidepressants) is contraindicated.
PRECAUTIONS FOR USE
CLARTEM-DS 80/480 is not recommended for prophylaxis.
The following adverse effects have been reported: dizziness and fatigue, patients receiving CLARTEM-DS 80/480 should not drive or use machine, anorexia, nausea, vomiting, abdominal pain, palpitations, myalgia, sleep disorders, arthralgia, headache and rash.
In children and adults treated with this combination, the frequency and degree of QTc prolongations were lower compared with other antimalarials. Studies show no indications of cardiotoxicity.
CLARTEM-DS 80/480 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 heamoglobin breakdown, to the non-toxic haenozoin, malaria pigment. Lumefantrine is thought to interfere with polymerisation process while artemether generates reactive metabolites as a result of the interactions between its peroxide nucleic acid, and protein synthesis within the malaria parasite. Data from in-vitro and in-vivo studies show that CLARTEM-DS 80/480 did not induce resistance.
The antimalarial activity of the combination of lumefantrine and artemether in CLARTEM-DS 80/480 is greater than that of either substances alone.
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 lat-tiem of up to 2 hours, with peak plasma concentration about 2 hours after dosing. Food enhances the absorption of both artemether and lumefantrmne: in healthy volunteers, the relative bioavailability of artemether was increased more than two-fold and that of lumefantrine more than sixteen-fold when CLARTEM-DS 80/480 was taken after a high-fat meal compared with fasted conditions. Food has also been shown to increase the absorption of lumefantrine in patients with malaria, although to lesser extent (approximately twofold), most probably due to the lower fat content of the food ingested by actually ill patients. The food interactions 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 medications with a normal diet as soon as food can be tolerated.
Artemeter and Lumefantrine are both highly bound to human serum proteins (97.9% and 99.9%), respectively.
Dihydroartemisinin is also bound to human serum proteins (47% – 76%). Protein binding to human plasma protein in linear.
Artemether is rapidly and extensively metabolised (substantial first metabolism both in-vitro and in humans. Human liver microsomes metabolised artemether to the biologically active main metabolic dihydroartemisinin (demethylation), predominantly through the enzyme CYP3A4/5. The pharmcokinetics of the 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 some capacity to induce cytochrome iso-enzymes CYP2C19 and CYP3A4.
Lumefantrine is N-debutylated mainly by CYP3A4, in human liver microsomes in-vivo in animals (dogs and rats), glucuronidation of lumefantrine takes place directly and after oxidative biotransformation.
In-vitro lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.
Artemether and dihydroartemisimn are rapidly cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated very slowly with a terminal half-life 2-3 days in healthy volunteers and 54-6 days in patients with falciparium malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of CLARTEM-DS 80/480. No urinary excretion data are available for humans. In rats and dogs, unchanged artemether has not been detected in feaces and urine due to its rapid and high-first pass metabolism, but several metabolites (unidentified) have been detected in both feaces and urine. Lumefantrine is eliminated via the bile in rats and dogs, with excretion primarily in the feaces. After oral dosing in rats and dogs, qualitative and quantitative recovery of metabolites in bile and feaces was relatively low, most of the dose being recovered as parent drug.
CLARTEM-DS 80/480 is available in a box of 6 tablets.
Protect from heat, store below 30°C
CLARTEM-DS 80/480 should not be used after the date marked “EXP” on the box.
INSTRUCTION FOR USE AND HANDLING
Note: CLARTEM-DS 80/480 should be kept out of reach and sight of children.
Clarion Medicals Ltd
23 AfolabI Lesi Street, Ilupeju
Clarion Medicals Ltd
788-790 Finchley Road Golders Green London
NW11 7TJ, United Kingdom
Jiangsu Ruinian Qianjin Pharmaceutical Co., Ltd.
Chuanbu Village, Dingshu Town, Yixing City, Jiangsu Province, China
NAFDAC REG. NO.: B4-5445