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Sivometertrine Tablet 80/480 mg

Adpharm Pharmaceuticals Limited
60, Ajao Road, Surulere, Lagos State, Nigeria
Email: adpharm2010@yahoo.com; info@adpharmltd.com
Tel: +234(0)818-839-0519, +234(0)807-408-4334. Mobile: 08033481022
Website: http://adpharmltd.com/

Brand Name

Sivometertrine Tablet 80/480 mg

Manufacturer

JIANGSU RUINIAN QIANJIN PHARMACEUTICAL CO., LTD. Chuanbu Village. Yixing Economic Development Zone. Jiangsu Province. China.

Therapeutic Class

Antimalarial drugs

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Tablet (NRN: A4-8226): Each Tablet contains Artemether 80 mg, Lumefantrine 480 mg.

Pack size: 1 x 6's 

Sivometertrine Tablet80mg

 

Pharmacology

COMPOSITION AND PHARMACEUTICAL FORM
Active Substances:
(3R, 5aS, 6R, 8aS, 9R, 10S, 12aR)-Dechdro-10-methoxy 3, 6, 9-trimethyl -3, 12-epoxy-12-epoxy-12Hpyrano [4, 3-j]-1, 2-benzodioxpin (artemether) and [IR, 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 substance artemisinin.
Lumefantrine is a synthetic racemic flourine mixture.

PHARMACODYNAMICS
Pharmacodynamics 
Sivometertrine 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 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 Sivometertrine did not induce resistance.

The antimalarial activity of the combination of lumefantrine and artemether in Sivometertrine is greater than that of either substance alone.

PHARMACOKINETICS
Absorption
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 lumefantrine: in healthy volunteers, the relative bioavailability of artemether was increased more than two-fold and that of lumefantrine more than sixteen-fold when Sivometertrine 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 two-fold), 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.

Distribution
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.

Metabolism
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 pharmacokinetics of the metabolite has also been described m 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 CYP206 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 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 Sivometertrine.

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 dogs, qualitative and quantitative recovery of metabolites in bile and faeces was relatively low, most of the dose being recovered as parent drug.

Indications

Sivometertrine 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 falciparum or mixed infection including P. Falciparium and strains from multidrug resistant areas.

Sivometertrine is recommended for use as a standby emergency treatment for travellers to areas where the parasite is resistant to other drugs.

Contra-indications

Sivometertrine is contraindicated in:

-Hypersensitivity to artemether, lumefantrine or to any of the excipients of Sivometertrine

-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 hypokalaemia or hypomagnesaemia

-Patients taking any drug, which is metabolised by the cytochrome enzyme CYP206 (e.g Flecainde, metoprolol, imipramine, amitriptyline, clomipramine)

-Patients taking drugs that are known to prolong the QTc interval such as antiarrhythics of classes IA and III, neuroleptics, and antidepressive agents.

Precautions/Warnings

Sivometertrine is not recommended for prophylaxis.

Interactions

Although the likelihood of Sivometertrine interactions with other drugs is minimal in view of its short duration of administration and wide therapeutic index, three specific pharmacokinetic and pharmacodynamics drug-drug interaction studies with ketoconazole (a potent CYP3A4
inhibitor), mefloquine and quinine have been conducted in healthy volunteers.

Interaction with antimalarials:
As patients to be treated with Sivometertrine 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 Sivometertrine had no effect on plasma concentration or artemether or the artemether / 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 in 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 Sivometertrine 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 Sivometertrine 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 infused after

Sivometertrine 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 Sivometertrine.
When Sivometertrine 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.

Sivometertrine should not be given concurrently with antimalarial other than mefloquine or quinine in patients previously treated with halofantrine. Sivometertrine should be administered at least one month after the last halofantrine dose.

If a patient deteriorates while taking Sivometertrine, 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 disturbance.

Interaction with concomitant treatment other than antimalarials:
No safety issues that could be duel to drug interactions arose during, clinical studies with Sivometertrine, in which most patients received antipyretic medication, antibiotics and fluid electrolyte replacement.

Interaction with a CVP450 3A4 inhibitor (ketoconazole)
The concurrent oral administration of ketoconazole with Sivometertrine 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. Based on this study, dose adjustment of Sivometertrine 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 Sivometertrine with drugs that are metabolised by this iso-enzymes (e.g neuroleptics and tricyclic antidepressants) is contraindicated.

Adverse Effects

The following adverse effects have been reported:dizziness and fatigue, patients receiving Sivometertrine 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.

Dosage & Administration

Sivometertrine 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 absorption of artemether and lumefantrine. In the event of vomiting within 1 hour of administration, a repeat dose should be taken.

 Weight in Kg   Total Tablets   Dosage Regimen 
 35 kgs And above   Day 1  Day 2   Day 3 
 0 hr   8 hrs   24 hrs   36 hrs   48 hrs   60 hrs 
 6  1  1   1  1  1  1

Second dose to be taken strictly after 8 hours of first dose. Better taken with high-fat foods or drinks such as milk.

Storage/Handling Recommendations

Protect from heat, store below 30°C.

Sivometertrine should not be used after the date marked "EXP" on the box.

INSTRUCTION FOR USE AND HANDLING
Note: Sivometertrine should be kept out of reach and sight of children.

Review Date

2017-08-14 04:28:58