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Co-fan 80/480

Al-Tinez Pharmaceuticals Limited
9, Olowogbowo Str off Obokun Str by Coker Rd, Ilupeju, Lagos
Tel: 01-4826452; 0802-307-7320, 0803-305-7978

Brand Name

Co-fan 80/480

Manufacturer

SAO KIM PHARMACEUTICAL JOINT STOCK COMPANY, Quang Minh Industry Zone - Me Linh - Ha Noi - Viet Nam.

Therapeutic Class

Antimalarial drugs

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Tablet (NRN:   ): Artemether 80 mg Lumefantrine 480 mg Exicipients: microcrystalline cellulose, lactose, talcum, magnesium stearate, polyvinyl pyrrolidon q.s. 1 tablet.

Pack size: Box of 1 blister x 6 tablets.

co fan Q

Pharmacology

Artemether and lumefantrine are blood schizontocides. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin.

Artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum. Both are shown to inhibit nucleic acid and protein synthesis. The exact mechanism by which they exert antimalarial effect is not well defined.

Co-fan is a fixed combination with a ratio of 1:6 parts of artemether and lumefantrine respectively.

Both artemether and lumefantrine act as blood schizonticides. The site of antiparasitic action of both components of the combination is the food-vacuole of the malarial 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.

- Parasites in the infected erythrocytes ingest and degrade haemoglobin and concentrate the iron in a food- vacuole in the form of toxic haem. Normally, the haem is then made harmless by conversion into heamozoin.

-Artemether is concentrated in the food-vacuole. It then splits its endoperoxide bridge as it interacts with haem, blocking conversion to haemozoin, destroying existing haemozoin and releasing haem and a cluster of free radicals into the parasite.

Lumefantrine is thought to interfere with the haem polymerisation process, a critical detoxifying pathway for the malaria parasite. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid and protein synthesis within the malarial parasite. The combination is also associated with rapid gametocyte clearance.

-Artemether is fast acting drug with a short half-life.

-Lumefantrine acts slowly and has a longer half-life.

Artemether rapidly reduces parasite biomass and quickly resolves clinical symptoms, whilst the long acting action of lumefantrine is thought to prevent recrudescence. This dual effect also appears to reduce the selective pressure on the parasite to develop resistance. The antimalarial activity of the combination of lumefantrine and artemether in Co-fan is greater than that of either substance alone.

Pharmacokinetics

Absorbtion

- 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 period of up to 2 hours, with peak plasma concentration about 6-8 hours after dosing.

- Food enhances the absorption of both artemether and lumefantrine. The relative bioavailability of artemether was increased more than two fold and that of lumefantrine sixteen fold compared with fasted conditions when artemether and lumefantrine tablets were taken after a high fat meal. In order to improve bioavailability, patients should be encouraged to take the drug 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. 7%, respectively). The artemisinin metabolite dihydroartemisinin is also bound to human serum proteins (4 7%-76%).
Metabolism

- Artemether is rapidly and extensively metabolised by human liver microsomes (mostly through the enzyme CYP3A4/5) in vitro and in vivo, with a substantial first pass metabolism. The main active metabolite is dihydroartemisinin.

- Lumefantrine is also metabolised predominantly by the enzyme CYP3A4 in human liver microsomes. At therapeutic plasma concentrations, lumefantrine significantly inhibits the enzyme CYP206 in vitro.

Elimination

- Artemether and dihydroartemisinin are rapidly cleared from plasma with an elimination half-life of approximately 2-3 hours. Conversely, 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.

- No urinary excretion data are available for humans. In animal studies, unchanged artemether has not been detected in both 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.

Indications

Co-fan is a fixed combination of artemether and lumefantrine which acts as blood schizontocide.

Co-fan is indicated for:

The treatment of acute and uncomplicated malaria caused by Plasmodium falciparum.

Co-fan is effective against both drug-sensitive and multidrug-resistant Plasmodium falciparum.

Stand-by emergency treatment: most tourists and business travellers, considered to be non-immune, will able to obtain prompt medical attention if malaria is suspected.

However, a minority at risk of infection may be unable to obtain such care within 24 hours of the onset of symptoms, particularly if they are in an isolated location far from medical services.

In such cases, prescribers are adviced to issue Co-fan to be carried by the traveller for self-administration. (“stand-by emergency treatment").

Contra-indications

Known hypersensitivity to any components.

In cases of severe malaria according to WHO definition.

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, patients with clinically relevant bradycardia or with severe cardiac disease, family history of sudden death, disturbances of electrolyte balance e.g., hypokalaemia or hypomagnesaemia.

Concomitant use of drugs that are known to be metabolised by cytochrome enzyme CYP2D6 (e.g. flecainide, metoprolol, imipramine, amitriptylline, clofipramine).

Patients taking drugs that are known to prolong the QTc interval such as antiarrhythmics of classes IA and III, neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, f1uoroquinolones, imidazole or azole antifungal agents, certain non-sedating antihistamines (terfenadine, astemizole), cisapride.

Co-fan is not indicated for prophylaxis of malaria.

The drug should be used with caution in patients with renal or hepatic failure.

Precautions/Warnings

Patients with severe hepatic or renal insufficiency and patients refusing food intake.

Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater.

Read enclosed leaflet carefully before use 

For further information please ask Doctor's advice.

Interactions

The sequential oral administration of mefloquine prior to artemether and lumefantrine combination had no effect on plasma concentrations of artemether or, the artemether/dihydroartemisinin (DHA) ratio but there was a significant (around 30-40%) reduction plasma levels (Cmax and AUC) of lumefantrine, possibly due to lower absorption, secondary to a mefloquine-induced decrease in bile production. Such patients should therefore be encouraged to eat at dosing times to compensate for this decrease in bioavailability.

Quinine alone caused a transient prolongation of the QTc interval, which was consistent with its known cardiotoxicity. This effect was slightly but significantly greater when quinine was infused after artemether and lumefantrine combination. Thus, prior administration of artemether and lumefantrine combination appears to enhance the inherent risk of QTc prolongation from IV quinine.

Hence, when artemether and lumefantrine combination is given to patients following administration of mefloquine or quinine, close monitoring of food intake (for mefloquine) or the ECG (for quinine) should be carried out.

In patients previously treated with halofantrine, artemether/lumefantrine tablets should be administered at least one month after the last halofantrine dose.

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 enzymes CYP2C19 and CYP3A4. It is possible that iso-enzyme induction could alter the therapeutic effects of drugs that are predominantly metabolized by these enzymes.

Lumefantrine was found to inhibit CYP2D6 in vitro. Co-administration of artemether and lumefantrine tablets with drugs that are metabolized by this iso-enzyme (e.g., neuroleptics and tricyclic antidepressants) is contraindicated.

Pregnancy and lactation:

This medicine is contraindicated during the first trimester of pregnancy. During the second and third trimester, treatment should only be considered if the expected benefit to the mother outweighs the risk to the fetus.

Breast-feeding women should not take artemether/lumefantrine tablets. Due to long elimination half-life of lumefantrine (4 to 6 days), it is recommended that breast-feeding should not resume before day 28 unless potential benefits to mother and child outweigh the risks of Co-fan treatment.

Effects on ability to drive and use machines:

Patients should be warned that dizziness or fatigue/asthenia might occur in which case they should not drive or use machines.

Adverse Effects

Co-fan is well tolerated in children and adults, with most adverse events being of mild to moderate severity and duration. Many of the reported events are likely to be related to the underlying malaria and/or to an unsatisfactory response to treatment rather than to the medicine.

Common adverse events reported with artemether/lumefantrine combination include headache, dizziness, sleeplessness, abdominal pain, anorexia, diarrhea, vomiting, nausea, cough, palpitation, arthralgia, myalgia, pruritus, rash, asthenia and fatigue.

Other adverse effects reported with artemether/lumefantrine combination are somnolence, involuntary muscle contractions, paraesthesia, hypoaesthesia, abnormal gait, ataxia.

Rare adverse event included hypersensitivity.

Unspecified personality disorders have also been reported in children under 5 years of age treated with artemether/lumefantrine combination.

Report any side effects to your doctor during period of treatment.

Dosage & Administration

Co-fan QS is suitable for adults and children weighing 35 kg and over. A standard three days treatment schedule with a total of 6 doses is recommended as follow:

DOSING SCHEDULE

Body weight in kg

(Age in years)

 First day  Second day  Third day
 0 hours 8 hours  Morning  Evening Morning Evening
Adult and children 35kg & above (>14)   1  1 1  1 1 1

No special precautions or dosage adjustments are considered necessary in elderly and in patients with hepatic impairment.

ADMINISTRATION

- Co-tan QS is administrated by oral route.

- Co-fan QS should be taken with milk or high fat food - particularly on the second and third days of treatment.

Note that patients with acute malaria are frequently averse to food.

Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of the medicine. In the event of vomiting within 1 hour of administration a repeat dose should be taken.

Storage/Handling Recommendations

Store in a cool and dry place below 28°C, protect from light.

Shelf-life: 24 months from the date of manufacturing.

KEEP OUT OF REACH OF CHILDREN. READ ENCLOSED LEAFLET CAREFULLY BEFORE USE. FOR FURTHER INFORMATION PLEASE ASK DOCTOR'S ADVICE

Review Date

2016-12-02 07:20:07