Ipca Lumerax Artemether and Lumefantrine Tablets

Lumerax
Artemether and Lumefantrine Tablets

For the use only of a Registered Medical Practitioner or a Laboratory

 

DESCRIPTION

Artemether and Lumefantrine combination is a fixed dose artemisinin-based combination therapy (ACT) combining artemether, an artemisinin derivative, and lumefantrine a synthetic antimalarial drug.

Chemical formula of artemether is (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 whereas chemical formula of lumefantrine is (1R,S)-2-Dibutylamino-1-{2,7-dichloro-9-[(Z)(4-chlorobenzylidene)-9H-fluoren-4-yl)-ethanol.

Artemether is a sesquiterpene lactone derived from artemisinin. Artemisinin is a compound derived from the sweet wormwood plant and has been used for centuries in traditional Chinese medicine to treat fever. Lumefantrine is a sythentic aryl-amino alcohol antimalarial (quinine, mefloquine and halofantrine are members of the same group).

 

COMPOSITION

Lumerax 20/120

Each tablet contains:

Artemether Ph. Int. 20mg

Lumefantrine Ph. Int. 120mg

Lumerax 40/240

Each tablet contains:

Artemether Ph. Lnt. 40mg

Lumefantrine Ph. Int. 240mg

Lumerax 80/480

Each tablet contains:

Artemether Ph. Int. 80mg

Lumefantrine Ph. Int. 480mg

 

PHARMACODYNAMICS

Both artemether and lumefantrine act as blood schizontocides.

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 haemozin, 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 haemozoin.

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

Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid and protein synthesis within the malarial parasite.

Artemether and lumefantrine combination is active against the blood stages of P. vivax, but is not active against hypnozoites. Therefore, an 8-amino-quinine derivative such as primaquine should be given sequentitally after the combination in cases of mixed infections of P. falciparum and P. vivax to achieve hypnozoites eradication.

Rationale for the combination of artemether and lumefantrine

Artemisinin and its derivatives are at present, the only effective drugs against drug resistant malaria. However their use alone may result in development of resistance to these life saving drugs. According to the new WHO malaria treatment guidelines, uncomplicated falciparum malaria must be treated with artemisinin combination therapy (ACT) and not by artemisinin alone or any other monotherapy. Artemisinin when used correctly in combination with other anti-malarial drugs is not only effective in curing malaria, but also the parasite is highly unlikely to become drug resistant.

Artemether is fast acting drug with a short half-life. Lumefantrine acts slowly and has a longest half-life. Artemether rapidly reduces parasite biomass and quickly resolves clinical symptoms, whilst the long-acting activity 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 is greater than that of either substance alone.

 

PHARMACOKINETICS

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 Iumefantrine tablets were taken after a high fat meal. Likewise, in patients with malaria, food increases the absorption of lumefantrine, although to a lesser extent (approximately two-fold), most probably due to the lower fat content of the food eaten by acutely ill patients. Acutely ill patients are reluctant to eat and tend to avoid high-fat foods. In order to improve bioavailability, patients should be encouraged to take the drug 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). The artemisinin metabolite dihydroartemisinin is also bound to human serum proteins (47%-76%).

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

Lumefantrine is also metabolized predominantly by the enzyme CYP3A4 in human liver microsomes. At therapeutic plasma concentrations, lumefantrine significantly inhibits the enzyme CYP2D6 in vitro. Artemether and dihydroartemisinin are rapidly cleared from plasma with an elimination half-life of 2-3 days in healthy volunteers and 4-6 days in patients with falciparum malaraia.

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 snd 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

Artemether and lumefantrine tablets are indicated for the treatment, including standby emergency treatment of adults and children with acute, uncomplicated infections due to P. falciparum or mixed infections including P. faciparum. Because the combination 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 malarials.

 

CONTRAINDICATIONS

Artemether and lumefantrine tablets are contraindicated:

• In those with hypersensitivity to the active substances or any of the excipients.

• In cases of severe malaria.

• In the 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 intervals 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, metoprol, imipramine, amitriptyline, clomipramine).

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

Artemether and lumefantrine tablets are not indicated for prophylaxis, or for treating severe malaria, including cerebral malaria, or malaria with pulmonary oedema or renal failure. It is also not indicated for and has not been evaluated in, the treatment of malaria due to P. vivax, P. malariae or P. ovale.

 

PRECAUTIONS

Use with caution in 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.

Effects on ability to drive and use machines – Driving and use of machinery is not recommended due to risk of dizziness and fatigue/asthenia.

Usage in pregnancy and lactation

Artemether and lumefantrine tablets are 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 feotus.

As the drug is contraindicated during the first trimester of pregnancy, women of child-bearing potential should not conceive while on artemether and lumefantrine treat for malaria. This includes women prescribed the combination for standby emergency treatment of malaria during their travel, in case they may require treatment for malaria.

Women of child-bearing potential should be advised to practice contraceptive during travel with standby emergency treatment, while on artemether and lumefantrine and until the start of next menstruation after the treatment.

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

Drug 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 in 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 transients 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 Iumefantrine combination. Thus, prior administration of artemether and lumefantrine combination appears to enhance the inherent risk of QTc-prolongation from I.V. 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 and lumefantrine yablest should be administered at least one month after the last halofantrine dose.

Due to limited data on safety and efficacy, the combination should not be given concurrent with other antimalarials unless there is no other treatment option. However, if a patient deteriorates while taking the combination, alternative treatments for malaria should be commenced without delay. In such cases, monitoring of the ECG is recommended and steps should be taken to correct electrolyte disturbances.
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 induction could alter 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 artemether and lumefantrine tablets with drugs that are metabolized by this iso-enzyme (e.g. neuroleptics and tricylic antidepressants) is contraindicated.

 

ADVERSE DRUG REACTIONS

Artemether and lumefantrine combination is well tolerated by 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 responses to treatment rather than to the combination.

Common adverse events reported with artemether and lumefantrine combination included headache, dizziness, sleep disorder, abdominal pain, anorexia, diarrhoea, vomiting, nausea, palpitation, cough, arthralgia, myalgia, pruitus, rash, asthenia and fatigue. Somnolence, involuntary muscle contractions, paraesthesia, hypoaesthesia, abnormal gait, ataxia were other adverse effects reported with artemether and lumefantrine combination. Rare adverse event included hypersensitivity.

Unspecified personality disorders have also been reported in children < 5 years treated with artemether and lumefantrine combination.

 

DOSAGE AND ADMINISTRATION

Artemether and lumefantrine tablets should be taken with high fat food or drinks such as milk. 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 artemether and of 6 doses lumefantrine. In the event of vomiting within 1 hour of administration a repeat dose should be taken.
A total of 6 doses is recommended as follows: The first dose is taken at the time of initial diagnosis, second dose after eight hours and then each dose twice daily (morning and evening) on following two days. With very small children the tablet should be crushed before giving.

Dosage schedule

Body weight Day 1 Day 2 Day 3
0 hr 8 hrs after Morning Evening Morning Evening
5 to less than 15 kg Artemether 20mg + Lumefantrine 120mg Artemether 20mg + Lumefantrine 120mg Artemether 20mg + Lumefantrine 120mg Artemether 20mg + Lumefantrine 120mg Artemether 20mg + Lumefantrine 120mg Artemether 20mg + Lumefantrine 120mg
15 to less than 25 kg Artemether 40mg + Lumefantrine 240mg Artemether 40mg + Lumefantrine 240mg Artemether 40mg + Lumefantrine 240mg Artemether 40mg + Lumefantrine 240mg Artemether 40mg + Lumefantrine 240mg Artemether 40mg + Lumefantrine 240mg
25 to less than 35 kg Artemether 60mg + Lumefantrine 360mg Artemether 60mg + Lumefantrine 360mg Artemether 60mg + Lumefantrine 360mg Artemether 60mg + Lumefantrine 360mg Artemether 60mg + Lumefantrine 360mg Artemether 60mg + Lumefantrine 360mg
Adults and children 35 kg and above Artemether 80mg + Lumefantrine 480mg Artemether 80mg + Lumefantrine 480mg Artemether 80mg + Lumefantrine 480mg Artemether 80mg + Lumefantrine 480mg Artemether 80mg + Lumefantrine 480mg Artemether 80mg + Lumefantrine 480mg

Appropriate tablet strength can be chosen depending upon the dosage.

Standby emergency treatment

The same six-dose regimen should be instituted at the onset of symptoms, with 1-4 tablets per dose, depending on body weight, being administered over the course of three days. Most tourists and business travelers, considered to be non-immune, will be 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 from medical services. In such cases, prescribers are advised to issue artemether and lumefantrine combination to be carried by the traveler for self-administration (‘standby emergency treatment’).

Special populations

Dosage in elderly patients

Although no studies have been carried out in the elderly, no special precautions or dosage adjustments are considered necessary in such patients.

Dosage in patients with renal or hepatic impairment

No specific studies have been carried out in these groups of patients and no specific dose adjustment recommendations can be made for these patients. Most patients with acute malaria present with some degree of related hepatic impairment. The adverse event profile did not differ in patients with and those without hepatic impairment. Moreover, baseline abnormalities in liver function tests improved in nearly all patients after treatment with artemether and lumefantrine combination.

New and recrudescent infections in adults, children and infants
Data for a limited number of patients show that new and recrudescent infections can be treated with a second course artemether and lumefantrine combination.

 

OVERDOSAGE

In cases of suspended overdosage, symptomatic and supportive therapy should be given as appropriate. ECG and blood potassium levels should be monitored.

 

STORAGE

Store below 30oC, in a dry place.

KEEP OUT OF REACH OF CHILDREN

 

PRESENTATION

Lumerax 20/120: BIister strip of 6 and 8 tablets

Lumerax 40/240: Blister strip of 6 tablets

Lumerax 80/480: Blister strip of 6 tablets

 

Made in India by

Ipca Laboratories Ltd.

Regd. Off.: 48, Kandivli Ind. Estate,

Mumbai 400 067

Advertisements