Artemether 80 mg & Lumefantrine 480 mg Tablets
Each uncoated tablet contains:
The Chemical name of Artemether is (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]-2-benzopyran
The Chemical name of Lumefantrine is 2-(Dibutyl amino)-1-[(9Z)-2, 7- dichloro-9-(4-ctilorobenzylidene)-9H-fluoren-4-yl] ethanol
Antimalarials, blood schizontocide
It comprises a fixed ratio of 1:6 parts of Artemether and Lumefantrine, respectively. The site of antiparasitic action of both components is the food vacuole of the malarial parasite, where they are thought to interfere with the conversion of haem, a toxic intermediate produced during hemoglobin breakdown, to the nontoxic 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.
Absorption: Artemether is absorbed fairly rapidly and dihydroartemisinin, the active metabolite of Artemether, appears rapidly in the systemic circulation with peak plasma concentrations of both compounds reached about 2 hours after dosing. Mean Cmax and AUC values of Artemether ranged between 60.0-104 ng/mL and 146-338 ngh/mL, respectively, in fed healthy adults after a single dose, 80mg Artemether 1480mg Lumefantrine. Mean Cmax and AUC values of dihydroartemisinin ranged between 49.7-104 ng/mL and 169-308 ng’h/mL, respectively. Absorption of Lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentration (mean between 5.10-9.80 µg/mL) about 6-8 hours after dosing. Mean AUC values of Lumefantrine ranged between 108 and 243µg’h/mL. 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 sixteen-fold compared with fasted conditions when it was taken after a high-fat meal.
Food has also been shown to increase the absorption of Lumefantrine in patients with malaria, although to a lesser extent (approximately two-fold), most probably due to the lower fat content of the food ingested by acutely ill patients. The food interaction 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 medication with a normal diet as soon as food can be tolerated.
Distribution: Artemether and Lumefantflne are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47-76%).
Metabolism: Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolize Artemether to the biologically active main metabolite dihydroartemisinin (demethylatton), predominantiy through the isoenzyme CYP3A4/5. This metabolite has also been detected in humans in vivo.
Dihydroartemisinin is further converted to inactive metabolites.
The pharmacokinetics of Artemether in adults is time-dependent. During repeated administration, plasma Artemether levels decreased significantly, while levels of the active metabolite (dihydroartemisinin) increased, although not to a statistically significant degree. The ratio of day 3/day 1 AUC for Artemether was between 0.19 and 0.44, and was between 1.06 and 2.50 for dihydroartemisinin. This suggests that there was induction of the enzyme responsible for the metabolism of Artemether. Artemether and dihydroartemisinin were reported to have a mild inducing effect on CYP3A4 activity. The clinical evidence of induction is consistent with the in vitro data.
Lumefantrine is N-butylated, 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 humans, the exposure to Lumefantrine increases with repeated administration of tablet over the 3- day treatment period, consistent with the slow elimination of the compound. Systemic exposure to the metabolite desbutyl-lumefantrine, for which the in vitro antiparasitic effect is 5 to 8 fold higher than that for Lumefantrine, was less than 1% of the exposure to the parent drug. Desbutyl-lumefantrine data is not available specifically for an African population. In vitro, Lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.
Elimination: Artemether and dihydroartemisinin are rapidly cleared from plasma with a terminal, half-life of about 2 hours. Lumefantrine is eliminated very slowly with an elimination half-life of 2 to 6 days. Limited urinary excretion data are available for humans. In 16 healthy volunteers, neither Lumefantrine nor Artemether was found in urine after administration of this tablet, and only traces of dihydroartemisinin were detected (urinary excretion of dihydroartemisinin amounted to less than 0.01% of the Artemether dose). In animals (rats and dogs), no unchanged Artemether was detected in faeces and urine due to its rapid and extensive first-pass metabolism, but numerous metabolites (partly identified) have been detected in faeces, bile and urine. Lumefantrine was excreted unchanged in faeces and with traces only in urine. Metabolites of Lumefantrine were eliminated in bile/faeces.
INDICATIONS AND USES
It is indicated for the treatment of acute uncomplicated Plasmodium faiciparum malaria in adults and children (above 35kg). Consideration should be given to official guidance regarding the appropriate use of antimalarial agents.
It is contraindicated in:
• Patients with known hypersensitivity to the active substances or to any of the excipients.
• Patients with severe malaria according to WHO definition.
• Patients who are taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (e.g. metoprolol, imipramine, amitriptyline, clomipramine).
• Patients with a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.
• Patients taking drugs that are known to prolong the QTc interval (proarrhythmic). These drugs include: antiarrhythmic of classes IA and III, neuroleptics, Antidepressive agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents, certain non-sedating antihistamines (terfenadine, astemizole), Cisapride flecainide
• Patients with a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
SIDE EFFECTS / ADVERSE EFFECTS
It has been evaluated in 20 clinical trials with more than 3500 patients. A total of 1810 adults and adolescents above 12 years of age as well as 1788 infants and children of 12 years of age and below have received in clinical trials.
Adverse reactions reported from clinical studies and post-marketing experience are listed below according to system organ class.
Adverse reactions are ranked under headings of frequency using the
MedDRA frequency convention:
Very common (≥1/1 0)
Common (≥1/100 to <1/10)
Uncommon (≥1/1 000 to <1/100)
Rare (≥1/10,000 to<1/1 000)
Very rare (<1/10,000)
Not known (cannot be estimated from available data).
Table 1 Frequency of Undesirable effects
|Adults and adolescents above 12 years of age||Infants and children of 12 years of age and below (incidence estimates)|
|Immune system disorders|
|Metabolism and nutrition disorders|
|Decreased appetite||Very common||Very common (16.8%)|
|Sleep disorders||Very common||Common (6.4%)|
|Nervous system disorders|
|Headache||Very common||Very common (17.1%)|
|Dizziness||Very common||Common (5.5%)|
|Palpitations||Very common||Common (1.8%)|
|Electrocardiogram QT prolonged||Common||Common (5.3%)|
|Respiratory, Thoracic and mediastinal disorders|
|Common||Common||Very common (22.7%)|
|Vomiting||Very common||Very common (20.2%)|
|Abdominal pain||Very common||Very common (12.1%)|
|Nausea||Very common||Common (6.5%)|
|Liver function tests increased||Uncommon||Common (4.1%)|
|Skin and subcutaneous tissue disorders|
|Angioedema||Not known||Not known|
PRECAUTIONS / WARNINGS
It must not be used in the first trimester of pregnancy in situations where other suitable and effective antimalarials are available.
It has not been evaluated for the treatment of severe malaria, including cases of cerebral malaria or other severe manifestations such as pulmonary oedema or renal failure.
Due to limited data on safety and efficacy, it should not be given concurrently with any other antimalarial agent unless there is no other treatment option.
If a patient deteriorates whilst taking this, 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.
The long elimination half-life of Lumefantrine must be taken into account when administering quinine in patients previously treated with Artemether & Lumefantrine.
If it is given after mefloquine, dose monitoring of food intake is advised.
In patients previously treated with halofantrine, it should not be administered earlier than one month after the last halofantrine dose.
It is not indicated and has not been evaluated for prophylaxis.
It should be used cautiously in patients on ARTs since decreased Artemether, DHA, and/or Lumafantrine concentrations may result in a decrease of antimalarial efficacy of Artemether & Lumefantrine.
Renal Impairment: No specific Studies have been carried out in this group of patients. There is no significant renal excretion of Lumefantrine, Artemether and dihydroartemisinin in studies conducted in healthy volunteers and clinical experience is limited. No dose adjustment for the use of this tablet in patients with renal impairment is recommended. Caution is advised when administering this tablet to patients with severe renal impairment. In these patients, ECG and blood potassium monitoring is advised.
Hepatic Impairment: No specific studies have been carried out in this group of patients. No dose adjustment is recommended for patients with mild to moderate hepatic impairment. Caution is advised when administering this to patients with severe hepatic impairment. In these patients, ECG and blood potassium monitoring is advised.
Elderly: There is no information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.
Contraindications of concomitant use
Interaction with drugs that are known to prolong the QTc interval
It is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval and Torsade de Pointes) such as: antiarrhythmic of classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminic (terfenadine, astemizole), cisapride, flecainide
Interaction with drugs metabolized by CYP2D6
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 & Lumefantrine with drugs that are metabolised by this iso-enzyme is contraindicated (e.g. neuroleptics, metoprolol, and tricyclic antidepressants such as imipramine, amitriptyline, clomipramine) is contraindicated.
Concomitant use not recommended
Interaction with other antimalarial drugs
Data on safety and efficacy are limited, and it should therefore not be given concurrently with other antimalarials unless there is no other treatment option.
If it is given following administration of mefloquine or quinine, close monitoring of food intake (for mefloquine) or of the ECG (for quinine) is advised. The long elimination half-life of Lumefantrine must be taken into account when administering quinine in patients previously with Artemether & Lumefantrine. In patients previously treated with halofantrine, it should not be administered earlier than one month after the last halofantrine dose.
Mefloquine: A drug interaction study with Artemether & Lumefantrine in man involved administration of a 6-dose regimen over 60 hours in healthy volunteers which was commenced at 12 hours after completion of a 3-dose regimen of mefloquine or placebo. Plasma mefloquine concentrations from the time of addition of this tablet were not affected compared with a group which received mefloquine followed by placebo. Pre-treatment with mefloquine had no effect on plasma concentrations of Artemether or the Artemether/dihydroartemisinin ratio but there was a significant reduction in plasma levels 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 the decrease in bioavailability.
Concomitant use requiring caution
Interactions affecting the use of Artemether & Lumefantrine:
Interaction with CYP3A4 inhibitors
Both Artemether and Lumefantrine are metaboilsed predominantly by the cytochrome enzyme CYP3A4, but do not inhibit this enzyme at therapeutic concentrations.
Ketoconazole: The concurrent oral administration of ketoconazole with it led to a modest increase (≤ 2-fold) in Artemether, DHA, and Lumefantrine exposure in healthy adult subjects. This 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 it is considered unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors. It should be used cautiously with drugs that inhibit CYP3A4 and are contraindicated with drugs which additionally are known to prolong QTc, due to potential for increased concentrations of Lumefantrine which could lead to QT prolongation.
USE IN PREGNANCY AND LACTATION
Pregnancy: There is insufficient data from the use of Artemether and Lumefantrine in pregnant women. Based on animal data, it is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with Artemether have shown evidence of post-implantation losses and teratogenicity in rats and rabbits. Other artemisinin derivatives have also demonstrated teratogenic potential with an increased risk during early gestation.
Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Artemether & Lumefantrine (including a third of patients who were exposed in the first trimester), and published data of another over 500 pregnant women who were exposed to Artemether-Lumefantrine (including over 50 patients who were exposed in the first trimester), as well as published data of over 1,000 pregnant women who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rates.
Artemether & Lumefantrine treatment must not be used during the first trimester of pregnancy in situations where other suitable and effective antimalarials are available. However, it should not be withheld in life threatening situations, where no other effective antimalarials are available. During the second and third trimester, treatment should only be considered if the expected benefit to the mother outweighs the risk to the foetus.
Lactation: Animal data suggest excretion into breast milk but no data are available in humans. Women taking this tablet should not breast-feed during their treatment. Due to the long elimination half-life of Lumefantrine (2 to 6 days), it is recommended that breast-feeding should not resume until at least one week after the last dose of Artemether & Lumefantrine unless potential benefits to the mother and child outweigh the risks of Artemether & Lumefantrine treatment.
Fertility: There is no information on the effects of Artemether & Lumefantrine on human fertility.
DOSAGE AND ADMINISTRATION
Oral. Should be taken with food. In acute uncomplicated falciparum malaria a six dose regimen over three days is recommended, as described below:
Tablets have to be taken at interval of 8 hours after each dose. Adults and adolescents weighing 35kg and above 80mg/480mg Tablets:
|Weight in kg||Total Tablets||Dosage Regimen|
|35 kgs and above||0 Hour (initial dose)||8 Hours (after 1st dose)||24 Hours||36 Hours||48 Hours||60 Hours|
|6||1 tab||1 tab||1 tab||1 tab||1 tab||1 tab|
To benefit from the full therapeutic effect, the full course of medication (i.e., all 6 tablets) must be taken over the 60 hours at intervals as indicated.
* If you vomit within one hour of taking the tablets, accidentally taken too many tablets, forget a dose, contact your doctor or pharmacist immediately.
OVERDOSAGE, SYMPTOMS AND ANTIDOTE
In cases of suspected over dosage symptomatic and supportive therapy should be given as appropriate, which should include ECG and blood potassium monitoring.
Keep in cool, dry place. Keep out of reach of children.
DATE OF REVISION
NAFDAC Reg. No. : A4-3489
MICRO LABS LIMITED
HOSUR-635 126. INDIA.
1, African Church Close
Off Coker Road,
Ilupeju, Lagos, Nigeria.