استطباب: Antiprotozoal for malaria disease

Composition:
Each tablet contains: Artemether 20 mg and Lumefantrine 120 mg.
Indications:
Artemet is a fixed combination of artemether and lumefantrine, which acts as a
blood schizonticide. It is indicated for:
Treatment:
Including stand-by emergency treatment of adults and children with acute, uncomplicated infections due to plasmodium falciparum or mixed infections including P.falciparum. Because Artemet 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 antimalarials.
Stand-by emergency treatment:
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 24 hours of the onset of symptoms, particularly if they are in an isolated location far from medical services. In such cases, prescribers are advised to issue Artemet to be carried by the traveller for self-administration (stand-by emergency treatment). Consideration should be given to official guidance regarding the appropriate used antimalarial agents.
Dosage and Administration:
Tablets for oral administration.
Patients with acute malaria are frequently averse to food. The dose may be taken with fluids. 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.
Dosage in Adults:
Treatment: Four tablets as a single dose at the time of initial diagnosis, and then 8, 24 and 48 hours thereafter (total course comprises 16 tablets).
In areas of multi-drug-resistant malaria (e.g.Thailand) and in non-immune patients an intensive 3-day course is recommended, with four tablets as a single dose at the time of initial diagnosis, again after 8 hours and then twice daily on each of the following two days. ( total course comprises 24 tablets).
Stand-by emergency treatment:
For stand-by emergency treatment an intensive-3day course is recommended, with four tablets as a single dose at the time of the onset of symptoms, again after 8 hours and then twice daily on each of the following two days(total course comprises 24 tablets).
Dosage In Children:
Treatment:
5-< 15 kg bodyweight: One tablet at the time of initial diagnosis, and then 8 , 24 and 48 hours thereafter ( total course comprises 4 tablets).
15-< 25 kg bodyweight: Two tablets as a single dose at the time of initial diagnosis, and then 8, 24and 48 hours thereafter (total course comprises 8 tablets).
25-<35 Kg bodyweight: Three tablets as a single dose at the time of initial diagnosis, and then 8,24 and 48 hours thereafter (total course comprises 12 tablets).
Treatment in areas where multi-drug resistance is present or developing and in non-immune children:
In areas of multi-drug resistant malaria (e.g. Thailand) and for treatment of non-immune children an intensive 3-day course is recommended, with one to three tablets ( depending on body-weight ) given as a single dose at the time of initial diagnosis, again after 8 hours and then twice daily on each of the following two days ( total course comprises 6 , 12 or 18 tablets depending on bodyweight).
10-<15 kg bodyweight: One tablet at the time of initial diagnosis, again after 8 hours and then twice daily on each of the following two days.(total course comprises 6 tablets).
15-<25 kg bodyweight : Two tablets as a single dose at the time of initial diagnosis, again after 8 hours and then twice daily on each of the following two days( total course comprises 12 tablets).
25-<35 kg bodyweight: Three tablets as a single dose at the time of initial diagnosis, again after 8 hours and then twice daily on each of the following two days ( total course comprises 18 tablets).
Stand-by emergency treatment:
For stand-by emergency treatment an intensive 3-day course is recommended, with one to three tablets ( depending on bodyweight) given as a single dose at the time of the onset of symptoms, again after 8 hours and then twice daily on each of the following two days (total course comprises 6,12 or 18 tablets depending on bodyweight ).
10-<15 kg bodyweight: One tablet at the time of onset of symptoms, again after 8 hours and then twice daily on each of the following two days (total course comprises 6 tablets).
15-<25 kg bodyweight: Two tablets as a single dose at the time of onset of symptoms, again after 8 hours and then twice daily on each of the following two days ( total course comprises 12 tablets).
25-<35 kg bodyweight: Three tablets as a single dose at the time of the onset of symptoms, again after 8 hours and then twice daily on each of the following two days
( total course comprises 18 tablets).
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:
Although no specific studies have been carried out, no special precautions or dosage adjustments are considered necessary for these conditions.
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 Artemet.
New and recrudesecent in adults and children:
Data for a limited number of patients show that new and recrudescent infections can be treated with a second course of Artemet.
Contraindications:
Artemet is contraindicated in :
– Hypersensitivity to the active substances or to any of the excipients.
– Patients with severe malaria according to WHO definition.
– Patients with a family history or congential 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, with clinically relevant bradycardia or with severe cardiac disease.
– Patients with known disturbances of electrolyte balance e.g. hypokalaemia or hypomagnesaemia.
– Patients taking any drug which is metabolized by the cytochrome enzyme CYP2D6 (e.g. Flecainide, metoprolol, imipramine, amitriptyline, clomipramine).
– Patients taking drugs that are known to prolong the QTc intervals such as antiarrhythmics 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 antihistaminics ( terfenadine, astemizole), cisapride.
Special Warnings and Precautions for Use:
Artemet has not been evaluated for prophylaxis and is therefore not indicated. Artemet has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria including pulmonary oedema or renal failur.
Artemet is not indicated for, and has not been evaluated in, the treatment of malaria due to P.vivax, P.malariae or P.ovale, although some patients in clinical studies had co-infection with P.falciparum and P.vivax at baseline. Artemet is active against blood stages of Plasmodium vivax, but is not active against hypnozoites. Therefore, sequential treatment with primpaquine should be used to achieve hypnozoite eradication in case of co-infection with Plasmodium vivax. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater. Concurrent administration of Artemet and antimalarials other than mefloquine and quinine should be avoided ( see section Interactions).
Interactions:
Although the likelihood of Artemet 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.
Interaction with antimalarials:
When Artemet is given sequentially with 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, Artemet should not be given concurrently with antimalarials other than mefloquine or quinine. In patients previously treated with halofantrine, Artemet should be administered at least one month after the last halofantrine dose. If a patient deteriorates whilst taking Artemet, 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.
Interactions with concomitant treatment with other than antimalarials:
No safety issues that could be attributed to drug interactions arose during clinical studies with Artemet, in which most patients received antipyretic medication, antibiotics and fluid electrolyte replacement.
Interaction with a CYP 450 3A4 inhibitor ( ketoconazole):
Dose adjustment of Artemet is considered unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 in vitro. inhibitors.
Interaction with CYP450 enzymes:
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 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 Artemet with drugs that are metabolized by this iso-enzyme
( e.g. Neuroleptics and tricyclic antidepressants) is contraindicated ( see section contraindications).
Pregnancy and Lactation:
Pregnancy:
The safe use of artemether and lumefantrine during pregnancy has not been established. Reproductive toxicity studies in rates and rabbits have shown no
evidence of teratogenicity for the combination or for the individual components, lumefantrine and artemether. Artemet treatment should be considered if the
expected benefit to the mother outweighs the risk to the fetus.

Lactation:
Animal data suggest excretion into breast milk but no data are available in humans, breast-feeding women should not take Artemet. Due to the long elimination half-life of lumefantrine (4to 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 Artemet treatment.
Effects on Ability to Drive and Use Machines:
Patients receiving Artemet should be warned that dizziness or fatigue/asthenia might occur in which case they should not drive or use machines.
Undesirable Effects:
The frequency of adverse events reported during clinical trials with Artemet was similar to or lower than that of other antimalarial drugs used as comparators.
Artemet was generally very 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 response to the treatment rather than to Artemet. For other reports alternative factors were identified as the more likely cause of the events
( e.g. Concomitant drugs, concomitant infections ) or the information provided was too scarce to draw any conclusion. A causal relationship with the use of Artemet could not be excluded for the following adverse events ( see table the next column).

Common Asthenia, fatigue.

Overdose:
In cases of suspected overdosage, symptomatic and supportive therapy should be given as appropriate. ECG and blood potassium levels should be monitored.
Pharmacodynamics:
Pharmacodynamic effects:
Artemet comprises a fixed ratio of 1 : 6 parts of artemether and lumefantine, 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 haemoglobin breakdown, to the non-toxic 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. Data from in-vitro and in-vivo studies show that Artemet did not induce resistance.
The antimalarial activity of combination of lumefantrine and artemether in Artemet is greater than that of either substance alone.
Artemet is active against blood stages of Plasmodium vivax, but is not active against hypnozoites. Therefore, sequential treatment with primaquine should be used to achieve hypnozoite eradication.
Pharmacokinetics:
Pharmacokinetics characterization of Artemet is limited by the lack of an intravenous formulation, and the very high inter-and intrasubject variability of artemether and lumefantrine plasma concentrations and derived pharmacokinetic parameters( AUC, C max ).
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 lag-time of up to 2 hours, with peak plasma concentration about 6-8 hours after dosing. Food enhances the absorption of both artemether and lumefantrine: in healthy volunteers the relative bioavailability of artemether was increased more two-fold, and that of lumefantrine sixteen-fold compared with fasted conditions when Artemet 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 fasting conditions would be< 10% of the dose). Patients should therefore be encouraged to take the medication with normal diet as soon as food can be tolerated.

Distribution:
Artemether and lumefantrine are both highly bound to human serum proteins in vitro ( 97.9% and 99.9% respectively ). Dihydroartemisinin is also bound to
human serum proteins ( 47 % – 76 % ) protein binding to human plasma protein is linear.
Metabolism:
Artemether is rapidly and extensively metabolized ( substantial first- pass metabolism) both in vitro and in humans. Human liver microsomes metabolize artemether to the biologically active main metabolite dihydroartemisinin (demethylation ), predominantly through the enzyme CYP3A4/5. The pharmacokinetics of this metabolite has also been described in humans in vivo. The artemether/dihydroartemisinin AUC ratio is 1.2 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 isoenzymes CYP2C19 and CYP3A4 ( see special warnings and precautions for use and interactions).
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.
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 of 2-3 days in healthy volunteers and 4-6 days in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of Artemet.
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 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.
Preclinical Safety Data:
General toxicity:
The main changes observed in repeat-dose toxicity studies were associated with the expected pharmacological action on erythrocytes, accompanied by responsive
secondary haematopoiesis.
Mutagenicity:
No evidence of Artemet mutagenicity was detected in vitro or in vivo tests. In the micronucleus test myelotoxicity was seen at all dose levels ( 500, 1000, and 2000 mg/kg ), but recovery was almost complete 48 hours after dosing.
Carcinogenicity:
Due to the short time of treatment carcinogenicity studies with Artemether/lumefantrine combination were not conducted.
Reproductive toxicity studies:
Reproductive toxicity studies with this combination showed both materno and embryotoxic effects at doses ³ 50 mg/kg in rats without evidence of teratogenicity at any level. It was not embryotoxic in rats at a dose of £ 25 mg/kg. In rabbits, materno-and embryotoxicity were seen at 175 mg/kg but no fetotoxicity or teratogenicity, while the next lower dose levels of 105 mg/kg was entirely free of treatment-induced effects.
Lumefantrine doses as high as 1000 mg/kg showed no evidence to suggest materno-, embryo-or fetotoxicity or teratogenicity in rats and rabbits.
Artemisinins are known to be embryotoxic in animals. Artemether did not show effects in rabbits at doses up to 25 mg/kg, but materno-embryo-and fetotoxicity were noted at 10 mg/kg, but without evidence of teratogenicity at any dose levels.
Cardiovascular Pharmacology:
In toxicity studies in dogs, only at higher doses than intended for use in man
(³ 600 mg/kg/day), there was some evidence of prolongation of the QTc interval.
Packing:
Box contains ( 12-24 ) tablets.
Storage:
Store at (15 -30 )° C , in a dry place