Arexel

Overdose

In cases of suspected overdosage symptomatic and supportive therapy should be given as appropriate, which should include ECG and blood potassium monitoring.

Contraindications

Arexel is contraindicated in:

- patients with known hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- 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, amitryptyline, 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 (proarrythmic). These drugs include:

- 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 antihistamines (terfenadine, astemizole),

- cisapride.

- flecainide

- patients with a history of symptomatic cardiac arrythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

- patients with disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.

- patients taking drugs that are strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum).

(*Presence of one or more of the following clinical or laboratory features:

Clinical manifestation: Prostration; impaired consciousness or unarousable coma; failure to feed; deep breathing, respiratory distress (acidotic breathing); multiple convulsions; circulatory collapse or shock; pulmonary edema (radiological); abnormal bleeding; clinical jaundice; hemoglobinuria

Laboratory test: Severe normocytic anemia; hemoglobuniuria; hypoglycemia; metabolic acidosis; renal impairment; hyperlactatemia; hyperparasitemia)

Incompatibilities

Not applicable.

Undesirable effects

The safety of Arexel 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 Arexel 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 (>1/10)

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

*: These adverse reactions were reported during post-marketing experience. Because these spontaneously reported events are from a population of uncertain size, it is difficult to estimate their frequency.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

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.

Neurotoxicity

Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic cytoplasmic granulation, spheroids, apoptosis and dark neurons. Lesions were observed in rats dosed for at least 7 days and dogs for at least 8 days, but lesions were not observed after shorter intramuscular treatment courses or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level is approximately 7-fold greater or more than the estimated artemether 24 h AUC in humans. The hearing threshold was affected at 20 dB by oral artemether administration to dogs at a dose of about 29 times the highest artemether clinical dose (160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study.

Mutagenicity

Artemether and lumefantrine were not genotoxic/clastogenic based on in vitro and in vivo testing.

Carcinogenicity

Carcinogenicity studies were not conducted.

Reproductive toxicity studies

Embryotoxicity was observed in rat and rabbit reproductive toxicity studies conducted with artemether, a derivative of artemisinin. Artemisinins are known to be embryotoxic. Lumefantrine alone caused no sign of reproductive or development toxicity at doses up to 1,000 mg/kg/day in rats and rabbits, doses which are at least 10 times higher than the daily human dose based on body surface area comparisons.

Reproductive toxicity studies performed with the artemether:lumefantrine combination caused maternal toxicity and increased post-implantation loss in rats and rabbits.

Artemether caused increases in post-implantation loss and teratogenicity (characterised as a low incidence of cardiovascular and skeletal malformations) in rats and rabbits. The embryotoxic artemether dose in the rat yields artemether and dihydroartemisinin exposures similar to those achieved in humans based on AUC.

Fertility

Artemether-lumefantrine administration yielded altered sperm motility, abnormal sperm, reduced epididymal sperm count, increased testes weight, and embryotoxicity; other reproductive effects (decreased implants and viable embryos, increased preimplantation loss) were also observed. The no adverse effect level for fertility was 300 mg/kg/day. The relevance to this finding in humans is unknown.

Juvenile toxicity studies

A study investigated the neurotoxicity of oral artemether in juvenile rats. Mortality, clinical signs and reductions in body weight parameters occurred most notably in younger rats. Despite the systemic toxicity noted, there were no effects of artemether on any of the functional tests performed and there was no evidence of a direct neurotoxic effect in juvenile rats.

Very young animals are more sensitive to the toxic effect of artemether than adult animals. There is no difference in sensitivity in slightly older animals compared to adult animals. Clinical studies have established the safety of artemether and lumefantrine administration in patients weighing 5 kg and above.

Cardiovascular Safety Pharmacology

In toxicity studies in dogs at doses >600 mg/kg/day, there was some evidence of prolongation of the QTc interval (safety margin of 1.3-fold to 2.2-fold for artemether using calculated free Cmax), at higher doses than intended for use in man. In vitro hERG assays showed a safety margin of >100 for artemether and dihydroartemisinin. The hERG IC50 was 8.1 µM for lumefantrine and 5.5 µM for its desbutyl metabolite.

Based on the available non-clinical data, a potential for QTc prolongation in the human cannot be discounted.4 and 5.1.

Therapeutic indications

Arexel is indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria in adults, children and infants of 5 kg and above.

Consideration should be given to official guidance regarding the appropriate use of antimalarial agents.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: antimalarials, blood schizontocide, ATC code: P01 BF01.

Pharmacodynamic effects

Arexel 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 haemoglobin breakdown, to the nontoxic haemozoin, malaria pigment. Lumefantrine is thought to interfere with the polymerisation 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.

Treatment of Acute Uncomplicated P. falciparum Malaria

The efficacy of Arexel Tablets was evaluated for the treatment of acute, uncomplicated malaria (defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction) in five 6-dose regimen studies and one study comparing the 6-dose regimen with the 4-dose regimen. Baseline parasite density ranged from 500/μL - 200,000/μL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in otherwise healthy, partially immune or non-immune adults and children (>5kg body weight) with uncomplicated malaria in Thailand, sub-Saharan Africa, Europe, and South America.

Efficacy endpoints consisted of:

- 28-day cure rate, proportion of patients with clearance of asexual parasites within 7 days without recrudescence by day 28

- parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for a further 48 hours

- fever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients with temperature >37.5°C at baseline)

The modified intent to treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least one dose of study drug. Evaluable patients generally are all patients who had a day 7 and a day 28 parasitological assessment or experienced treatment failure by day 28. The results are presented in the table below:

Table 2 Clinical efficacy results

1 Efficacy cure rate based on blood smear microscopy

2 mITT population

3 For patients who had a body temperature >37.5°C at baseline only

4Only the 6-dose regimen over 60 hours group data is presented

CT -Arexel tablets administered as crushed tablets

DT -Arexel Dispersible tablets

Arexel 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. Arexel is active against blood stages of Plasmodium vivax, but is not active against hypnozoites.

Paediatric population

Two studies have been conducted

Study A2403 was conducted in Africa in 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillary temperature >37.5°C. Results of 28-day cure rate (PCR-corrected), median parasite clearance time (PCT), and fever clearance time (FCT) are reported in table 3 below.

Study B2303 was conducted in Africa in 452 infants and children, aged 3 months to 12 years, weighing 5 kg to <35 kg, with fever (>37.5°C axillary or >38°C rectally) or history of fever in the preceding 24 hours. This study compared crushed tablets and dispersible tablets. Results of 28-day cure rate (PCR-corrected), median parasite clearance time (PCT), and fever clearance time (FCT) for crushed tablets are reported in table 3 below.

Table 3 Clinical efficacy by weight for pediatric studies

1 mITT population

2 Efficacy cure rate based on blood smear microscopy

CT Arexel tablets administered as crushed tablets

QT/QTc Prolongation:

Adults and children with malaria

For information on the risk of QT/

Healthy adults

In a healthy adult volunteer parallel group study including a placebo and moxifloxacin control group (n=42 per group), the administration of the six dose regimen of Arexel was associated with prolongation of QTcF. The mean changes from baseline at 68, 72, 96, and 108 hours post first dose were 7.45, 7.29, 6.12 and 6.84 msec, respectively. At 156 and 168 hours after first dose, the changes from baseline for QTcF had no difference from zero. No subject had a >30 msec increase from baseline nor an absolute increase to >500 msec. Moxifloxacin control was associated with a QTcF increase as compared to placebo for 12 hours after the single dose with a maximal change at 1 hour after dose of 14.1 msec.

In the adult/adolescent population included in clinical trials, 8 patients (0.8%) receiving Arexel experienced a QTcB >500 msec and 3 patients (0.4%) a QTcF >500 msec. Prolongation of QTcF interval >30 msec was observed in 36% of patients.

In clinical trials conducted in children with the 6-dose regimen, no patient had post-baseline QTcF >500 msec whereas 29.4% had QTcF increase from baseline >30 msec and 5.1% >60 msec. In clinical trials conducted in adults and adolescents with the 6-dose regimen, post-baseline QTcF prolongation of >500 msec was reported in 0.2% of patients, whereas QTcF increase from baseline >30 msec was reported in 33.9% and >60 msec in 6.2% of patients.

In the infant/children population included in clinical trials, 3 patients (0.2%) experienced a QTcB >500 msec. No patient had QTcF >500 msec. Prolongation of QTcF intervals >30 msec was observed in 34% of children weighing 5-10 kg, 31% of children weighing 10-15 kg and 24% of children weighing 15-25 kg, and 32% of children weighing 25-35 kg.

Pharmacokinetic properties

Pharmacokinetic characterisation of Arexel is limited by the lack of an intravenous formulation, and the very high inter-and intra-subject variability of artemether and lumefantrine plasma concentrations and derived pharmacokinetic parameters (AUC, Cmax).

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 ng·h/mL, respectively, in fed healthy adults after a single dose of Arexel, 80 mg artemether/480 mg 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 243 µg·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 Arexel 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 lumefantrine 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%).

Biotransformation

Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolise artemether to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly 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.

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 humans, the exposure to lumefantrine increases with repeated administration of Arexel 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. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of Arexel.

Limited urinary excretion data are available for humans. In 16 healthy volunteers, neither lumefantrine nor artemether was found in urine after administration of Arexel, 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.

Dose proportionality

No specific dose proportionality studies were performed. Limited data suggest a dose-proportional increase of systemic exposure to lumefantrine when doubling the Arexel dose. No conclusive data is available for artemether.

Bioavailability/bioequivalence studies

Systemic exposure to lumefantrine, artemether and dihydroartemisinin was similar following administration of Arexel as dispersible tablets and crushed tablets in healthy adults.

Systemic exposure to lumefantrine was similar following administration of Arexel dispersible tablets and intact tablets in healthy adults. However, exposure to artemether and dihydroartemisinin was significantly lower (by 20-35%) for the dispersible than for the intact tablet. These findings are not considered to be clinically relevant for the use of the dispersible tablets in the paediatric population since adequate efficacy of Arexel dispersible tablets was demonstrated in this population. The dispersible tablet is not recommended for use in adults.

Older people

No specific pharmacokinetic studies have been performed in elderly patients. However, there is no information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.

Paediatric population

In paediatric malaria patients, mean Cmax (CV%) of artemether (observed after first dose of Arexel) were 223 (139%), 198 (90%) and 174 ng/mL (83%) for body weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to 186 ng/mL (67%) in adult malaria patients. The associated mean Cmax of DHA were 54.7 (108%), 79.8 (101%) and 65.3 ng/mL (36%), respectively compared to 101 ng/mL (57%) in adult malaria patients. AUC of lumefantrine (population mean, covering the six doses of Arexel) were 577, 699 and 1150 µg-h/mL for paediatric malaria patients in body weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to a mean AUC of 758 µg-h/mL (87%) in adult malaria patients. The elimination half-lives of artemether and lumefantrine in children are unknown.

Hepatic and Renal impairment

No specific pharmacokinetic studies have been performed either in patients with hepatic or renal insufficiency or elderly patients. The primary clearance mechanism of both artemether and lumefantrine may be affected in patients with hepatic impairment. In patients with severe hepatic impairment, a clinically significant increase of exposure to artemether and lumefantrine and/or their metabolites cannot be ruled out. Therefore caution should be exercised in dosing patients with severe hepatic impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and dihydroartemisinin, no dose adjustment for the use of Arexel in patients with renal impairment is advised.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Arexel must not be used in the first trimester of pregnancy in situations where other suitable and effective antimalarials are available.

Arexel 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, Arexel should not be given concurrently with any other antimalarial agent unless there is no other treatment option.

If a patient deteriorates whilst taking Arexel, 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 Arexel.

If quinine is given after Arexel, close monitoring of the ECG is advised.

If Arexel is given after mefloquine, close monitoring of food intake is advised.

In patients previously treated with halofantrine, Arexel should not be administered earlier than one month after the last halofantrine dose.

Arexel is not indicated and has not been evaluated for prophylaxis of malaria.

Arexel should be used cautiously in patients on anti-retroviral drugs (ARTs) since decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Arexel,.

Like other antimalarials (e.g. halofantrine, quinine and quinidine) Arexel has the potential to cause QT prolongation.

Caution is recommended when combining Arexel with drugs exhibiting variable patterns of inhibition, moderate induction or competition for CYP3A4 as the therapeutic effects of some drugs could be altered. Drugs that have a mixed inhibitory/induction effect on CYP3A4, especially anti-retroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors should be used with caution in patients taking Arexel.

Caution is recommended when combining Arexel with hormonal contraceptives. Arexel may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control for about one month.

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

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 Arexel in patients with renal impairment is recommended. Caution is advised when administering Arexel 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. In patients with severe hepatic impairment, a clinically relevant increase of exposure to artemether and lumefantrine and/or their metabolites cannot be ruled out. Therefore caution should be exercised in dosing patients with severe hepatic impairment. In these patients, ECG and blood potassium monitoring is advised. No dose adjustment is recommended for patients with mild to moderate hepatic impairment.

Older people

There is no information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.

New infections

Data for a limited number of patients in a malaria endemic area show that new infections can be treated with a second course of Arexel. In the absence of carcinogenicity study data, and due to lack of clinical experience, more than two courses of Arexel cannot be recommended.

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

Posology

Adults and children weighing 35 kg and above

For patients 12 years of age and above and 35 kg body weight and above, a course of treatment comprises six doses of four tablets i.e. total of 24 tablets, given over a period of 60 hours as follows: the first dose of four tablets, given at the time of initial diagnosis, should be followed by five further doses of four tablets given at 8, 24, 36, 48 and 60 hours thereafter.

Children and infants weighing 5 kg to less than 35 kg

A six-dose regimen is recommended with 1 to 3 tablets per dose, depending on bodyweight:

5 to less than 15 kg bodyweight: the first dose of one tablet, given at the time of initial diagnosis, should be followed by five further doses of one tablet given at 8, 24, 36, 48 and 60 hours thereafter.

15 to less than 25 kg bodyweight: the first dose of two tablets, given at the time of initial diagnosis, should be followed by five further doses of two tablets given at 8, 24, 36, 48 and 60 hours thereafter.

25 to less than 35 kg bodyweight: the first dose of three tablets, given at the time of initial diagnosis, should be followed by five further doses of three tablets given at 8, 24, 36, 48 and 60 hours thereafter.

Method of administration

Tablets for oral administration.

To increase absorption, Arexel should be taken with food or a milky drink. If patients are unable to tolerate food, Arexel should be administered with water, but the systemic exposure may be reduced. Patients who vomit within 1 hour of taking the medication should repeat the dose.

For administration to small children and infants, the tablet/s may be crushed.

Special precautions for disposal and other handling

For the treatment of children and infants, the 24-tablets pack should be prescribed. The prescriber and pharmacist should instruct the parent or care giver on the posology for their child and that a variable number of tablets (depending on the child's body weight) will be requested for the full treatment. Therefore, the whole pack may not be used. After successful treatment the remaining tablets should be discarded or returned to the pharmacist.