Riamet 20mg/120mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Riamet 20mg/120mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 20mg artemether and 120mg lumefantrine For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Light yellow, round tablet with “NC” debossed on one side and “CG” on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

4.2 Posology and method of administration

Tablets for oral administration.

To increase absorption, Riamet should be taken with food or a milky drink (see section 5.2). If patients are unable to tolerate food, Riamet should be administered, 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. Adults and children weighing 35kg and above

For patients 12 years of age and above and 35kg 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 5kg to less than 35kg

A six-dose regimen is recommended with 1 to 3 tablets per dose, depending on bodyweight: 5 to less than 15kg 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 25kg 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 35kg 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.

4.3 Contraindications

Riamet 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, 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. hypokalaemia or hypomagnesaemia.

• 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 oedema (radiological); abnormal bleeding; clinical jaundice; hemoglobinuria

Laboratory test: Severe normocytic anaemia; hemoglobuniuria; hypoglycaemia; metabolic acidosis; renal impairment; hyperlactatemia; hyperparasitemia)

4.4 Special warnings and precautions for use

Riamet must not be used in the first trimester of pregnancy in situations where other suitable and effective antimalarials are available (see section 4.6).

Riamet 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, Riamet should not be given concurrently with any other antimalarial agent (see section 4.5) unless there is no other treatment option.

If a patient deteriorates whilst taking Riamet, 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 Riamet.

If quinine is given after Riamet, close monitoring of the ECG is advised (see section 4.5).

If Riamet is given after mefloquine, close monitoring of food intake is advised (see section 4.5).

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

Riamet is not indicated and has not been evaluated for prophylaxis.

Riamet should be used cautiously in patients on ARTs since decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Riamet, (see section 4.5).

Like other antimalarials (e.g. halofantrine, quinine and quinidine) Riamet has the potential to cause QT prolongation (see section 5.1).

Caution is recommended when combining Riamet 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 Riamet (see sections

4.5 and 5.2).

Caution is recommended when combining Riamet with hormonal contraceptives. Riamet 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 nonhormonal method of birth control for about one month (see sections 4.5).

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

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 (see section 5.2).

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 Riamet in patients with renal impairment is recommended. Caution is advised when administering Riamet 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 Riamet 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.

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 Riamet. In the absence of carcinogenicity study data, and due to lack of clinical experience, more than two courses of Riamet cannot be recommended.

4.5 Interaction with other medicinal products and other forms of interaction Contraindications of concomitant use

Interaction with drugs that are known to prolong the QTc interval Riamet is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval and Torsade de Pointes) such as: antiarrhythmics 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 antihistaminics (terfenadine, astemizole), cisapride, flecainide (see section 4.3).

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. Coadministration of Riamet 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 (see sections 4.3 and 5.2).

Interaction with strong inducers of CYP3A4 such as rifampin Oral administration of rifampin (600 mg daily), a strong CYP3A4 inducer, with Riamet Tablets (6-dose regimen over 3 days) in six HIV-1 and tuberculosis co-infected adults without malaria resulted in significant decreases in exposure to artemether (89%), DHA (85%) and lumefantrine (68%) when compared to exposure values after Riamet alone. Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, St. John’s Wort is contraindicated with Riamet (see section 4.3).

Inducers should not be administered at least one month after Riamet administration, unless critical to use as judged by the prescriber.

Concomitant use not recommended

Interaction with other antimalarial drugs (see section 4.4)

Data on safety and efficacy are limited, and Riamet should therefore not be given concurrently with other antimalarials unless there is no other treatment option (see section 4.4).

If Riamet 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 treated with Riamet. In patients previously treated with halofantrine, Riamet should not be administered earlier than one month after the last halofantrine dose (see section 4.4).

Mefloquine

A drug interaction study with Riamet 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 Riamet 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.

Quinine

A drug interaction study in healthy male volunteers showed that the plasma concentrations of lumefantrine and quinine were not affected when i.v. quinine (10 mg/kg BW over 2 hours) was given sequentially 2 hours after the last (sixth) dose of Riamet (so as to produce concurrent plasma peak levels of lumefantrine and quinine). Plasma concentrations of artemether and dihydroartemisinin (DHA) appeared to be lower. In this study, administration of Riamet to 14 subjects had no effect on QTc interval. Infusion of quinine alone in 14 other subjects caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine. This effect was slightly, but significantly, greater when quinine was infused after Riamet in 14 additional subjects. It would thus appear that the inherent risk of QTc prolongation associated with i.v. quinine was enhanced by prior administration of Riamet.

Concomitant use requiring caution Interactions affecting the use of Riamet

Interaction with CYP3A4 inhibitors

Both artemether and lumefantrine are metabolised predominantly by the cytochrome enzyme CYP3A4, but do not inhibit this enzyme at therapeutic concentrations.

Ketoconazole

The concurrent oral administration of ketoconazole with Riamet 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 Riamet is considered unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

Riamet should be used cautiously with drugs that inhibit CYP3A4 and are contraindicated with drugs which additionally are known to prolong QTc (see Section 4.3 Contraindications), due to potential for increased concentrations of lumefantrine which could lead to QT prolongation.

Grapefruit juice

Administration of artemether with grapefruit juice in healthy adult subjects resulted in an approximately two fold increase in systemic exposure to the parent drug. Grapefruit juice should be used cautiously during Riamet treatment.

Interaction with weak to moderate inducers of CYP3A4 When Riamet is co-administered with moderate inducers of CYP3A4, it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy (see section 4.4).

Interaction with anti-retroviral drugs such as protease inhibitors and nonnucleoside reverse transcriptase inhibitors

Both artemether and lumefantrine are metabolized by CYP3A4. Anti-retroviral drugs (ARTs), such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. Riamet should be used cautiously in patients on ARTs since decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Riamet, and increased lumefantrine concentrations may cause QT prolongation (see Section 4.4)

Lopinavir/ ritonavir

In a clinical study in healthy volunteers, lopinavir/ritonavir decreased the systemic exposures to artemether and DHA by approximately 40% but increased the exposure to lumefantrine by approximately 2.3- fold. Exposures to lopinavir/ritonavir were not significantly affected by concomitant use of Riamet.

Nevirapine

In a clinical study in HIV-infected adults, nevirapine significantly reduced the median Cmax and AUC of artemether by approximately 61% and 72%, respectively and reduced the median Cmax and AUC of dihydroartemisinin by approximately 45% and 37%, respectively. Lumefantrine Cmax and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced the median Cmax and AUC of nevirapine by approximately 43% and 46% respectively.

Efavirenz

Efavirenz decreased the exposures to artemether, DHA, and lumefantrine by approximately 50%, 45%, and 20%, respectively. Exposures to efavirenz were not significantly affected by concomitant use of Riamet.

Interactions resulting in effects of Riamet on other drugs

Interaction with drugs metabolized by CYP450 enzymes When Riamet is co-administered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. Studies in humans have demonstrated that artemisinins have some capacity to induce CYP3A4 and CYP2C19 and inhibit CYP2D6 and CYP1A2. Although the magnitude of the changes was generally low it is possible that these effects could alter the therapeutic response of drugs that are predominantly metabolised by these enzymes (see sections 4.4 and 5.2).

Interaction with hormonal contraceptives

In vitro, the metabolism of ethinyl estradiol and levonorgestrel was not induced by artemether, DHA, or lumefantrine. However, artemether has been reported to weakly induce, in humans, the activity of CYP2C19, CYP2B6, and CYP3A. Therefore, Riamet may potentially reduce the effectiveness of hormonal contraceptives. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional nonhormonal method of birth control for about one month (see sections 4.4 and 4.6).

Drug-food/drink interactions

Riamet should be taken with food or drinks rich in fat such as milk as the absorption of both artemether and lumefantrine is increased (see Section 4.2). Grapefruit juice should be used cautiously during Riamet treatment.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is insufficient data from the use of artemether and lumefantrine in pregnant women. Based on animal data, Riamet is suspected to cause serious birth defects when administered during the first trimester of pregnancy (see sections 4.4 and 5.3). 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 (see section 5.3). Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Riamet (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.

Riamet treatment must not be used during the first trimester of pregnancy in situations where other suitable and effective antimalarials are available (see section 4.4). 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.

Women of childbearing potential

Women 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 (see section 4.4).

Lactation

Animal data suggest excretion into breast milk but no data are available in humans. Women taking Riamet 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 Riamet unless potential benefits to the mother and child outweigh the risks of Riamet treatment.

Fertility

There is no information on the effects of Riamet on human fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The safety of Riamet 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 Riamet 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

Adults and adolescents Infants and children of above 12 years of age 12 years of age and __ below (incidence_

		estimates)
Immune system disorders
Hypersensitivity	Not known	Rare
Metabolism and nutrition disorders
Decreased appetite	Very common	Very common (16.8 %)
Psychiatric disorders
Sleep disorders	Very common	Common (6.4 %)
Insomnia	Common	Uncommon
Nervous system disorders
Headache	Very common	Very common (17.1 %)
Dizziness	Very common	Common (5.5 %)
Paraesthesia	Common	--
Ataxia, hypoaesthesia	Uncommon	--
Somnolence	Uncommon	Uncommon
Clonus	Common	Uncommon
Cardiac disorders
Palpitations	Very common	Common (1.8 %)
Electrocardiogram QT prolonged	Common	Common (5.3 %)
Respiratory, thoracic and mediastinal disorders
Cough	Common	Very common (22.7 %)
Gastrointestinal disorders
Vomiting	Very common	Very common (20.2 %)
Abdominal pain	Very common	Very common (12.1 %)
Nausea	Very common	Common (6.5 %)
Diarrhoea	Common	Common (8.4 %)
Hepatobiliary disorders
Liver function tests increased	Uncommon	Common (4.1 %)
Skin and subcutaneous tissue disorders
Rash	Common	Common (2.7 %)
Pruritus	Common	Uncommon
Urticaria	Uncommon	Uncommon
Angioedema*	Not known	Not known
Musculoskeletal and connective tissue disorders
Arthralgia	Very common	Common (2.1 %)
Myalgia	Very common	Common (2.2 %)
General disorders and administration site conditions
Asthenia	Very common	Common (5.2 %)
Fatigue	Very common	Common (9.2 %)
Gait disturbance	Common	--

*: 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).

4.9 Overdose

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Pharmacodynamic effects

Riamet comprises a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively. The site of anti-parasitic 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 Riamet 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/pL -200,000/pL (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, subSaharan 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

Study No.	Age	Polymerase chain reaction (PCR)-corrected 28-day cure rate¹ n/N (%) in evaluable patients	Median FCT²[25^th, 75^thpercentile]	Median PCT² [25^th, 75^th percentile]	Year/ Study location
A025⁴	3-62 years	93/96 (96.9)	n³=59 35 hours [20, 46]	n=118 44 hours [22, 47]	1996-97 Thailand
A026	2-63 years	130/133 (97.7)	n³=87 22 hours [19, 44]	NA	1997-98 Thailand
A028	12-71 years	148/154 (96.1)	n³=76 29 hours [8, 51]	n=164 29 hours [18, 40]	1998-99 Thailand
A2401	16-66 years	119/124 (96.0)	n³=100 37 hours [18, 44]	n=162 42 hours [34, 63]	2001-05 Europe, Columbia
A2403	2 months-9 years	289/299 (96.7)	n³=309 8 hours [8, 24]	n=310 24 hours [24, 36]	2002-03 3 countries in Africa
B2303^C T	3 months-12 years	403/419 (96.2)	n³=323 8 hours [8, 23]	n=452 35 hours [24, 36]	2006-07 5 countries in Africa
B2303^D T	3 months-12 years	394/416 (94.7)	n³=311 8 hours [8, 24]	n=446 34 hours [24, 36]	2006-07 5 countries in Africa

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

⁴ Only the 6-dose regimen over 60 hours group data is presented ^CT Riamet tablets administered as crushed tablets

^DT Riamet Dispersible tablets

Riamet 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. Riamet 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 5kg to 25kg, 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 paediatric studies

Study No. Weight category	Median PCT¹[25^th, 75^thpercentile]	PCR-corrected 28-day cure rate² n/N (%) in evaluable patients
Study A2403 5 - <10 kg 10 - <15 kg 15 -25 kg	24 hours [24, 36] 35 hours [24, 36] 24 hours [24, 36]	145/149 (97.3) 103/107 (96.3) 41/43 (95.3)
Study B2303^ct5 - <10 kg 10 - <15 kg 15 -<25 kg 25-35 kg	36 hours [24, 36] 35 hours [24, 36] 35 hours [24, 36] 26 hours [24, 36]	65/69 (94.2) 174/179 (97.2) 134/140 (95.7) 30/31 (96.8)

mITT population

² Efficacy cure rate based on blood smear microscopy ^CT Riamet tablets administered as crushed tablets

QT/QTc Prolongation:

Adults and children with malaria:

For information on the risk of QT/QTc prolongation in patients see section 4.4.

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 Riamet 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 6.84msec, respectively. At 156 and 168 hours after first dose, the changes from baseline for QTcF had no difference from zero. No subject had a >30msec increase from baseline nor an absolute increase to >500msec.

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 14.1msec.

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

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

In the infant/children population included in clinical trials, 3 patients (0.2%) experienced a QTcB >500msec. No patient had QTcF >500msec. Prolongation of QTcF intervals >30msec was observed in 34% of children weighing 510kg, 31% of children weighing 10-15kg and 24% of children weighing 1525kg, and 32% of children weighing 25-35kg.

5.2 Pharmacokinetic properties

Pharmacokinetic characterisation of Riamet 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 60.0-104ng/mL and 146-338ng*h/mL, respectively, in fed healthy adults after a single dose of Riamet, 80mg artemether/480mg lumefantrine. Mean Cmax and AUC values of dihydroartemisinin ranged between 49.7-104ng/mL and 169-308ng»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 5.10-9.80pg/mL) about 6 8 hours after dosing. Mean AUC values of lumefantrine ranged between 108 and 243pg*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 Riamet 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%).

Metabolism

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. During repeated administration of Riamet, 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 described in section 4.5

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 Riamet over the 3-day treatment period, consistent with the slow elimination of the compound (see section 5.2 Elimination). Systemic exposure to the metabolite desbutyl-lumefantrine, for which the in vitro anti-parasitic 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 (see sections 4.3 and 4.5).

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 Riamet.

Limited urinary excretion data are available for humans. In 16 healthy volunteers, neither lumefantrine nor artemether was found in urine after administration of Riamet, 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 artem ether 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 Riamet dose. No conclusive data is available for artemether.

Bioavailability/bioequivalence studies

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

Systemic exposure to lumefantrine was similar following administration of Riamet dispersible tablets and intact tablets in healthy adults. However, exposure to artemether and dihydroartemisinin was significantly lower (by 2035%) 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 Riamet dispersible tablets was demonstrated in this population. The dispersible tablet is not recommended for use in adults.

Special populations

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.

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

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 Riamet in patients with renal impairment is advised.

5.3 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 with artemether at 25mg/kg for 7 or 14 days and dogs dosed at 20mg/kg for 8 days or longer, but lesions were not observed after shorter courses of drug or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level (10mg/kg/day given intramuscularly) is approximately 7-fold greater than the estimated artemether 24 h AUC in humans on day 1 of the standard 3-day oral treatment regimen; oral exposure in humans decreases on subsequent days, thus the exposure margin increases. Dogs dosed orally with 143mg/kg artemether showed a statistically measureable effect on the hearing threshold at 20 dB. This dose is equivalent to about 29 times the highest artemether clinical dose (160mg/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

No evidence of mutagenicity was detected in in vitro or in vivo tests with an artemether:lumefantrine combination (consisting of 1 part artemether:6 parts lumefantrine). In the micronucleus test myelotoxicity was seen at all dose levels (500, 1,000 and 2,000mg/kg), but recovery was almost complete 48 hours after dosing.

Carcinogenicity

Carcinogenicity studies with the artemether:lumefantrine combination were not conducted.

Reproductive toxicity studies

Reproductive toxicity studies performed with the artemether:lumefantrine combination caused maternal toxicity and increased post-implantation loss in rats and rabbits at doses >50mg/kg/day (corresponding to approximately 7mg/kg/day artemether) and 175mg/kg/day (corresponding to 25mg/kg/day artemether) respectively. These effects were not observed at lower doses.

Lumefantrine alone caused no sign of reproductive or development toxicity at doses up to 1,000mg/kg/day in rats and rabbits.

Embryotoxicity has been observed in rat and rabbit reproductive toxicity studies conducted with artemether, a derivative of artemisinin. Artemisinins (e.g. artesunate) are known to be embryotoxic.

Artemether caused increases in post-implantation loss and teratogenicity (characterised as a low incidence of cardiovascular and skeletal malformations) in rats at 19.4mg/kg, and in rabbits at 30mg/kg. Maternal toxicity was also observed in rabbits at 30mg/kg/day. No other adverse effects were observed at lower doses in rabbits. The no observed effect dose was 3mg/kg/day in rats and 25mg/kg/day in rabbits.

The embryotoxic artemether dose, 20mg/kg/day in the rat, yields artemether and dihydroartemisinin exposures similar to those achieved in humans.

Artesunate, a structurally related compound, also caused increases in postimplantation loss and teratogenicity (low incidence of cardiovascular and skeletal malformations) in rats at 6mg/kg and in the lowest dose tested in the rabbits, 5mg/kg/day.

Fertility

After artemether-lumefantrine administration for 10 weeks in males and 2 weeks in females, reduced fertility occurred at 1000mg/kg/day where altered sperm motility, abnormal sperm, reduced epididymal sperm count, increased testes weight, and embryotoxicity and other reproductive effects (decreased implants and viable embryos, increased preimplantation loss) were also observed. General toxicity was observed in males and females at doses >300mg/kg/day. The no adverse effect level for fertility was 300mg/kg/day. The relevance of this finding in humans is unknown.

Juvenile toxicity studies

A specific study to investigate the neurotoxicity of artemether in juvenile rats involved oral administration of artemether during four different dosing intervals, at doses of 30 or 80mg/kg/day on post-partum days 7 to 13, and at doses of 30 or 120mg/kg/day on post-partum days 14 to 21, 22 to 28, or 29 to 36. Mortality, clinical signs and reductions in body weight parameters occurred most notably during the first two dosing intervals. 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 of orally administered artemether on the brain of juvenile rats.

Juvenile studies in the rat indicate that very young animals (aged 7-21 days) are more sensitive to artemether than adult animals. There is no difference in sensitivity in slightly older (3-5 weeks of age) animals following 13 weeks of artemether/lumefantrine administration. Consistent with the later data, clinical studies have established the safety of artemether and lumefantrine administration in patients weighing 5kg and above.

Cardiovascular Safety Pharmacology

In toxicity studies in dogs at doses >600mg/kg/day only, 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 an in vitro assay of HERG channels stably expressed in HEK293 cells, lumefantrine and the main metabolite desbutyl-lumefantrine showed some inhibitory potential in one of the currents responsible for cardiac repolarization. The potency was lower than the other antimalarial drugs tested. From the estimated IC50 values, the order of potency of HERG current block was halofantrine (IC₅₀ = 0.04^M) >chloroquine (2.5^M) >mefloquine 2.6^M) >desbutyl-lumefantrine (5.5^M) >lumefantrine (8.1 ^M).

Additional studies were performed to evaluate the in vitro effects of artemether and its active metabolite, dihydroartemisinin, on the HERG current. At concentrations that produced significant inhibition, the safety margins for artemether and dihydroartemisinin are greater than 100 if they are estimated using the total therapeutic concentration at Cmax or greater than 1000 if they are estimated using the calculated free Cmax. Based on the available non-clinical data, a potential for QTc prolongation in the human cannot be discounted. For effects in the human see sections 4.3, 4.4 and 5.1.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polysorbate 80 Hypromellose Microcrystalline cellulose Colloidal anhydrous silica Croscarmellose sodium Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

PVC/PE/PVDC/aluminium blisters Packs of 24

No specific pack for the treatment of children and infants is available. The 24-tablets pack should be used for this patient population and the parent or care giver should be given the necessary information (see section 6.6).

6.6 Special precautions for disposal

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.

7 MARKETING AUTHORISATION HOLDER

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

8 MARKETING AUTHORISATION NUMBER(S)

PL 00101/0566

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/11/1999 / 29/11/2009

10 DATE OF REVISION OF THE TEXT

27/07/2015