4.1. Therapeutic indications

Riamet 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.

4.2. 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.

Infants weighing less than 5 kg

The safety and efficacy of Riamet tablets have not been established in infants weighing less than 5 kg and no dosing recommendations can be made. Currently available data are described in section 5.1 and 5.2.

Older people

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

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 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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Riamet is not recommended during 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 of malaria.

Riamet 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 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 non-hormonal 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.

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. 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). In these patients, ECG and blood potassium monitoring is advised. No dose adjustment is recommended for patients with mild to moderate hepatic impairment.

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.

Excipient with known effect:

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially “sodium-free.”

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 antihistamines (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. Co-administration 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 coinfected 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.

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 non-nucleoside reverse transcriptase inhibitors

Both artemether and lumefantrine are metabolized by CYP3A4. 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. Administration of artemether with grapefruit juice in healthy adult subjects resulted in an approximately two fold increase in systemic exposure to the parent drug.

4.6. Fertility, pregnancy and lactation

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).

Pregnancy

A meta-analysis of observational studies including over 500 artemether-lumefantrine exposed women in their first trimester of pregnancy assessed adverse pregnancy outcomes. The data showed that compared to quinine, artemisinin treatment, including artemether-lumefantrine, was not associated with an increased risk of miscarriage, stillbirth or congenital anomalies. However, due to the limitations of these studies, the risk of adverse pregnancy outcomes for artemether-lumefantrine exposed women in early pregnancy cannot be excluded.

Safety data from pregnancy studies including over 1200 pregnant women who were exposed to artemether-lumefantrine during the second or third trimester did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rates.

Studies in animals have shown reproductive toxicity (see section 5.3).

Riamet treatment is not recommended 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, Riamet treatment should be considered if the expected benefit to the mother outweighs the risk to the foetus.

Breast-feeding

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 above 12 years of age

Infants and children of 12 years of age and below (incidence estimates)

Blood and lymphatic system disorders

Delayed haemolytic anaemia#

Not Known

Not Known

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.

#: Has been reported up to a few weeks after treatment has been stopped.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.