Artemether/Lumefantrine 20 mg/120 mg Tablets(Ipca Laboratories Ltd), MA062

WHOPAR Part 4

April 2023

WHO-PQ RECOMMENDED
SUMMARY OF PRODUCT CHARACTERISTICS

This summary of product characteristics focuses on uses of the medicine covered by WHO’s Prequalification
Team - Medicines. The recommendations for use are based on WHO guidelines and on information fromstringent regulatory authorities.*
The medicine may be authorised for additional or different uses by national medicines regulatory
authorities.

*

https://extranet.who.int/pqweb/sites/default/files/documents/75%20SRA%20clarification_Feb2017_newtempl.pdf

Page 1 of 16Artemether/Lumefantrine 20 mg/120 mg Tablets(Ipca Laboratories Ltd), MA062

1.

WHOPAR Part 4

April 2023

NAME OF THE MEDICINAL PRODUCT[MA062-trade name]†

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg artemether and 120 mg lumefantrine.
For a full list of excipients, see section 6.1.
Excipient with potential clinical effect
Each tablet also contains 62.4 mg anhydrous lactose.

3.

PHARMACEUTICAL FORM

Yellow-coloured, circular, uncoated, flat-faced, bevelled edged, matt finished tablets, with a break line on
one side and plain on the other side.
The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications[MA062 trade name] is indicated for the treatment of uncomplicated malaria due to Plasmodium falciparum.
Treatment regimens should take into account the most recent official treatment guidelines (e.g. those of theWHO) and local information on the prevalence of resistance to antimalarial drugs.
4.2

Posology and method of administration

Oral use.
Treatment should be administered at the time of initial diagnosis or at the onset of symptoms.
It is preferable that the patient has a positive diagnostic test before administration.
Posology
The recommended daily dose range of artemether/lumefantrine is between 5–24 mg of artemether and 29–
144 mg of lumefantrine per kg body weight.
[MA062 trade name] is taken twice daily for 3 days as indicated in the table below. It is important to ensurethat the number of tablets (packs) supplied to the patient is sufficient for a full 3-day treatment course.
Patient body weight

Number of tablets

Dose of active substances supplied

5 to less than 15 kg

1 tablet twice daily

20 mg artemether/120 mg lumefantrine twice daily

15 to less than 25 kg*

2 tablets twice daily

40 mg artemether/240 mg lumefantrine twice daily

25 to less than 35 kg*

3 tablets twice daily

60 mg artemether/360 mg lumefantrine twice daily

35 kg or more*

4 tablets twice daily

80 mg artemether/480 mg lumefantrine twice daily*Other products containing a higher amount of artemether and lumefantrine should be used when available to reduce
the patient’s pill load.

The first and second doses should be given 8 hours apart. Subsequent doses of [MA062 trade name] should
be given 12 hours apart, in the morning and evening.
†

Trade names are not prequalified by WHO. This is the national medicines regulatory agency’s responsibility.
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April 2023

Missed dose and vomiting after a dose
If a dose is missed, it should be taken as soon as realized and then the recommended regimen continued until
the full course of treatment has been completed.
Patients who vomit within 1 hour of taking the medicine should repeat the dose.
Special populations
Pregnancy
Treatment with artemether/lumefantrine at standard doses is recommended by WHO to treat uncomplicatedfalciparum malaria during the first trimester of pregnancy. The combination can also be used during thesecond and third trimester of pregnancy.
Renal or hepatic impairment
No dose adjustments are necessary in patients with renal or hepatic impairment. However, caution is advisedwhen administering [MA062 trade name] to patients with severe renal or hepatic impairment (see section
4.4).
Elderly
No dosage adjustments are necessary in elderly patients.
Method of administration
To increase absorption, [MA062 trade name] should be taken with food or a milky drink (see section 5.2). If
a patient is unable to tolerate food, [MA062 trade name] should still be administered, but the systemic
exposure may be reduced.
For young children or patients not able to swallow the tablets whole , the tablets may be crushed and added
to a small amount of semi-solid food or liquid, all of which should be consumed immediately.
4.3

Contraindications[MA062 trade name] is contraindicated in:- patients with known hypersensitivity to artemether, lumefantrine or to any of the excipients.
- patients with severe malaria according to WHO definition.
- patients with a personal or family history of congenital prolongation of the QTc interval or sudden
death, or with any other clinical condition known to prolong the QTc interval, such as patients with ahistory of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe cardiac diseases.
- patients taking medicines that are known to prolong QTc interval 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).
- patients with known disturbances of electrolyte balance e.g. hypokalaemia or hypomagnesaemia.
- patients taking any drug which is metabolized by the cytochrome enzyme CYP2D6 (e.g.flecainide,
metoprolol, imipramine, amitriptyline, clomipramine.
- patients taking drugs that are strong inducers of CYP3A4 such as rifampicin, carbamazepine, phenytoin,
St John’s wort.
4.4

Special warnings and precautions for use

To improve absorption, [MA062 trade name] should be taken with food or a milky drink. Patients who areunable or unwilling to eat during treatment should be closely monitored, as the risk of recrudescence may begreater.
If a patient deteriorates while taking [MA062 trade name] alternative treatment for malaria should be started
without delay (but see also under section 4.5). In such cases, monitoring of the ECG is recommended andsteps should be taken to correct any electrolyte disturbances.
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April 2023

Renal/hepatic dysfunction
Artemether/lumefantrine has not been studied in patients with severe renal or hepatic impairment. In thesepatients, ECG and blood potassium monitoring is advised.
Malaria prophylaxis
Artemether/lumefantrine has not been evaluated for malaria prophylaxis.
Malaria not caused by P. falciparum
Artemether/lumefantrine has not been evaluated for the treatment of malaria due to P. vivax, P. malariae, P.
ovale or P. knowlesi (see section 5.1).
Following treatment of mixed infections including P. vivax, follow-up treatment must be given in order toeradicate the exoerythrocytic forms of P. vivax.
Excipients[MA062 trade name] contains lactose. Patients with congenital lactase deficiency, galactosaemia or glucosegalactose intolerance must not be given this medicine unless strictly necessary.
The small amount of lactose in each dose is unlikely to cause symptoms of lactose intolerance in other
patients.
It is important to consider the contribution of excipients from all the medicines that the patient is taking.
4.5

Interaction with other medicinal products and other forms of interaction[MA062 trade name] should not be used in patients taking medicines that are known to prolong the QTcinterval (see section 4.3), as effects may be additive and increase the risk of cardiac arrhythmia.
[MA062 trade name] should not be given concurrently with any other antimalarial agent unless there is noother treatment option, due to limited data on safety and efficacy.. In addition, due to the propensity of some
antimalarial agents to prolong the QTc interval, caution is advised when administering [MA062 trade name]to patients in whom there may still be detectable concentrations of these drugs in the plasma following priortreatments. See also the table below.
Interaction with CYP450 enzymes
Both artemether and lumefantrine are metabolised predominantly by the cytochrome enzyme CYP3A4, but
do not inhibit this enzyme at therapeutic concentrations. 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 thetherapeutic response or safety profile of drugs that are predominantly metabolised by these enzymes.
Lumefantrine was found to inhibit CYP2D6 in vitro. This may be of particular clinical relevance forcompounds with a narrow therapeutic index (see section 4.3).
Interactions with particular medicines
Whenever co-prescribing any drug together with [MA062 trade name], the possibility of a drug-druginteraction should be considered. The following list of drug interactions with [MA062 trade name] is not
exhaustive, but is a selection of interactions of potential relevance.
Drugs (grouped by therapeutic
area)Interaction

Recommendation on coadministration

Potential additive/synergistic effects
on QT-interval[MA062 trade name] should not begiven until at least one month after thelast halofantrine dose due to the longelimination half-life of halofantrine.

Antimalarials
Halofantrine

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April 2023

Drugs (grouped by therapeutic
area)Interaction

Recommendation on coadministration

Mefloquine

lumefantrine plasma concentrations
 30-40%
possibly due to lower absorption
secondary to a mefloquine-induced
decrease in bile production

Patients who have been pretreated withmefloquine should be encouraged totake doses of [MA062 trade name]with food, to compensate for thedecrease in bioavailability.

Quininerisk of QTc prolongation associatedwith i.v. quinine was enhanced byprior administration ofartemether/lumefantrine

Use with caution and appropriatemonitoring.

HIV antiretrovirals
Nucleoside/nucleotide transcriptase inhibitors
Abacavir
Emtricitabine
Lamivudine
Tenofovir disoproxil oralafenamide
Zidovudine

Co-administration has not been studied
but based on metabolism and clearance
a clinically significant interaction isconsidered unlikely

No additional measures needed.

Non-nucleoside/nucleotide transcriptase inhibitors
Efavirenz

artemether AUC  50-80%
dihydroartemsisin AUC  45-75%
lumefantrine AUC  20-55%[MA062 trade name] should be usedwith caution in patients receiving
efavirenz, as antimalarial efficacy may
be decreased.

No significant effect on efavirenz
exposure
Etravirine

artemether AUC 

Etravirine AUC  10%, Cmin  8%,
Cmax  11%

Caution and close monitoring of
antimalarial response is warranted
when co-administering etravirine andlumefantrine/artemether as it isunknown whether the decrease in
exposure of artemether or its active
metabolite, dihydroartemisinin, could
result in decreased antimalarial
efficacy.
No dose adjustment is needed foretravirine.

artemether AUC  72%

Use with caution.

dihydroartemsisin AUC 
lumefantrine AUC  13%, Cmin  3%

Nevirapine

dihydroartemisinin AUC  37%
lumefantrine AUC  20%
Nevirapine AUC  46%
Rilpivirine

Co-administration has not been studied
but based on metabolism and clearancea pharmacokinetic interaction isunlikely.

Page 5 of 16

Caution is nonetheless advisable withco-administration since rilpivirine may
prolong the QT-interval at higher
doses.

Artemether/Lumefantrine 20 mg/120 mg Tablets(Ipca Laboratories Ltd), MA062

Drugs (grouped by therapeuticarea)

WHOPAR Part 4

April 2023

Interaction

Recommendation on coadministration

artemisinins Cmax 

Caution is required since both
lumefantrine and atazanavir may
prolong the QT-interval.

HIV protease inhibitors
Atazanavir

lumefantrine Cmax Darunavir

artemether AUC ↓ 16%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%

Use with caution due to the increase inlumefantrine exposure.

Lopinavir/ritonavir

dihydroartemisinin AUC ↓ 40-60%

Clinical significance unclear but
caution is required since both
lumefantrine and lopinavir can prolong
the QT-interval.

lumefantrine AUC  2.3-fold, Cmax 
1.4-foldIntegrase strand transfer inhibitors (INSTIs)
Dolutegravir
Raltegravir
Bictegravir
Cabotegravir

Co-administration has not been studied
but based on metabolism/eliminationand toxicity profiles there is little
potential for interaction

No additional measures needed.

Elvitegravir/cobicistat

Co-administration has not beenstudied. Elvitegravir/cobicistat may
increase concentrations of artemisinins
and lumefantrine

Monitor patients if co-administration isrequired.

Ritonavir

Co-administration may increase
plasma levels of artemisinins andlumefantrine, as both are metabolised
by CYP3A4

Caution is recommended in coadministration.

Cobicistat

Co-administration has not beenstudied. Cobicistat may increase
concentrations of artemisinins andlumefantrine by inhibition of CYP3A4.

Monitor patients if co-administration isrequired.

Pharmacokinetic enhancers

Antivirals for hepatitis B/C
Ombitasvir/paritaprevir/ritonavir Lumefantrine exposure may 
Lumefantrine is a substrate of
CYP3A4, which is inhibited byritonavir.

Co-administration is not recommended
unless there is no alternative.
If unavoidable, patients should beclosely monitored.

Antifungals
Ketoconazole
Itraconazole
Voriconazole

Modest increase (2 fold or less) inartemether, DHA and lumefantrine
exposure

Page 6 of 16

No dose adjustment required but use
with caution.

Artemether/Lumefantrine 20 mg/120 mg Tablets(Ipca Laboratories Ltd), MA062

Drugs (grouped by therapeuticarea)

WHOPAR Part 4

April 2023

Interaction

Recommendation on coadministration

No interaction seen in vitro. However,artemether may weakly induce
CYP2C19, 2B6 and 3A

Artemether/lumefantrine may
potentially reduce the effectiveness ofhormonal contraceptives. Patientsusing oral, transdermal patch, or othersystemic hormonal contraceptives
should be advised to use an additional
non-hormonal method of birth control
for about one month (see sections 4.4
and 4.6).

Hormonal contraceptives
Ethinylestradiol
Levonorgestrel

Drug-food/drink interactions
Artemether/lumefantrine should be taken with food or drinks rich in fat such as milk as the absorption ofboth artemether and lumefantrine is increased (see section 4.2).
Grapefruit juice should be used cautiously during [MA062 trade name] treatment. Administration ofartemether with grapefruit juice in healthy adult subjects resulted in an approximately two-fold increase insystemic exposure to the parent drug.
4.6

Fertility, pregnancy and breastfeeding

Pregnancy[MA062 trade name] is recommended by WHO to treat uncomplicated falciparum malaria during the firsttrimester of pregnancy. [MA062 trade name] can also be used during the second and third trimester ofpregnancy.
While available studies cannot definitively establish the absence of risk, a meta-analysis of observational
studies including over 500 artemether/lumefantrine-exposed women in their first trimester of pregnancy, datafrom observational, and open label-studies including more than 1200 pregnant women in their second or
third trimester exposed to artemether/lumefantrine compared to other antimalarials, and pharmacovigilancedata have not demonstrated an increase in major birth defects, miscarriage, or adverse maternal or fetal
outcomes. Artemether/lumefantrine in the first trimester of pregnancy appeared to have a lower risk foradverse pregnancy outcomes than previously recommended alternative regimens. Published epidemiologicalstudies have important methodological limitations which hinder interpretation of data, including inability tocontrol for confounders, such as underlying maternal disease, and maternal use of concomitant medications
and missing information on the dose and duration of use.
These data provide assurance in counselling women exposed to artemether/lumefantrine early in the firsttrimester.
Breast-feeding
The amounts of artemether, dihydroartemisinin and lumefantrine in breast milk are small. Therefore, breastfeeding women can receive artemisinin-based combination therapies (including [MA062 trade name]) for
malaria treatment.
Fertility
There is no information on the effects of [MA062 trade name] on fertility in humans.
4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients receiving[MA062 trade name] should be warned that dizziness, fatigue or asthenia may occur, in which case theirability to drive or operate machines may be impaired.

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4.8

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April 2023

Undesirable effects

The safety of artemether/lumefantrine has been evaluated in adults, adolescents and children in clinical trials
with more than 3500 patients.
Adverse reactions reported from clinical studies and post-marketing experience are listed below according tosystem organ class.
Adverse reactions are ranked in the following table 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).
Frequency of undesirable effects
Adults and adolescents above 12
years of age

Infants and children of 12 yearsof age and below (incidence
estimates*)

Cardiac disorders
Palpitations
Very common
CommonElectrocardiogram QT prolonged
CommonCommonNervous system disorders
Headache
Very common
Very common
Dizziness
Very common
CommonParaesthesia
Common-Ataxia, hypoaesthesia
Uncommon-Clonic movements
CommonUncommonSomnolence
UncommonUncommonRespiratory, thoracic and mediastinal disorders
Cough
CommonVery common
Gastrointestinal disorders
Vomiting
Very common
Very common
Abdominal pain
Very common
Very common
NauseaVery common
CommonDiarrhoea
CommonCommonSkin and subcutaneous tissue disorders
Rash
CommonCommonPruritus
CommonUncommonUrticaria
UncommonUncommon
Angioedema*Not known
Not known
Musculoskeletal and connective tissue disorders
Arthralgia
Very common
CommonMyalgia
Very common
CommonGeneral disorders and administration site conditions
Asthenia
Very common
CommonFatigue
Very common
CommonGait disturbanceCommon-Immune system disorders
Hypersensitivity
Not known
Rare
Blood and lymphatic system disorders
Delayed haemolytic anaemia*#
Not known
Not known
Metabolism and nutrition disorders
Decreased appetite
Very common
Very common
Hepatobiliary disorders
Liver function tests abnormal
UncommonCommonPsychiatric disorders
Sleep disorders
Very common
CommonInsomnia
CommonUncommon* These adverse reactions were reported during post-marketing experience. Because these spontaneously reported
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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
Health care providers are asked to report adverse reactions that may be linked to a medicine, to the marketing
authorisation holder, or, if available, to the national reporting system. Reports of suspected adverse reactions
to a medicine are important for the monitoring of the medicine’s benefits and risks.
4.9

Overdose

Experience of overdosage with artemether/lumefantrine is limited.
In cases of suspected overdosage symptomatic and supportive therapy should be given as appropriate, whichshould include monitoring of ECG and serum electrolytes.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimalarials, blood schizontocide, ATC code: P01BF01
Pharmacodynamic effects[MA062 trade name] comprises a fixed ratio of 1:6 parts of artemether/lumefantrine, respectively. The site of
antiparasitic action of both components is the food vacuole of the malarial parasite, where they are thought tointerfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to thenontoxic 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 andhaem iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acidand protein synthesis within the malarial parasite.
Resistance
By 2015, resistance to artemisinins emerged in Southeast Asia. Studies with artemether/lumefantrine in thisregion showed delayed parasite clearance (manifested as a higher proportion of patients with parasitaemia on
Day 3 after initiation of treatment), although overall efficacy as measured by cure rates after 28 days
remained high (WHO 2014). In Africa, only isolated reports on delayed parasite clearance are available anda clear trend towards resistance development was not observed.
Clinical efficacy
The efficacy of artemether/lumefantrine was evaluated for the treatment of acute, uncomplicated malaria(defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence ofvital 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 to 200,000/μL (0.01% to 4% parasitaemia) in
the majority of patients.
Studies were conducted in otherwise healthy, partially immune or non-immune adults and children (≥5 kg
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 withtemperature >37.5°C at baseline)
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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 thetable below:
Clinical efficacy results
Study No. Age

Polymerase chain
reaction (PCR)corrected 28-day
cure rate1 n/N (%)
in evaluable
patients

Median FCT2Median PCT2

[25th, 75th
percentile][25th, 75th
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
ThailandA026

2-63 years

130/133 (97.7)

n3=87
22 hours [19, 44]NA

1997-98
ThailandA028

12-71 years

148/154 (96.1)

n3=76
29 hours [8, 51]n=164
29 hours [18, 40]

1998-99
ThailandA2401

16-66 years

119/124 (96.0)

n3=10037 hours [18, 44]n=162
42 hours [34, 63]

2001-05
Europe,Columbia

A2403

2 months9 years

289/299 (96.7)

n3=3098 hours [8, 24]n=310
24 hours [24, 36]

2002-033 countries
in Africa

B2303CT

3 months12 years

403/419 (96.2)

n3=323
8 hours [8, 23]n=452
35 hours [24, 36]

2006-07
5 countries
in Africa

B2303DT

3 months12 years

394/416 (94.7)

n3=3118 hours [8, 24]

n=446
34 hours [24, 36]

2006-07
5 countries
in Africa

1

Efficacy cure rate based on blood smear microscopymITT population3
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
Artemether/lumefantrine tablets administered as crushed tablets
DT
Artemether/lumefantrine dispersible tablets
2

Artemether/lumefantrine 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. Artemether/lumefantrine is active against blood stages of Plasmodium
vivax, but is not active against hypnozoites.
Paediatric population
Two major 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 the table 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 artemether/lumefantrine crushed tablets and dispersible tablets. Results of 28-day cure rate
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(PCR-corrected), median parasite clearance time (PCT), and fever clearance time (FCT) for crushed tablets
are reported in the table below.
Clinical efficacy by weight for paediatric studies
Study No.
Weight category

Median PCT1
[25th, 75th percentile]

PCR-corrected 28-day cure rate2 n/N(%) in evaluable patients

Study A2403
5 to less than 10 kg
10 to less than 15 kg
15 to 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 B2303CT
5 to less than 10 kg
10 to less than 15 kg
15 to less than 25 kg
25 to 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)

1
2

mITT population
Efficacy cure rate based on blood smear microscopy

CT

Artemether/lumefantrine tablets administered as crushed tablets

QT/QTc Prolongation:
For information on the risk of QT/QTc prolongation in patients see section 4.3 and 4.4.
In a healthy adult volunteer parallel group study including a placebo and moxifloxacin control group (n = 42
per group), the administration of the 6-dose regimen of artemether/lumefantrine with food was associatedwith a moderate prolongation of QTcF (QT interval corrected by Fridericias formula). 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 amaximal change at 1 hour after dose of 14.1 msec.
In the adult/adolescent population included in clinical trials, 8 patients (0.8%) receiving
artemether/lumefantrine 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% ofchildren 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.

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5.2

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April 2023

Pharmacokinetic properties

The absorption characteristics of [MA062 trade name] have been determined after administration of tabletsof [MA062 trade name] in healthy volunteers in the fasting state as follows:
Pharmacokinetic variable

Mean value ± standard deviation
arithmetic mean ± SD
Artemether
Lumefantrine
107 ± 585891 ± 2256

Maximum concentration (Cmax)
ng/ml
Area under the curve (AUC0–∞), a
measure of the extent of absorption
ng.hour/ml
Time to attain maximum
concentration (tmax) hour

328 ± 174

126.0 ± 63.6

2.51 ± 1.01

6.27 ± 1.65

Pharmacokinetics of artemether and lumefantrine
Artemether

Lumefantrine

Absolutebioavailability

NA*

NA*

Oral bioavailability

NA*

NA*

Food effect

A high fat meal increased
bioavailability more than 2-fold.

A high fat meal increased
bioavailability 16-fold.

Artemether: 95.4%.
Dihydroartemisinin: 47-76%

99.7%

Extensively metabolised
predominantly throughisoenzyme CYP3A4/5.

Lumefantrine is mainly metabolised by
CYP3A4.

Dihydroartemisinin is further
metabolised throughglucuronidation.

Desbutyl-lumefantrine, but exposure
less than 1% compared to parent.

Artemether: about 2 h

3 – 6 days

GeneralAbsorption

Distribution
Volume of distribution(mean)
Plasma protein
binding in vitro
Tissue distribution
Metabolism

Active metabolites

Elimination
Elimination half life

Dihydroartemisinin: about 2 h
Mean systemic
clearance (Cl/F)

NA*

NA*

% of dose excreted inurine

Artemether: NA*

NA*

Dihydroartemisinin:<0.01%
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WHOPAR Part 4% of dose excreted in
faecesNot detected

Excreted primarily in faeces

Pharmacokinetic
linearityNA*linearMay induce CYP2C19, CYP2B6,
and CYP3A

Inhibits CYP 2D6April 2023

Drug interactions(in vitro)
Transporters
Metabolising enzymes*Information not available
Pharmacokinetics in special patient populations
Older people
No specific pharmacokinetic studies have been performed in elderly patients (see section 4.2).
Hepatic and renal impairment
Specific pharmacokinetic studies have not been performed in patients with hepatic or renal insufficiency. No
pharmacokinetic studies are available in 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. Based on the pharmacokinetic
data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether anddihydroartemisinin, no dose adjustment for the use in patients with renal impairment is advised.
Paediatric population
In paediatric malaria patients, mean Cmax (CV%) of artemether (observed after first dose) 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 6 doses of artemether/lumefantrine) were 577, 699 and1150 µgh/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.
Infants weighing <5 kgStudy B2306 (see section 5.1) showed that the Cmax of artemether and DHA in infants with uncomplicated P.
falciparum malaria weighing <5 kg and older than 28 days of age who were treated withartemether/lumefantrine dispersible tablets was on average 2- to 3-fold higher than that in paediatric patientswith a body weight ≥5 kg and children up to 12 years of age treated with the same dose ofartemether/lumefantrinetablets. The mean Cmax of lumefantrine was similar to that observed in paediatricpatients with a body weight ≥5 kg.
Race/Ethnicity
Pharmacokinetics of artemether, DHA and lumefantrine in the Japanese population was found to beconsistent with other populations.
5.3

Preclinical safety data

General toxicity
The main changes observed in repeat-dose toxicity studies were associated with the expectedpharmacological action on erythrocytes, accompanied by responsive secondary haematopoiesis.
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Mutagenicity
Artemether and lumefantrine were not genotoxic/clastogenic based on in vitro and in vivo testing.
Carcinogenicity
Carcinogenicity studies with the artemether/lumefantrine combination were not conducted.
Reproductive toxicity studies
Embryotoxicity was observed in rat and rabbit reproductive toxicity studies conducted with artemether, aderivative of artemisinin. Artemisinins are known to be embryotoxic. Lumefantrine alone caused no sign ofreproductive or development toxicity at doses up to 1,000 mg/kg/day in rats and rabbits, doses which are atleast 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 andviable 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 andreductions 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 evidenceof a direct neurotoxic effect in juvenile rats.
Very young animals are more sensitive to the toxic effect of artemether than adult animals. There is nodifference in sensitivity in slightly older animals compared to adult animals. Clinical studies have establishedthe 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 QTcinterval (safety margin of 1.3-fold to 2.2-fold for artemether using calculated free Cmax), at higher doses thanintended for use in man. In vitro hERG assays showed a safety margin of >100 for artemether anddihydroartemisinin. 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. For effects in the human see sections 4.3, 4.4 and 5.1.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Colloidal silicon dioxide
Croscarmellose sodium
Hypromellose
Lactose anhydrous
Magnesium stearate
Polysorbate 80
Purified talc
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This medicine is essentially ‘sodium-free’. It contains less than 1 mmol sodium (23 mg) per tablet

6.2

Incompatibilities

Not applicable
6.3

Shelf life

36 months
6.4

Special precautions for storage

Do not store above 30°C. Store in the original package in order to protect from light.
6.5

Nature and contents of container

Clear PVC-PVDC/Aluminium blister packs.
The presentations are as follows:• One carton containing 1, 2, 3 or 4 blister packs of 6 tablets.
• One blister pack of 6, 12, 18 or 24 tablets packed in a single monocarton. 30 suchmonocartons packed in an outer printed box.
• 30 blister packs of 6, 12, 18 or 24 tablets packed in an outer printed box.
6.6

Special precautions for disposal and other handling

Not applicable

7.

SUPPLIER

Ipca Laboratories Ltd
48 Kandivli Industrial Estate
Kandivli (West)
Mumbai 400 067,
India
Tel. No.: +91-22-6210 5100/6210 5000
Fax No.: +91-22-/+91-22-6210 5005
Email: pharmacovigilance.mumbai@ipca.com

8.

WHO REFERENCE NUMBER (WHO Prequalification Programme)

MA062

9.

DATE OF PREQUALIFICATION

15 December 200910.

DATE OF REVISION OF THE TEXT

April 2023
References
General reference sources for this SmPC include:
Riamet Summary of Product Characteristics, Novartis Pharmaceuticals UK Ltd,
last updated September 2021. Available at: https://www.medicines.org.uk/emc/product/1628
Coartem label, Novartis Pharmaceuticals Corp. USA; last updated August 2019. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022268s021lbl.pdf
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WHO guidelines for malaria, 14 March 2023. Available at: https://apps.who.int/iris/rest/bitstreams/1493946/retrieve
Section 4.5
University of Liverpool, HIV and Hepatitis Drug Interactions websites. Available at:https://www.hiv-druginteractions.org/
https://www.hep-druginteractions.org/
Section 4.6 and others (information related to use in pregnancy)
Malaria Policy Advisory Committee Meeting, 16–18 September 2015, Geneva, Switzerland, Background document for
Session 4; WHO/HTM/GMP/MPAC/2015.13; Malaria in pregnancy. Available at:
http://www.who.int/malaria/mpac/mpac-sept2015-erg-mip-report.pdf?ua=1
Dellicour S, Sevene E, McGready R et al. First-trimester artemisinin derivatives and quinine treatments and the risk ofadverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies. PLoS Med 2017; 14(5):e1002290: https://doi.org/10.1371/journal.pmed.1002290
Saito M, McGready R, Tinto H, et al. Pregnancy outcomes after first-trimester treatment with artemisinin derivatives
versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis. Lancet 2022 (inpress). Available at: https://doi.org/10.1016/S0140-6736(22)01881-5
All weblinks were last accessed on 19 March 2023.

Detailed information on this medicine is available on the World Health Organization (WHO) website:
https://extranet.who.int/pqweb/medicines

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