National Agency for Food & Drug Administration &

Control (NAFDAC)

Registration & Regulatory Affairs (R & R)

Directorate

SUMMARY OF PRODUCT CHARACTERISTICS

(SmPC) TEMPLATE

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 1. NAME OF THE MEDICINAL PRODUCT

LUFART 20/120 TABLETS (Artemether 20mg & Lumefantrine 120 mg Tablets)

2. QUALITATIVE AND QUANTITATIVECOMPOSITION

Each Uncoated Tablet contains:

Artemether Ph.Int 20 mg
Lumefantrine Ph.Int
120 mg
Excipients q.s.

3. PHARMACEUTICAL FORM

Tablet.

FOR ORAL USE ONLY

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 4. Clinical particulars

Therapeuticindications

LUFART 20/120 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.

Posology and method ofadministration

Posology
Adults and children weighing 35 kg and above
For patients 12 years of age and above and 35 kg body weight and above, a course of treatment
comprises six doses of four tablets i.e. total of 24 tablets, given over a period of 60 hours as follows:
the first dose of four tablets, given at the time of initial diagnosis, should be followed by five further
doses of four tablets given at 8, 24, 36, 48 and 60 hours thereafter.
Children and infants weighing 5 kg to less than 35 kg
A six-dose regimen is recommended with 1 to 3 tablets per dose, depending on bodyweight:
5 to less than 15 kg bodyweight: the first dose of one tablet, given at the time of initial diagnosis,
should be followed by five further doses of one tablet given at 8, 24, 36, 48 and 60 hours thereafter.
15 to less than 25 kg bodyweight: the first dose of two tablets, given at the time of initial diagnosis,
should be followed by five further doses of two tablets given at 8, 24, 36, 48 and 60 hours thereafter.
25 to less than 35 kg bodyweight: the first dose of three tablets, given at the time of initial diagnosis,
should be followed by five further doses of three tablets given at 8, 24, 36, 48 and 60 hours
thereafter.

Method of administration

Tablets for oral administration.

To increase absorption, LUFART 20/120 should be taken with food or a milky drink. If patients are
unable to tolerate food, LUFART 20/120 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.

Contraindications

LUFART 20/120 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.

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 • patients taking drugs that are known to prolong the QTc interval (proarrythmic). These drugs

include:

- antiarrhythmics of classes IA and III,

- neuroleptics, antidepressive agents,

- certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones,

imidazole and triazole antifungal agents,

- certain non-sedating antihistamines (terfenadine, astemizole),

- cisapride.

- flecainide

• patients with a history of symptomatic cardiac arrythmias or with clinically relevant bradycardia
or

with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

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

• patients taking drugs that are strong inducers of CYP3A4 such as rifampin, carbamazepine,

phenytoin, St. John's wort (Hypericum perforatum).

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

Clinical manifestation: Prostration; impaired consciousness or unarousable coma; failure to feed;

deep breathing, respiratory distress (acidotic breathing); multiple convulsions; circulatory collapse
or

shock; pulmonary edema (radiological); abnormal bleeding; clinical jaundice; hemoglobinuria

Laboratory test: Severe normocytic anemia; hemoglobuniuria; hypoglycemia; metabolic acidosis;

renal impairment; hyperlactatemia; hyperparasitemia).

Special warnings and precautions foruse

LUFART 20/120 must not be used in the first trimester of pregnancy in situations where other
suitable and
effective antimalarials are available (see section 4.6).
LUFART 20/120 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, LUFART 20/120 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 LUFART 20/120, 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.
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The long elimination half-life of lumefantrine must be taken into account when administering
quinine in patients previously treated with LUFART 20/120.
If quinine is given after LUFART 20/120, close monitoring of the ECG is advised (see section 4.5).
If LUFART 20/120 is given after mefloquine, close monitoring of food intake is advised (see
section 4.5). In patients previously treated with halofantrine, LUFART 20/120 should not be
administered earlier thanonemonth after the last halofantrine dose.

LUFART 20/120 is not indicated and has not been evaluated for prophylaxis of malaria.
LUFART 20/120 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 LUFART 20/120, (see section 4.5).
Like other antimalarials (e.g. halofantrine, quinine and quinidine) LUFART 20/120 has the potential
to cause QT prolongation (see section 5.1).
Caution is recommended when combining LUFART 20/120 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
antiretroviral
drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors
should be used with caution in patients taking LUFART 20/120 (see sections 4.5 and 5.2).
Caution is recommended when combining LUFART 20/120 with hormonal contraceptives.
LUFART 20/120 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 LUFART 20/120 in
patients with renal impairment is recommended. Caution is advised when administering LUFART
20/120 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.
Older people
There is no information suggesting that the dosage in patients over 65 years of age should be
different than in younger adults.
New infections
Data for a limited number of patients in a malaria endemic area show that new infections can be
treated with a second course of LUFART 20/120. In the absence of carcinogenicity study data, and
due to lack of clinical experience, more than two courses of LUFART 20/120 cannot be
recommended.
Interaction with other medicinal products and other forms ofinteraction
Interaction with drugs that are known to prolong the QTc interval
LUFART 20/120 is contraindicated with concomitant use of drugs (they may cause
prolonged QTc interval and
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Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and

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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. Co-administration of LUFART 20/120 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 LUFART
20/120 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 LUFART 20/120 alone. Concomitant use of strong
inducers of CYP3A4
such as rifampin, carbamazepine, phenytoin, St. John's Wort is contraindicated with
LUFART 20/120 (see
section 4.3).
Inducers should not be administered at least one month after LUFART 20/120
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 LUFART 20/120 should therefore not
be given concurrently with
other antimalarials unless there is no other treatment option (see section 4.4).
If LUFART 20/120 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

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 with LUFART 20/120. In patients previously treated with halofantrine, LUFART
20/120 should not be administered
earlier than one month after the last halofantrine dose (see section 4.4).
MefloquineA drug interaction study with LUFART 20/120 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 LUFART
20/120 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 LUFART 20/120 (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 LUFART
20/120 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 LUFART
20/120 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 LUFART 20/120.
Concomitant use requiring caution
Interactions affecting the use of
LUFART 20/120 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 LUFART 20/120 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 LUFART 20/120 is
considered unnecessary in falciparum malaria patients when administered in association with
ketoconazole or other potent CYP3A4 inhibitors.
LUFART 20/120 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 LUFART 20/120 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. LUFART 20/120 should be used cautiously in
patients on ARTs since decreased artemether, DHA, and/or lumefantrine concentrations may result
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in a decrease of antimalarial efficacy of LUFART 20/120, and increased lumefantrine concentrations
may cause QT prolongation (see Section 4.4).
Lopinavir/ritonavir

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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 LUFART 20/120.
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 LUFART 20/120.
Interactions resulting in effects of LUFART 20/120 on other drugs
Interaction with drugs metabolized by CYP450 enzymes
When LUFART 20/120 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, LUFART 20/120 may potentially reduce
theeffectiveness 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
LUFART 20/120 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 LUFART 20/120 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.

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
Based on animal data, LUFART 20/120 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
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exposed to LUFART 20/120 (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.
LUFART 20/120 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.
Breast-feeding
Animal data suggest excretion into breast milk but no data are available in humans. Women taking
LUFART 20/120 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 LUFART 20/120 unless potential benefits to the mother and child outweigh
the risks of LUFART 20/120 treatment.

Fertility
There is no information on the effects of LUFART 20/120 on human fertility (see section 5.3).

Effects on ability to drive and usemachines

Patients receiving LUFART 20/120 should be warned that dizziness or fatigue/asthenia may occur
in which case they should not drive or use machines.

Undesirable effects

The safety of LUFART 20/120 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 LUFART 20/120 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).

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Page 13of 21
 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
Pharmacodynamics properties
Pharmacotherapeutic group:. antimalarials, blood schizontocide.
ATC code: P01 BF01.
Pharmacodynamic effects
LUFART 20/120 comprises a fixed ratio of 1:6 parts of artemether and lumefantrine,
respectively.
The site of
antiparasitic action of both components is the food vacuole of the malarial parasite, where
they are
thought to interfere with the conversion of haem, a toxic intermediate produced during
haemoglobin
breakdown, to the nontoxic haemozoin, malaria pigment. Lumefantrine is thought to
interfere with.
the polymerisation process, while artemether generates reactive metabolites as a result of the
interaction between its peroxide bridge and haem iron. Both artemether and lumefantrine have a
secondary action involving inhibition of nucleic acid- and protein synthesis within the malarial
parasite.
Treatment of Acute Uncomplicated P. falciparum Malaria
The efficacy of LUFART 20/120 Tablets was evaluated for the treatment of acute, uncomplicated
malaria (defined as symptomatic P. falciparum malaria without signs and symptoms of severe
malaria or evidence of vital organ dysfunction) in five 6-dose regimen studies and one study
comparing the 6-
dose regimen with the 4-dose regimen. Baseline parasite density ranged from 500/μL -
200,000/μL
(0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in otherwise
healthy,
partially immune or non-immune adults and children (≥5kg body weight) with uncomplicated
malaria in Thailand, sub-Saharan Africa, Europe, and South America.
Efficacy endpoints consisted of:
• 28-day cure rate, proportion of patients with clearance of asexual parasites within 7 days
without
recrudescence by day 28
• parasite clearance time (PCT), defined as time from first dose until first total and continued
disappearance of asexual parasite which continues for a further 48 hours
• fever clearance time (FCT), defined as time from first dose until the first time body
temperature
fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients
with
temperature >37.5°C at baseline)
The modified intent to treat (mITT) population includes all patients with malaria diagnosis
confirmation who received at least one dose of study drug. Evaluable patients generally are all
patients who had a day 7 and a day 28 parasitological assessment or experienced treatment
failure by
day 28. The results are presented in the table below:
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LUFART 20/120 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. LUFART 20/120 is active against blood stages of Plasmodium
vivax, but is not active against hypnozoites.
Paediatric population
Two studies have been conducted
Study A2403 was conducted in Africa in 310 infants and children aged 2 months to 9 years,
weighing 5 kg to 25 kg, with an axillary temperature ≥37.5°C. Results of 28-day cure rate
(PCRcorrected),
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,

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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.

1 mITT population
2 Efficacy cure rate based on blood smear microscopy
CT LUFART 20/120 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 LUFART 20/120 was associated
with prolongation of QTcF. The mean changes from baseline at 68, 72, 96, and 108 hours post first
dose were 7.45, 7.29, 6.12 and 6.84 msec, respectively. At 156 and 168 hours after first dose, the
changes from baseline for QTcF had no difference from zero. No subject had a >30 msec increase
from baseline nor an absolute increase to >500 msec. Moxifloxacin control was associated with a
QTcF increase as compared to placebo for 12 hours after the single dose with a maximal change at 1
hour after dose of 14.1 msec.
In the adult/adolescent population included in clinical trials, 8 patients (0.8%) receiving
LUFART 20/120 experienced a QTcB >500 msec and 3 patients (0.4%) a QTcF >500 msec.
Prolongation of QTcF interval >30 msec was observed in 36% of patients.
In clinical trials conducted in children with the 6-dose regimen, no patient had post-baseline QTcF
>500 msec whereas 29.4% had QTcF increase from baseline >30 msec and 5.1% >60 msec. In
clinical trials conducted in adults and adolescents with the 6-dose regimen, post-baseline QTcF
prolongation of >500 msec was reported in 0.2% of patients, whereas QTcF increase from baseline
>30 msec was reported in 33.9% and >60 msec in 6.2% of patients.
In the infant/children population included in clinical trials, 3 patients (0.2%) experienced a QTcB
>500 msec. No patient had QTcF >500 msec. Prolongation of QTcF intervals >30 msec was
observed in 34% of children weighing 5-10 kg, 31% of children weighing 10-15 kg and 24% of
children weighing 15-25 kg, and 32% of children weighing 25-35 kg.

Pharmacokinetic properties
Pharmacokinetic characterisation of LUFART 20/120 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
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Artemether is absorbed fairly rapidly and dihydroartemisinin, the active metabolite of artemether,
appears rapidly in the systemic circulation with peak plasma concentrations of both compounds
reached about 2 hours after dosing. Mean Cmax and AUC values of artemether ranged between
60.0-104 ng/mL and 146-338 ng·h/mL, respectively, in fed healthy adults after a single dose of
LUFART 20/120, 80 mg artemether/480 mg lumefantrine. Mean Cmax and AUC values of
dihydroartemisinin ranged between 49.7-104 ng/mL and 169-308 ng·h/mL, respectively. Absorption
of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak
plasma concentration (mean between 5.10-9.80 μg/mL) about 6-8 hours after dosing. Mean AUC
values of lumefantrine ranged between 108 and 243 μg·h/mL. Food enhances the absorption of both
artemether and lumefantrine: in healthy volunteers the relative bioavailability of artemether was
increased more than two-fold, and that of lumefantrine sixteen-fold compared with fasted conditions
when LUFART 20/120 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 ofthe
food ingested by acutely ill patients. The food interaction data indicate that absorption of
lumefantrine under fasted conditions is very poor (assuming 100% absorption after a high-fat meal,
the amount absorbed under fasted conditions would be <10% of the dose). Patients should therefore
be encouraged to take the medication with a normal diet as soon as food can be tolerated.
Distribution
Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and
99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47-76%).
Biotransformation
Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro
and in humans. Human liver microsomes metabolise artemether to the biologically active main
metabolite dihydroartemisinin (demethylation), predominantly through the isoenzyme CYP3A4/5.
This metabolite has also been detected in humans in vivo.
Dihydroartemisinin is further converted to inactive metabolites.
The pharmacokinetics of artemether in adults is time-dependent. During repeated administration of
LUFART 20/120, 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 LUFART 20/120 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 antiparasitic effect is 5 to 8 fold higher than that for lumefantrine, was less than 1% of the
exposure to the parent drug. Desbutyl-lumefantrine data is not available specifically for an African
population. In vitro, lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma
concentrations (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 LUFART 20/120.
Limited urinary excretion data are available for humans. In 16 healthy volunteers, neither
lumefantrine nor artemether was found in urine after administration of LUFART 20/120, and only
traces of dihydroartemisinin were detected (urinary excretion of dihydroartemisinin amounted to
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less than 0.01% of the artemether dose).

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In animals (rats and dogs), no unchanged artemether was detected in faeces and urine due to its rapid
and extensive first-pass metabolism, but numerous metabolites (partly identified) have been detected
in faeces, bile and urine. Lumefantrine was excreted unchanged in faeces and with traces only in
urine. Metabolites of lumefantrine were eliminated in bile/faeces.
Dose proportionality
No specific dose proportionality studies were performed. Limited data suggest a dose-proportional
increase of systemic exposure to lumefantrine when doubling the LUFART 20/120 dose. No conclusive
data is available for artemether.
Bioavailability/bioequivalence studiesSystemic exposure to lumefantrine, artemether and
dihydroartemisinin was similar following
administration of LUFART 20/120 as dispersible tablets and crushed tablets in healthy adults.
Systemic exposure to lumefantrine was similar following administration of LUFART 20/120
dispersible tablets and intact tablets in healthy adults. However, exposure to artemether and
dihydroartemisinin was significantly lower (by 20-35%) for the dispersible than for the intact tablet.
These findings are not considered to be clinically relevant for the use of the dispersible tablets in the
paediatric population since adequate efficacy of LUFART 20/120 dispersible tablets was demonstrated
in this population. The dispersible tablet is not recommended for use in adults.
Older people
No specific pharmacokinetic studies have been performed in elderly patients. However, there is no
information suggesting that the dosage in patients over 65 years of age should be different than in
younger adults.
Paediatric population
In paediatric malaria patients, mean Cmax (CV%) of artemether (observed after first dose of LUFART
20/120) were 223 (139%), 198 (90%) and 174 ng/mL (83%) for body weight groups 5-<15, 15-<25
and 25-
<35 kg, respectively, compared to 186 ng/mL (67%) in adult malaria patients. The associated mean
Cmax of DHA were 54.7 (108%), 79.8 (101%) and 65.3 ng/mL (36%), respectively compared to 101
ng/mL (57%) in adult malaria patients. AUC of lumefantrine (population mean, covering the six
doses of LUFART 20/120) were 577, 699 and 1150 μg•h/mL for paediatric malaria patients in body
weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to a mean AUC of 758
μg•h/mL (87%) in adult malaria patients. The elimination half-lives of artemether and lumefantrine
in children are unknown.
Hepatic and Renal impairment
No specific pharmacokinetic studies have been performed either in patients with hepatic or renal
insufficiency or elderly patients. The primary clearance mechanism of both artemether and
lumefantrine may be affected in patients with hepatic impairment. In patients with severe hepatic
impairment, a clinically significant increase of exposure to artemether and lumefantrine and/or their
metabolites cannot be ruled out. Therefore caution should be exercised in dosing patients with severe
hepatic impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or
insignificant renal excretion of lumefantrine, artemether and dihydroartemisinin, no dose adjustment
for the use of LUFART 20/120 in patients with renal impairment is advised.

Pre-clinical Safety:
General toxicity
The main changes observed in repeat-dose toxicity studies were associated with the expected
pharmacological action on erythrocytes, accompanied by responsive secondary haematopoiesis.
Neurotoxicity
Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain
lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic
cytoplasmic granulation, spheroids, apoptosis and dark neurons. Lesions were observed in rats dosed
for at least 7 days and dogs for at least 8 days, but lesions were not observed after shorter
intramuscular treatment courses or after oral dosing. The estimated artemether 24 h AUC after 7
days of dosing at the no observed effect level is approximately 7-fold greater or more than the
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estimated artemether 24 h AUC in humans. The hearing threshold was affected at 20 dB by oral

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 artemether administration to dogs at a dose of about 29 times the highest artemether clinical dose
(160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events
in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study.
Mutagenicity
Artemether and lumefantrine were not genotoxic/clastogenic based on in vitro and in vivo testing.
Carcinogenicity
Carcinogenicity studies were not conducted.
Reproductive toxicity studies
Embryotoxicity was observed in rat and rabbit reproductive toxicity studies conducted with
artemether, a derivative of artemisinin. Artemisinins are known to be embryotoxic. Lumefantrine
alone caused no sign of reproductive or development toxicity at doses up to 1,000 mg/kg/day in rats
and rabbits, doses which are at least 10 times higher than the daily human dose based on body
surface area comparisons.
Reproductive toxicity studies performed with the artemether:lumefantrine combination caused
maternal toxicity and increased post-implantation loss in rats and rabbits.
Artemether caused increases in post-implantation loss and teratogenicity (characterised as a low
incidence of cardiovascular and skeletal malformations) in rats and rabbits. The embryotoxic
artemether dose in the rat yields artemether and dihydroartemisinin exposures similar to those
achieved in humans based on AUC.
Fertility
Artemether-lumefantrine administration yielded altered sperm motility, abnormal sperm, reduced
epididymal sperm count, increased testes weight, and embryotoxicity; other reproductive effects
(decreased implants and viable embryos, increased preimplantation loss) were also observed. The no
adverse effect level for fertility was 300 mg/kg/day. The relevance to this finding in humans is
unknown.
Juvenile toxicity studies
A study investigated the neurotoxicity of oral artemether in juvenile rats . Mortality, clinical signs
and reductions in body weight parameters occurred most notably in younger rats. Despite the
systemic toxicity noted, there were no effects of artemether on any of the functional tests performed
and there was no evidence of a direct neurotoxic effect in juvenile rats.
Very young animals are more sensitive to the toxic effect of artemether than adult animals. There is
no difference in sensitivity in slightly older animals compared to adult animals. Clinical studies have
established the safety of artemether and lumefantrine administration in patients weighing 5 kg and
above.
Cardiovascular Safety Pharmacology
In toxicity studies in dogs at doses ≥600 mg/kg/day, there was some evidence of prolongation of the
QTc interval (safety margin of 1.3-fold to 2.2-fold for artemether using calculated free Cmax), at
higher doses than intended for use in man. In vitro hERG assays showed a safety margin of >100 for
artemether and dihydroartemisinin. The hERG IC50 was 8.1 μM for lumefantrine and 5.5 μM for its
desbutyl metabolite.Based on the available non-clinical data, a potential for QTc prolongation in the
human cannot be
discounted. For effects in the human see sections 4.3, 4.4 and 5.1.

6. PHARMACEUTICAL PARTICULARS

List ofexcipients
Polysorbate 80, Kyron T-134, PVP K 30, microcrystalline cellulose, Colloidal Silicon Dioxide
andmagnesium stearate.

Incompatibilities
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 Not Applicable

Shelflife
36 months from the date of manufacturing

Special precautions forstorage

Store below 30° C.
Store in the original package to protect from moisture.

Natureandcontentsofcontainer<andspecialequipmentforuse,administrationor
implantation>
Alu- Golden PVC Blister of 1 X 24 Tablets

Special precautions for disposal <and otherhandling>

No special requirements

7. <APPLICANT/MANUFACTURER>
E-Globa Pharma. GMBH Limited
6 Amichi Street, Coker Orile Iganmu Lagos State Nigeria

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