Artemether/lumefantrine 20mg/120mg
tablets (Macleods PharmaceuticalsLtd) MA091

WHOPAR Part 6

September 2014

This part outlines the scientific assessment and knowledge about this product at the time ofprequalification. Updates to this information are included in parts 1 to 5 and 8 of this WHOPAR.

SCIENTIFIC DISCUSSION

Name of the Finished Pharmaceutical
Product[MA091 trade name]*

Manufacturer of Prequalified Product

Macleods Pharmaceuticals Limited
Unit II, Phase II/Phase III, Plot No. 25 – 27
Survey No. 366
Premier Industrial Estate
Kachigam
Daman – 396210, India

Active Pharmaceutical Ingredient(s) (API)Artemether and lumefantrine

Pharmaco-therapeutic group(ATC Code)

Artemisinin and derivatives, combinations(P01BF01)

Therapeutic indication[MA091 trade name] is indicated for the treatment ofuncomplicated cases of malaria due to Plasmodium
falciparum in adults, children and infants of 5 kg and above.

1.

Introduction[MA091 trade name]is indicated for the treatment of uncomplicated cases of malaria due toPlasmodium falciparum in adults, children and infants weighing5 kg and above.
[MA091 trade name] should be initiated by a health care provider experienced in the management ofmalaria.
2.

Assessment of quality

The assessment was done in accordance with the requirements of WHO’s Guidelines on submission ofdocumentation for a multisource (generic) finished pharmaceutical product for the WHO
Prequalification of Medicines Programme: quality part.
Active pharmaceutical Ingredient (API)Artemether
Artemether is described in the Ph.Int. It is manufactured from artemisinin via dihydroartemisinin(artenimol). The specifications for the starting material and the intermediate ensure adequate control
thereof. The production includes a purification step for artemether and leads consistently to onepolymorphic form.
The API specifications include tests for description, solubility, identification (IR and TLC), melting
range, specific optical rotation, loss on drying, sulphated ash, related substances (HPLC), assay(HPLC), residual solvents and particle size distribution.

*

Trade names are not prequalified by WHO. This is the national medicines regulatory authority’s responsibility.
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Artemether/lumefantrine 20mg/120mg
tablets (Macleods PharmaceuticalsLtd) MA091

WHOPAR Part 6

September 2014

Stability testing was conducted according to the requirements of WHO. The proposed re-test period isjustified based on the stability results when the API is stored in the original packing material.
Lumefantrine
Lumefantrine is described in the Ph.Int. The manufacturing process leads consistently to one
polymorphic form.
The quality of the API is adequately controlled by its specifications, which include tests fordescription, solubility, identification (IR), los on drying, sulphated ash, heavy metals, related
substances (HPLC and GC), assay, residual solvents and particle size distribution.
Stability testing was conducted according to the requirements of WHO. The proposed re-test period isjustified based on the stability results when the API is stored in the original packing material.
Other ingredients
Other ingredients used in the tablet formulation include corn starch, colloidal silicon dioxide,
hypromellose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium starchglycolate and magnesium stearate. TSE/BSE certificates confirmed that none of the excipients arederived from animal sources or come into contact with any animal product.
Finished pharmaceutical product (FPP)
Pharmaceutical development and manufacture
The multisource product is a yellow coloured, circular, flat, bevelled edged, uncoated tablet having“MPL” debossed on one side and plain surface on the other side. The tablets are packaged in clear
PVC/Aclar-Alu and PVC/PE/PVdC-Alu blisters.
The development of the final composition of the tablets has been described. The objective was todevelop a stable, immediate release, fixed-dose combination tablet, which is bioequivalent to theWHO comparator product, Coartem®. The comparator product was characterised to define the quality
target product profile, including dissolution and other product attributes. Batches of the APIs wereevaluated for their key physico-chemical characteristics – such as solubility, particle size and flow
properties – which may influence the manufacture and performance of the finished product. The
selection of excipients for development was based on the desired process and product attributes, aswell as demonstrated acceptable compatibility with the APIs.
Due to its demonstrated poor flow characteristics, a non-aqueous granulation process was selected forthe lumefantrine part. Artemether, with acceptable flow characteristics, was incorporated in an extra
granular stage. The composition and process parameters were optimised to obtain tablets of desired
characteristics. The multisource product showed dissolution profiles similar to those of thecomparator product. Satisfactory in-process controls have been established.
Specifications
The FPP specifications include tests for description, identification of the APIs (HPLC and TLC),
average weight, hardness, friability, disintegration time, loss on drying, uniformity of dosage units (bycontent uniformity), dissolution (HPLC and UV), residual solvents, related compounds (HPLC andTLC), assay (HPLC) and microbial limits.
Stability testingStability studies have been conducted at 30 C/75%RH as long-term storage conditions and for six
months at accelerated conditions in the pack types proposed for marketing of the product. The productproved to be quite stable at both storage conditions in both proposed pack types, showing a slightincrease in degradation products, though staying within agreed limits. Based on the available stability
data, the proposed shelf life and storage conditions as stated in the SmPC are acceptable.

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Artemether/lumefantrine 20mg/120mg
tablets (Macleods PharmaceuticalsLtd) MA091

WHOPAR Part 6

September 2014

Conclusion
The quality part of the dossier is accepted.
3.

Assessment of bioequivalence

The following bioequivalence study has been performed in 2011 according to internationally accepted
guidelines:
Bioequivalence study of four tablets as single dose of fixed dose combination of Artemether 20 mg
and Lumefantrine 120 mg tablets manufactured by Macleods Pharmaceuticals Ltd., India incomparison with four tablets of Coartem® (artemether/ lumefantrine) tablets 20 mg/120 mg
manufactured and distributed by Novartis Pharmaceuticals Corporation, USA in healthy, adult, humansubjects under fed condition. (study no. BEQ-641-AL(F)-2010).
The objective of the study was to compare the bioavailability of the stated fixed doseArtemether/Lumefantrine 20/120 mg tablet manufactured by Macleods Pharmaceuticals Ltd., India(test drug) with the same dose of the reference formulation (Coartem®, Novartis Pharmaceuticals
Corporation) and to assess bioequivalence. The comparison was performed as a single centre, openlabel, randomized, crossover study in healthy male subjects under fed conditions. Each subject wasassigned to receive each of the following two treatments in a randomized fashion:
Test – 4 tablets Artemether/Lumefantrine 20/120 mg(artemether 80 mg + lumefantrine 480 mg)
Batch no. EAB5102A.
Treatment R: Reference – 4 tablets Coartem®
(artemether 80 mg + lumefantrine 480 mg)
Batch no. F1444L1.
A 30 day wash-out period was observed between administration of test and reference. Serial bloodsamples (1 pre-dose sample and 32 samples within 72 h post dose) were taken during each study
period to obtain bioavailability characteristics AUC, Cmax and tmax for bioequivalence evaluation. Drugconcentrations for artemether, dihydro-artemisinin and lumefantrine were analyzed using a validated
LC-MS/MS method. The limit of quantification was stated to be about 10 ng/ml for artemether anddihydro-artemisinin and about 100 ng/ml for lumefantrine.
Treatment T:

The study was performed with 60 participants; data generated from a total of 55 subjects were utilized
for analysis to establish pharmacokinetic parameters and assess bioequivalence.
Arithmetic mean and geometric mean values of the pharmacokinetic variables for artemether,dihydro-artemisinin (only supportive pharmacokinetic data) and lumefantrine as well as statisticalresults are summarised in the following tables:
Artemether
Pharmacokinetic
Parameter

Test formulation (T)arithmetic mean ± SD
(geometric mean)

Reference (R)arithmetic mean ± SD
(geometric mean)

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log-transformed parameters
Ratio
T/R (%)

Conventional
90% CI(ANOVAlog)Artemether/lumefantrine 20mg/120mg
tablets (Macleods Pharmaceuticals
Ltd) MA091

WHOPAR Part 6

tmax (h)2.19 ± 0.99

2.30 ± 1.03––Cmax (ng/mL)

217 ± 98(196)

203 ± 91
(182)

108.0

97.7 – 119.3

AUC0-t (ng·h/mL)

559 ± 252(497)

523 ± 250
(466)

106.699.7 – 114.0

AUC0-inf(ng·h/mL)594 ± 261
(531)

563 ± 255
(512)

103.6

96.0 – 111.9

September 2014

Dihydro-artemisinin
Test formulation (T)arithmetic mean ± SD
(geometric mean)

Reference (R)arithmetic mean ± SD
(geometric mean)

log-transformed parameters

Pharmacokinetic
Parameter

Ratio
T/R (%)

Conventional
90% CI(ANOVAlog)

tmax (h)2.37 ± 0.93

2.40 ± 0.93––

Cmax (ng/mL)

147 ± 65(134)

142 ± 72
(128)

105.3

AUC0-t (ng·h/mL)

393 ± 119(373)

382 ± 135
(358)

104.3

AUC0-inf(ng·h/mL)

422 ± 121(402)

410 ± 136(387)103.9

Test formulation (T)arithmetic mean ± SD
(geometric mean)

Reference (R)arithmetic mean ± SD
(geometric mean)

log-transformed parameters

Pharmacokinetic
Parameter

Ratio
T/R (%)

Conventional
90% CI(ANOVAlog)

tmax (h)6.32 ± 1.24

6.47 ± 1.21--Cmax (µg/mL)

7.65 ± 3.68(6.75)

7.07 ± 3.71
(6.19)

109.0

101.3 – 117.2

AUC0-72(µg·h/mL)

145 ± 81(122)131 ± 74(114)107.1

98.6 – 116.3

Lumefantrine

Conclusion
The results of the study show that preset acceptance limits of 80 -125 % are met by both AUC andCmax values regarding artemether and lumefantrine. Accordingly, the test fixed dose
Artemether/Lumefantrine 20/120 mg Tablets meets the criteria for bioequivalence with regard to therate and extent of absorption and is therefore bioequivalent to the reference Coartem® (Novartis
Pharmaceuticals Corporation).
4.

Summary of product safety and efficacy[MA091 trade name] has been shown to conform to the same relevant standards of quality, efficacy
and safety as those required of the innovator product. According to the submitted data on quality andPage 1 of 1

Artemether/lumefantrine 20mg/120mg
tablets (Macleods PharmaceuticalsLtd) MA091

WHOPAR Part 6

September 2014

bioavailability [MA091 trade name] is pharmaceutically and therapeutically equivalent and thusinterchangeable with the innovator product Coartem® for which benefits have been proven in terms ofclinical efficacy.
The clinical safety of this product is considered to be acceptable when guidance and restrictions as
stated in the Summary of Product Characteristics are taken into account. Reference is made to theSmPC (WHOPAR part 4) for data on clinical safety.
5.

Benefit risk assessment and overall conclusion

Quality
Physicochemical and biological aspects relevant to the uniform pharmaceutical characteristics havebeen investigated and are controlled in a satisfactory way. The quality of this product is considered tolead to an acceptable clinical performance when [MA091 trade name] is used in accordance with theSmPC.
Bioequivalence[MA091 trade name] has shown to be bioequivalent with Coartem® (artemether 20 mg +lumefantrine 120 mg tablets), Novartis Pharmaceuticals Corporation, USA.
Efficacy and Safety
Regarding clinical efficacy and safety, [MA091 trade name] is considered effective and safe to use
when the guidance and restrictions in the Summary of Product Characteristics are taken intoconsideration.
Benefit Risk Assessment
Based on WHO's assessment of data on quality, bioequivalence, safety and efficacy the team ofassessors considered that the benefit-risk profile of [MA091 trade name] was acceptable for thefollowing indication: ‘treatment of uncomplicated cases of malaria due to Plasmodium falciparum inadults, children and infants weighing 5 kg and above’ and would allow inclusion of [MA091 tradename], manufactured at Macleods Pharmaceuticals Limited, Unit II, Phase II, Plot No. 25 – 27,
Survey No. 366, Premier Industrial Estate, Kachigam, Daman 396210, India, in the list of prequalified
medicinal products.

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