Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),HA553

WHOPAR Part 6May 2017

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

SCIENTIFIC DISCUSSION

Name of the Finished Pharmaceutical Product[HA553 trade name]*

Manufacturer of Prequalified Product

Strides Shasun Limited
KRS Gardens
Tablet Block
36/7, Suragajakkanahalli
Indlavadi Cross
Anekal Taluk
Bangalore – 562 106IndiaActive Pharmaceutical Ingredients (APIs)

Efavirenz, emtricitabine, tenofovir disoproxil
fumarate.

Pharmaco-therapeutic group(ATC Code)

Antivirals for treatment of HIV infections,combinations (emtricitabine, tenofovir disoproxil
fumarate and efavirenz: J05AR06)

Therapeutic indication[HA553 trade name] is indicated for thetreatment of human immunodeficiency virus-1(HIV-1) infection in adults and adolescents from
10 years of age and weighing at least 35 kg

1. Introduction[HA553 trade name] is indicated for the treatment of human immunodeficiency virus-1 (HIV-1)
infection in adults and adolescents from 10 years of age and weighing at least 35 kg.
[HA553 trade name] should be initiated by a health care provider experienced in the management ofHIV infection.

2. Assessment of quality
The assessment was done in accordance with the requirements of WHO’s Guidelines on submission of
documentation for a multisource (generic) finished pharmaceutical product for the WHO
Prequalification of Medicines Programme: quality part.
Active pharmaceutical Ingredients (APIs)
Efavirenz
Efavirenz is a class 4/2 API according to Biopharmaceutics Classification System (WHO Technical
Report Series 937, Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model*Trade names are not prequalified by WHO. This is the national medicines regulatory authority’s (NMRA) responsibility.

ꭞ Formerly Strides Shasun Limited

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Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),
HA553

WHOPAR Part 6

May 2017

List of Essential Medicines immediate-release, solid oral dosage forms). Data provided show thatefavirenz is practically insoluble in aqueous medium over the physiological pH range.
Efavirenz is manufactured in several steps from a commercially available starting material. It can exist
in a number of crystalline forms. Form I is consistently produced as controlled with DSC.
The API specifications are pharmacopoeial based and include tests for description, solubility,identification (IR, HPLC, UV), polymorphic identity (DSC), water content (KF), specific opticalrotation, residue on ignition, heavy metals, organic impurities (HPLC), assay (HPLC), residualsolvents, limit of efavirenz enantiomer (chiral HPLC; ≤ 0.2%), particle size distribution, foreign
matter, microbial limits and completeness of solution.
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 packaging.
Emtricitabine
Based on scientific principles the WHO Prequalification Team-Medicines has identified emtricitabine(up to 200 mg oral dose) as a BCS class 1 API. Emtricitabine is thus highly soluble according to theBCS.
Emtricitabine, 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)pyrimidinone, has two chiral centres. The desired stereochemistry is built into the key intermediate in
the multi-step synthesis process, with L-menthol as the starting material for synthesis. Emtricitabine isknown to exhibit polymorphism. Form I is consistently produced.
The API specifications include tests for description, solubility, identification (IR, HPLC, specificoptical rotation), melting range, loss on drying, residue on ignition, heavy metals, limit of enantiomer(chiral HPLC; ≤ 0.3%), related substances (HPLC), assay (HPLC), residual solvents, particle sizedistribution, foreign matter, bulk density and content of alkyl methane sulfonates (each individual ≤ 3ppm).
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 packaging.

Tenofovir disoproxil fumarate (TDF)
Tenofovir disoproxil fumarate (TDF) is the salt of tenofovir disoproxil with fumaric acid. Tenofovir
disoproxil is a diester pro-drug of the purine based nucleotide analogue, tenofovir. The pro-drug has
increased oral bioavailability compared to tenofovir.
TDF, (R)-9-(2-phosphonomethoxypropyl)adenine disoproxil fumarate, is manufactured in several
steps from adenine via (R)-9-(2-hydroxypropyl)adenine. The specifications and test methods for theisolated intermediates are considered to be satisfactory. The structure and stereochemistry of TDF
were confirmed by the route of synthesis and spectrometric data.
The specifications for TDF include tests for description, solubility, identification of the API (IR,HPLC) and fumaric acid (HPLC), melting range, residue on ignition, heavy metals, water content(KF), related substances (HPLC), S-isomer content (chiral HPLC; ≤ 1.0%), assay (HPLC), fumaricacid content, residual solvents, foreign matter, particle size and clarity of solution. The specifications
also control the mutagenic 9-propenyladenine, which is a synthesis related substance, at ≤ 5 ppm. This
is in accordance with the requirement of Tenofovir disoproxil fumarate Ph.Int.

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Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),HA553

WHOPAR Part 6May 2017

TDF is known to exhibit polymorphism and exists in two forms, namely a low melting form (m.p.
112-1140C) and a high melting form (m.p. 114-1180C). The high melting form, controlled by melting
point, is consistently produced. The test methods have been adequately validated.
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 packaging.
Other ingredients
Other ingredients used in the core tablet formulation include microcrystalline cellulose, lactose,
croscarmellose sodium, sodium lauryl sulfate, hydroxypropyl cellulose and magnesium stearate.
Magnesium stearate is of vegetable origin. The commercially sourced proprietary film-coating mixture
contains polyvinyl alcohol – partly hydrolysed, macrogol/PEG, titanium dioxide, talc and FD&C Blue
#2/Indigo carmine aluminium lake.
Finished Pharmaceutical Product (FPP)
Pharmaceutical development and manufacture
Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of TDF equivalent to245 mg of tenofovir disoproxil.
The multisource product is a blue coloured, capsule shaped, biconvex film-coated tablet engraved TEEon one side and plain on the other side. The tablets are packaged in an HDPE bottle with HDPE screw
closure and containing a silica gel desiccant.
The objective of the development programme was to obtain a stable, robust, immediate-release FDC
tablet that is bioequivalent to the WHO comparator product, Atripla®. Similar to the comparator
product, a bilayer tablet containing the BCS low soluble efavirenz in one layer and the BCS highly
soluble emtricitabine and TDF in the other layer was developed. The selection of excipients was basedon their suitability to achieve the desired tablet characteristics, information of the qualitative
composition of the comparator product and compatibility with the APIs. Based on the stability andflow properties of the APIs it was decided to prepare the efavirenz blend by a wet granulation process
and the emtricitabine and tenofovir DF blend by a dry granulation process and compress into bilayer
tablets. To furthermore protect the product from moisture a silica gel desiccant is included in the bottle
packs. The process parameters were optimised to obtain tablets of desired characteristics, withdissolution profiles similar to that of the comparator product. Satisfactory in-process controls havebeen established.
Product specifications
The finished product specifications include tests for description, identification (HPLC and TLC),
average weight, uniformity of weight, uniformity of dosage units (by content uniformity), tablet
dimensions, moisture content (KF), dissolution (HPLC detection), related substances (HPLC), assay(HPLC) and microbial limits. The test methods have been satisfactorily validated.
Stability testingStability studies have been conducted at 25C/60%RH, 30C/65%RH and 30C/75%RH as long-term
storage conditions and for six months at accelerated conditions in the packaging proposed formarketing of the product. Degradation was observed and the studies showed that the product should beprotected from exposure to temperatures above 30ºC and to high relative humidity. Based on theavailable stability data, the proposed shelf life and storage conditions as stated in the SmPC areacceptable.
Conclusion
The quality part of the dossier is accepted.

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Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),HA553

WHOPAR Part 6May 2017

3. Assessment of bioequivalence
The following bioequivalence study has been performed in 2009 according to internationally acceptedguidelines.
A randomized, open label, two-treatment, two-period, two-sequence, single dose, crossover
bioequivalence study of Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate tablets[600/200/300 mg] of Strides Shasun Limited, India with ATRIPLATM (efavirenz 600 mg /emtricitabine 200 mg /tenofovir disoproxil fumarate 300 mg) tablets of Bristol-Myers Squibb & GileadSciences, USA in normal, healthy, adult, male and female human subjects under fasting condition(study no. ARL/09/315).
The objective of the study was to compare the bioavailability of the statedEfavirenz/Emtricitabine/Tenofovir disoproxil fumarate 600/200/300 mg FDC tablet manufactured byStrides Shasun Ltd., India (test drug) with the reference formulation Atripla® (Bristol-Myers Squibband Gilead Sciences) and to assess bioequivalence. The comparison was performed as a single centre,
open label, randomized, crossover study in healthy subjects under fasting conditions. Each subject wasassigned to receive each of the following two treatments in a randomized fashion:
Treatment T:

Treatment R:

Test – 1 tablet Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate
600/200/300mg(efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300mg)
Batch no. 7208715.
Reference – 1 tablet Atripla®
(efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300mg)
Batch no. FEG018A.

A 24 day wash-out period was observed between administration of test and reference. Serial blood
samples (1 pre-dose sample and 23 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 efavirenz, emtricitabine and tenofovir were analyzed using validated LC-MS/MSmethods. The limit of quantification was stated to be about 50 ng/ml for efavirenz, 35 ng/ml for
emtricitabine and 10 ng/ml for tenofovir.
The study was performed with 54 participants; data generated from a total of 44 subjects were utilized
for analysis to establish pharmacokinetic parameters and assess bioequivalence.
Arithmetic mean and geometric mean values of the pharmacokinetic variables for efavirenz,emtricitabine and tenofovir as well as statistical results are summarised in the following tables:
Efavirenz
PharmacokineticParametertmax (h)Cmax (ng/mL)
AUC0-72h (ng.h/mL)

Test formulation(T)arithmetic mean ± SD
(geometric mean)
4.34 ± 0.972324 ± 763(2208)
55153 ± 21306(51339)Reference(R)arithmetic mean ± SD
(geometric mean)
4.38 ± 1.02
2390 ± 550(2336)
58346 ± 15917(56242)

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log-transformed parameters
Ratio
Conventional
T/R (%)
90% CI(ANOVAlog)
94.5
87.3 – 102.3
91.3

84.5 – 98.6

Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),
HA553

WHOPAR Part 6

May 2017

Emtricitabine
PharmacokineticParametertmax (h)Cmax (ng/mL)
AUC0-t (ng.h/mL)
AUC0-inf (ng.h/mL)

Test formulation(T)arithmetic mean ± SD(geometric mean)
1.81 ± 0.87
1861 ± 396(1819)
10678 ± 2503
(10386)11110 ± 2540
(10828)Reference(R)arithmetic mean ± SD
(geometric mean)
1.90 ± 0.66
1916 ± 407(1874)
10859 ± 2057
(10653)11347 ± 2143
(11133)log-transformed parameters
Ratio
Conventional
T/R (%)
90% CI(ANOVAlog)
97.1
91.8 – 102.7

Test formulation(T)arithmetic mean ± SD
(geometric mean)
1.18 ± 0.64
342 ± 82(332)2165 ± 510(2103)
2578 ± 502(2527)

Reference(R)arithmetic mean ± SD
(geometric mean)
1.42 ± 0.60
354 ± 101(341)2290 ± 652(2194)
2688 ± 664(2603)

log-transformed parameters
Ratio
Conventional
T/R (%)
90% CI(ANOVAlog)
97.5
91.8 – 103.5

97.5

93.0 – 102.2

97.3

93.1 – 101.7

Tenofovir
Pharmacokinetic
Parameter
tmax (h)Cmax (ng/mL)
AUC0-t (ng.h/mL)
AUC0-inf (ng.h/mL)

95.9

89.8 – 102.4

97.1

92.1 – 102.4

Conclusion
The results of the study show that preset acceptance limits of 80 -125 % are met by both AUC and Cmax
values regarding efavirenz, emtricitabine and tenofovir. Accordingly, the test FDC tablet
Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate 600/200/300mg meets the criteria forbioequivalence with regard to the rate and extent of absorption and is therefore bioequivalent to thereference Atripla® (Bristol-Myers Squibb/Gilead Sciences Inc.).

4. Summary of Product Safety and Efficacy[HA553 trade name] has been shown to conform to the same relevant standards of quality, efficacy
and safety as those of the comparator product. According to the submitted data on quality andbioavailability [HA553 trade name] is pharmaceutically and therapeutically equivalent and thusinterchangeable with the comparator product AtriplaTM tablet (Bristol-Myers Squibb and Gilead
Sciences Inc, U.S.A.) for which benefits have been proven in terms of virological and immunologicalefficacy.
The clinical safety of [HA553 trade name] is considered to be acceptable when guidance andrestrictions as stated in the Summary of Product Characteristics are considered. Reference is made to
the SmPC (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 [HA553 trade name] is used in accordance with theconditions as stated in the SmPC.
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Efavirenz/emtricitabine/ tenofovir disoproxil fumarate
600 mg/200 mg/300 mg tablets (Strides Pharma Science Ltdꭞ),
HA553

WHOPAR Part 6May 2017

Bioequivalence[HA553 trade name] has shown to be bioequivalent with AtriplaTM tablet (Bristol-Myers Squibb and
Gilead Sciences Inc, U.S.A.).
Efficacy and Safety
Regarding clinical efficacy and safety, [HA553 trade name] is considered effective and safe to use
when the guidance and restrictions presented 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 [HA553 trade name] was acceptable for thefollowing indication: “treatment of human immunodeficiency virus-1 (HIV-1) infection in adults
and adolescents from 10 years of age and weighing at least 35 kg” and allow inclusion of [HA553
trade name], manufactured at Strides Shasun Limited KRS Gardens, Tablet Block, 36/7,
Suragajakkanahalli Indlavadi Cross, Anekal Taluk, Bangalore – 562 106, India in the list ofprequalified medicinal products.

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