Public Assessment Report. Scientific discussion. Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva, film-coated tablets

Transcription

1 Public Assessment Report Scientific discussion Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva, film-coated tablets (efavirenz/emtricitabine/tenofovir disoproxil) NL/H/3602/001/DC Date: 28 September 2017 Tis module reflects te scientific discussion for te approval of Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva 600 mg/200 mg/245 mg, film-coated tablets. Te procedure was finalised on 12 January For information on canges after tis date please refer to te steps taken after finalisation at te end of tis PAR.

2 List of abbreviations C B G ASF CEP CHP CD() CS EDF EDQ EEA ERA ICH AH P.Eur. PL RH RP SmPC TSE Active Substance aster File Certificate of Suitability to te monograps of te European Parmacopoeia Committee for edicinal Products for Human Use Coordination group for utual recognition and Decentralised procedure for uman medicinal products Concerned ember State European Drug aster File European Directorate for te Quality of edicines European Economic Area Environmental Risk Assessment International Conference of Harmonisation arketing Autorisation Holder European Parmacopoeia Package Leaflet Relative Humidity Risk anagement Plan Summary of Product Caracteristics Transmissible Spongiform Encepalopaty 2/11

3 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te ember States ave granted a marketing autorisation for Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva 600 mg/200 mg/245 mg, film-coated tablets, from Teva Nederland B.V. Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil pospate. It is indicated for te treatment of uman immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over wit virologic suppression to HIV-1 RNA levels of < 50 copies/ml on teir current combination antiretroviral terapy for more tan tree monts. Patients must not ave experienced virological failure on any prior antiretroviral terapy and must be known not to ave arboured virus strains wit mutations conferring significant resistance to any of te tree components contained in Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva prior to initiation of teir first antiretroviral treatment regimen. Tis decentralised procedure concerns a generic application claiming essential similarity wit te innovator product Atripla 600 mg/200 mg/245 mg film-coated tablets (EEA/H/C/000797) wic as been registered in EEA by Gilead Sciences International Ltd since 13 December 2007, troug a centralised procedure. Te concerned member states (CS) involved in tis procedure were Spain, Ireland, alta, Portugal and te United Kingdom. Te marketing autorisation as been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is a pink, oval saped, film-coated tablet, debossed wit TEE on one side and plain on te oter side. Eac film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to mg of tenofovir disoproxil pospate or 136 mg of tenofovir). Te tablets are packed in OPA/Alu/PE+ desiccant Alu/PE blister and ig-density polyetylene bottles wit a polypropylene cild resistance cap and a desiccant in te bottle. Te excipients are: Tablet core cellulose microcrystalline, croscarmellose sodium, mannitol (E421), ydroxypropylcellulose, low substituted ydroxypropylcellulose, poloxamer 407, crospovidone, ypromellose, ydrogenated vegetable oil and sodium stearyl fumarate. Film coating (Opadry II 85F Pink) polyvinyl alcool, titanium dioxide (E171), macrogol 3350, talc and carmine (E120). II.2 Drug Substances Te active substances are efavirenz, emtricitabine and tenofovir disoproxil pospate. All tree active substances are establised, owever not described in te European Parmacopoeia (P. Eur.). Efavirenz is described in te United Stated Parmacopoeia (USP) and emtricitabine and tenofovir disoproxil fumarate (related salt) are described in a pending draft USP monograp and in te WHO international parmacopoeia Te Active Substance aster File (ASF) procedure is used for all tree active substances. Te main objective of te ASF procedure, commonly known as te European Drug aster File (EDF) procedure, is to allow valuable confidential intellectual property or know-ow of te manufacturer of te active substance (AS) to be protected, wile at te same time allowing te applicant or marketing autorisation older (AH) to take full responsibility for te medicinal product, te quality 3/11

4 and quality control of te active substance. Competent Autorities/EA tus ave access to te complete information tat is necessary to evaluate te suitability of te use of te active substance in te medicinal product. Efavirenz Te active substance Efavirenz is a wite to off-wite powder and freely soluble in metanol and in diclorometane and practically insoluble in water in te ph range 1-8. Efavirenz as one ciral centre and contains te S-enantiomer. Te R-enantiomer is controlled in te specification. Te substance is not ygroscopic and exibits polymorpism. One polymorpic form is consistently manufactured. anufacturing process Te manufacturing process consists of two syntetic steps and multiple purification steps. Te active substance as been adequately caracterised and acceptable specifications ave been adopted for te starting materials, solvents and reagents. No class I solvents are used in te process. Quality control of drug substance Te efavirenz specification is in line wit te specification of te ASF older.. In addition, an inouse specification for particle size distribution was set. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided by te drug product manufacturer on 4 batces. Stability of drug substance Stability data on te active substance ave been provided for 5 batces stored at 30 /65% RH (24 monts) and 40 C/75% RH (6 monts) in accordance wit applicable European guidelines. All parameters tested remain relatively stable (wit te exception of some analytical variance) at bot storage conditions. Based on te stability data provided te proposed re-test period of 36 monts can be granted wen stored in a well closed container at controlled room temperature, protected from ligt. Emtricitabine Te active substance emtricitabine is a wite to almost wite crystalline powder and freely soluble in metanol and water and practically insoluble in diclorometane. Emtricitabine as two ciral centres and is te cis-enantiomer. Te substance exibits polymorpism and one polymorpic form is consistently manufactured. anufacturing process Te active substance is manufactured in two stages and a final purifications step. Te active substance as been adequately caracterised and acceptable specifications ave been adopted for te starting materials, solvents and reagents. No class I solvents or eavy metal catalysts are used in te process. Quality control of drug substance Te specification applied by te drug product manufacturer is in line wit te specification of te ASF older.. In addition, an in-ouse specification for particle size distribution was set. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for 2 batces by te drug product manufacturer. Stability of drug substance Stability data on te active substance ave been provided for 15 batces stored at 25 C/60% RH (up to 48 monts) and 40 C/75% RH (6 monts) in accordance wit applicable European guidelines. No clear up- or downward trends were observed, under bot long term and accelerated conditions. Te proposed retest period of 60 monts is acceptable, witout te need for special storage conditions. 4/11

5 Tenofovir disoproxil pospate C B G Te active substance tenofovir disoproxil pospate is a wite to off-wite powder and freely soluble in dimetylformamide and soluble in metanol. Te substance is sligtly ygroscopic and only one polymorp is known and manufactured. anufacturing process Te active substance is manufactured in tree stages, consisting of four cemical steps and a final salt formation and purification. Te active substance as been adequately caracterised and acceptable specifications ave been adopted for te starting materials, solvents and reagents. No class I solvents or eavy metal catalysts are used in te process. Quality control of drug substance Te tenofovir disoproxil pospate specification as adopted by te drug product manufacturer is fully in line wit te specification of te ASF older including te limits for particle size. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for 2 batces by te drug product manufacturer. Stability of drug substance Stability data on te active substance ave been provided for 2 pilot scaled batces and 3 full scaled batces stored at 5 C (18 monts for te full scale batces and 36 monts for te pilot batces) and 25 C/60% RH (6 monts). All results were witin te specifications set. Based on te provided stability data te retest period of 24 monts wit te storage condition Store at 2-8 C as proposed by te drug substance supplier is justified. II.3 edicinal Product Parmaceutical development Te product is an establised parmaceutical form and its development is adequately described in accordance wit te relevant European guidelines. Te coice of excipients is justified and teir functions explained. Te main development studies concerned te caracterisation of te reference product, formulation optimization studies, manufacturing process development studies and te performance of comparative dissolution studies. One in vivo bioequivalence was performed. Te results of te comparative in vitro dissolution studies between te bioequivalence study test and reference did not sow similarity in dissolution in all tree media witin te pysiological ph range and in te QC medium. However, te results of te in-vivo bioequivalence study prevail. Te possible reasons for te difference as been sufficiently discussed and is justified. anufacturing process Te manufacturing process as been validated according to relevant European guidelines. Te main steps of te manufacturing process are te separate wet granulation of te tree active substances, drying and screening, blending of te tree granulates, compression and film-coating. Process validation data on te product ave been presented for 2 pilot scale batces in accordance wit te relevant European guidelines. Te product is manufactured using conventional manufacturing tecniques. Process validation for full-scale batces will be performed post autorisation. Control of excipients Te excipients comply wit P.Eur., USP or in-ouse specifications. Tese specifications are acceptable. Quality control of drug product Te finised product specifications are adequate to control te relevant parameters for te dosage form. Te specification includes tests for appearance, identification, dissolution, uniformity of dosage units, assay, related substances, water content and microbial quality. Except for some of te impurities, te release and self-life limits are identical. Limits in te specification ave been justified and are considered appropriate for adequate quality control of te product. Satisfactory validation data for te analytical metods ave been provided. Batc analytical data 2 pilot scaled from te proposed production site ave been provided, demonstrating compliance wit te specification. 5/11

6 Stability of drug product Stability data on te product ave been provided for 2 pilot scaled batces stored at 25 C/60% RH (18 monts) and 40 C/75% RH (6 monts). Te conditions used in te stability studies are according to te ICH stability guideline. Te batces were stored in te proposed blisters and bottles. No clear trends or canges were seen in any of te tested parameters at bot storage conditions. Results of a potostability study sowed tat te drug product is not sensitive to ligt exposure. Te proposed self-life of 2 years and storage condition Store in te original blister in order to protect from moisture. Tis medicinal product does not require any special temperature storage conditions for te blister and Store in te original bottle in order to protect from moisture. Keep te bottle tigtly closed. Tis medicinal product does not require any special temperature storage conditions for te bottle are justified. Stability data as been provided demonstrating tat te product remains stable for 30 days following first opening of te container wen stored at 25 C/60% RH. No separate in-use self-life was laid down. Tis is justified. Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties Tere are no substances of ruminant animal origin present in te product nor ave any been used in te manufacturing of tis product, so a teoretical risk of transmitting TSE can be excluded. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva as a proven cemical-parmaceutical quality. Sufficient controls ave been laid down for te active substance and finised product. No postapproval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is intended for generic substitution, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. III.2 Discussion on te non-clinical aspects Tis product is a generic formulation of Atripla wic is available on te European market. Reference is made to te preclinical data obtained wit te innovator product. A non-clinical overview on te parmacology, parmacokinetics and toxicology as been provided, wic is based on up-to-date and adequate scientific literature. Te overview justifies wy tere is no need to generate additional nonclinical parmacology, parmacokinetics and toxicology data. Terefore, te member states agreed tat no furter non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Efavirenz, emtricitabine and tenofovir disoproxil pospate are well-known active substances wit establised efficacy and tolerability. A clinical overview as been provided, wic is based on scientific literature. Te overview justifies wy tere is no need to generate additional clinical data. Terefore, te member states agreed tat no furter clinical studies are required. 6/11

7 For tis generic application, te AH as submitted a bioequivalence study, wic is discussed below. IV.2 Parmacokinetics Te AH conducted a bioequivalence study in wic te parmacokinetic profile of te test product Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva 600 mg/200 mg/245 mg, film-coated tablets (Teva Nederland B.V,, NL) is compared wit te parmacokinetic profile of te reference product Atripla 600 mg/200 mg/245 mg, film-coated tablets (Gilead Sciences International Ltd., UK). Te coice of te reference product in te bioequivalence study as been justified. Te formula and preparation of te bioequivalence batc is identical to te formula proposed for marketing. Bioequivalence studies Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 60 ealty (40 males/20 females) subjects, aged years. Eac subject received a single dose (600 mg/200 mg/245 mg) of one of te 2 efavirenz/emtricitabine/tenofovir disoproxil formulations. Te tablet was orally administered wit 240 ml water after an overnigt fast. Tere were 2 dosing periods, separated by a wasout period of 28 days. Blood samples were collected pre-dose and at 0.25, 0.50, 0.67, 0.83, 1, 1.25, 1.50, 1.75, 2, 2.33, 2.67, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 36, 48 and 72 after administration of te products. A single dose, crossover study under fasting conditions to assess bioequivalence is considered adequate. According to te SmPC, te tablets sould be taken under fasting conditions. As suc, te fasting conditions applied in te study is considered adequate. Analytical/statistical metods Te analytical metod as been adequately validated and is considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. Tenofovir instead of tenofovir disoproxil was analysed, as tenofovir disoproxil is very rapidly converted into tenofovir, wic is agreed. Results One subject was witdrawn due to a positive alcool test result and one subjects witdrew consent for personal reasons (not related to clinical events). Terefore, 58 subjects completed te study and were eligible for parmacokinetic analysis. Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of evafirenz under fasted conditions. Treatment N=58 AUC 0-72 ng./ml C max ng/ml Test ± ± 722 Reference ± ± 861 *Ratio (90% CI) 1.06 ( ) 1.09 ( ) t max 3.5 ( ) 3.0 ( ) t 1/ ± ± CV (%) /11

8 AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CV coefficient of variation *ln-transformed values Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of emtricitabine under fasted conditions. Treatment N=58 AUC 0-t ng./ml AUC 0- <x>g./ml C max <x>g/ml t max t 1/2 Test ± ± ± ( ) 16.9 ± 7.6 Reference *Ratio (90% CI) ± ± ± ( ) ( ) 1.5 ( ) 15.8 ± CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CV coefficient of variation *ln-transformed values Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of tenofovir under fasted conditions. Treatment N=58 AUC 0-t ng./ml AUC 0- ng./ml C max ng/ml Test 2008 ± ± ± 100 Reference 2196 ± ± ± 107 t max 0.83 ( ) 0.83 ( ) t 1/ ± ± 3.7 *Ratio (90% CI) 0.91 ( ) ( ) CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CV coefficient of variation *ln-transformed values Conclusion on bioequivalence study 8/11

9 Te 90% confidence intervals calculated for AUC 0-t and C max are witin te bioequivalence acceptance range of Based on te submitted bioequivalence study Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is considered bioequivalent wit Atripla. Te EB as been assured tat te bioequivalence study as been conducted in accordance wit acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Risk anagement Plan Te AH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva. - Summary table of safety concerns as approved in RP Important identified risks - Renal toxicity - Bone events due to proximal renal tubulopaty/loss of bone mineral density - Psyciatric and nervous system symptoms - Skin ras and skin reactions (including Stevens-Jonson syndrome, toxic epidermal necrolysis and erytema multiforme - Hig grade epatic enzyme elevation and severe epatic events - Neural tube developmental abnormalities - Post-treatment epatic flares in uman immunodeficiency/epatitis B virus co-infected patients - Interaction wit didanosine - Alteration in efavirenz blood levels and CYP2B6 genetic polymorpisms - Pancreatitis Important potential risks - Lack of efficacy - Overdose - Urolitiasis/neprolitiasis - alignant neoplasms issing information - Safety in cildren (<3 monts old for efavirenz, including long-term safety for tenofovir disoproxil) - Safety in elderly patients - Safety in pregnancy - Safety in lactation - Safety in patient wit epatic impairment - Safety in patients wit renal impairment Te AH as followed te innovator product Atripla in te development of te educational material and as adopted te key elements tat need to be included in te educational material. Te arketing Autorisation Holder (AH) sall ensure tat all pysicians wo are expected to prescribe/use Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva are provided wit a pysician educational pack containing te following: Te Summary of Product Caracteristics HIV renal educational brocure, including te creatinine clearance slide ruler Te HIV renal educational brocure sould contain te following key messages: Tat tere is an increased risk of renal disease in HIV infected patients associated wit tenofovir disoproxil-containing products suc as Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is not recommended for patients wit moderate or severe renal impairment (creatinine clearance < 50 ml/min) 9/11

10 Tat use of Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva sould be avoided wit concomitant or recent use of neprotoxic medicinal products. If Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva is used wit neprotoxic medicinal products, renal function sould be closely monitored according to te recommended scedule. Tat patients sould ave teir baseline renal function assessed prior to initiating Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva terapy Te importance of regular monitoring of renal function during Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva terapy Recommended scedule for monitoring renal function considering te presence or absence of additional risk factors for renal impairment If serum pospate is < 1.5 mg/dl or creatinine clearance decreases during terapy to < 50 ml/min ten renal function must be re-evaluated witin one week. If creatinine clearance is confirmed as < 50 ml/min or serum pospate decreases to < 1.0 mg/dl ten Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva terapy sould be interrupted. Interrupting treatment wit Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva sould also be considered in case of progressive decline of renal function wen no oter cause as been identified. Instructions on te use of te creatinine clearance slide ruler IV.4 Discussion on te clinical aspects For tis autorisation, reference is made to te clinical studies and experience wit te innovator product Atripla. No new clinical studies were conducted. Te AH demonstrated troug a bioequivalence study tat te parmacokinetic profile of te product is similar to te parmacokinetic profile of tis reference product. Risk management is adequately addressed. Tis generic medicinal product can be used instead of te reference product. V. USER CONSULTATION Te package leaflet (PL) as been evaluated via a user consultation study in accordance wit te requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. It included an appropriate testing panel of 11 male and 12 female subjects of various age and education. Te questions covered various sections of te PL and addressed key messages. Te data sows te participants were able to correctly locate te answer te questions in 99% of te time and to correctly answer te questions 100% of te time. Te participants were given ample time to answer eac question. Te interviewer performed te testing in an appropriate fasion. No issues ave been identified. Te results sow tat te package leaflet meets te criteria for readability as set out in te Guideline on te readability of te label and package leaflet of medicinal products for uman use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSENT AND RECOENDATION Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva 600 mg/200 mg/245 mg, film-coated tablets as a proven cemical-parmaceutical quality and is a generic form of Atripla 600 mg/200 mg/245 mg filmcoated tablets. Atripla is a well-known medicinal product wit an establised favourable efficacy and safety profile. Bioequivalence as been sown to be in compliance wit te requirements of European guidance documents. Te Board followed te advice of te assessors. Tere was no discussion in te CD(). Agreement between member states was reaced during a written procedure. Te member states, on te basis of te data submitted, considered tat essential similarity as been demonstrated for Efavirenz/Emtricitabine/Tenofovirdisoproxil Teva, film-coated tablets wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised wit a positive outcome on 12 January /11

11 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUARY Procedure number Scope Produc t Inform ation affecte d Date of end of procedure Approval/ non approval Sum mary/ Justifi cation for refuse NL/H/3602/IB/001/G Cange in te name and/or address of: a manufacture (including were relevant quality control testing sites). Cange in te manufacturer of a starting material/reagent/intermediate used in te manufacturing process of te active substance or cange in te manufacturer (including were relevant quality control testing sites) of te active substance, were no P. Eur. Certificate of Suitability is part of te approved dossier. Canges in te manufacturing process of te active substance NL/H/3602/IB/002/G Cange in te name and/or address of: a manufacture (including were relevant quality control testing sites). Cange in batc size (including batc size ranges) of active substance or intermediate used in te manufacturing process of te active substance; up to 10-fold increase compared to te originally approved batc size Cange in test procedure for active substance or starting material/reagent/intermediate used in te manufacturing process of te active substance; minor canges to an approved test procedure Extension or introduction of a re-test period/storage period supported by real time data NL/H/3602/1/IB/003 Cange(s) in te Summary of Product Caracteristics, Labelling or Package Leaflet of a generic/ybrid/biosimilar medicinal products following assessment of te same cange for te reference product; Implementation of cange(s) for wic no new additional data is required to be submitted by te AH Approved Approved - PL Approved - 11/11