Zusammenfassung der Merkmale des Arzneimittels - Candesartancilexetil GENMED Pharma 16 mg Tabletten
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Candesartancilexetil JCSH Pharma 4 mg, 16 mg, 32 mg Tabletten |
| Name of the drug substance (INN name): | Candesartan |
| Pharmaco-therapeutic group (ATC Code): | C09CA06 |
| Pharmaceutical form(s) and strength(s): | Tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/5554/001+003–004/DC |
| Reference Member State: | DE |
| Member States concerned: | SE |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | JCSH Pharma Limited 47 Bloomfield Close GU21 2BL KNAPHILL, WOKING, SURREY Great Britain |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | ZeCare Limited 3 Howard Road PE19 8ET EATON SOCON, ST. NEOTS, CAMBRIDGESHIRE Great Britain Sciecure Pharma Limited 5 Millmead GU2 4BE GUILDFORD, SURREY Great Britain |
Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Candesartancilexetil JCSH Pharma 4 mg, 16 mg, 32 mg Tabletten, in the therapeutic indications:
Treatment of essential hypertension in adults. Treatment of hypertension in children and adolescents aged 6 to <18 years. Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) when Angiotensin Converting Enzyme (ACE) inhibitors are not tolerated or as add-on therapy to ACE inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not toleratedis approved.
II.1 Problem statement
For generic application this section is not applicable.
II.2 About the product
Active Substance
The active drug substance is Candesartan Cilexetil
Drug Product
-Candesartan 4 mg tablets
-Candesartan 8 mg tablets (withdrawn)
-Candesartan 16 mg tablets
-Candesartan 32 mg tablets
Mechanism of action
Candesartan is an angiotensin II (Ang-II) receptor antagonist acting on the AT1 receptor subtype thus blocking the effect of Ang-II in the renin angiotensin system (RAS) cascade.
It is administered orally as the inactive prodrug candesartan cilexetil which is rapidly and completely converted to candesartan during gastrointestinal absorption (ATC Code: C09CA06).
Therapeutic indications
Candesartan cilexetil tablet is indicated for the:
Treatment of essential hypertension in adults. Treatment of hypertension in children and adolescents aged 6 to <18 years. Treatment of adult patients with heart failure and impaired left ventricular systolic function (leftventricular ejection fraction ≤ 40%) when Angiotensin Converting Enzyme (ACE) inhibitors are not tolerated or as add-on therapy to ACE inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated
II.3
General comments on the submitted dossier
This decentralised application concerns a generic version of Candesartancilexetil JCSH Pharma 4 mg, 16 mg, 32 mg Tabletten.
The application is being made under Directive 2001/83/EC, Article 10.1 as amended.
The generic Candesartan cilexetil tablets are claimed to be essentially similar to the originator product Atacand 4 mg, 8 mg, 16 mg and 32 mg tablets by AstraZeneca GmbH, which is registered since 03-Dec-1997.
With Germany as the Reference Member State in this Decentralized Procedure, JCSH Pharma Limited applied for the Marketing Authorisations for Candesartancilexetil JCSH Pharma 4 mg, 16 mg, 32 mg Tabletten in the Concerned Member State Sweden (SE).
In addition, it was noticed for the quality part, that the different dossier parts are not in accordance with each other. Some quality aspects described differ between Module 1, Module 2 and Module 3. However, the modules need to be updated and harmonized accordingly.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles
GMP-Certificates
The GMP certificate provided for the finished product manufacturer was issued from the German competent Authority Freie und Hansestadt Hamburg based on an inspection conducted on April the 6th, 2017
The GMP certificate provided for another finished product manufacturer was issued from the MHRA, UK based on an inspection conducted on November the 16th, 2016. The certificate is valid.
The GMP certificate provided for another finished product manufacturer was issued from the MHRA, UK based on an inspection conducted on June the 19th, 2016. The certificate is valid.
QP-Declaration
A QP declaration based on an on-site audit conducted in May 2016 is provided. The QP-declaration is considered valid at the moment although in June 2019 the three years since the last on-site audit elapse. The applicant has confirmed that the next on-site audits are already initiated and will take place in September 2019. This is acceptable.
According to the applicant the two pivotal bioequivalence studies (CAN-T008 & CAN-T009) have been carried out according to GCP.
III.1 Quality aspects
The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Candesartancilexetil JCSH Pharma 4 mg, 16 mg, 32 mg Tabletten are of sufficient quality in view of the present European regulatory requirements.
The active substance Candesartan Cilexetile is described in the European Pharmacopoeia and the current Ph.Eur. Certificates of Suitability (CEPs) is provided. It includes additional testing for the N-nitrosamine impurities.
The control tests and specifications for drug substance product are adequately drawn up.
The re-test period is included in the CEP. It is 36 months if stored under nitrogen in a polyethylene bag in an aluminium bag, placed in an aluminium tin.
JCSH Pharma Limited requested marketing authorisations for medicinal products containing 4 mg, 16mg and 32mg of the known active substance Candesartan cilexetile via a decentralised procedure in accordance with Article 10(1) of Directive 2001/83/EC. The reference medicinal product is Atacand resp. Atacand protect, Astra Zeneca GmbH, which has been firstly authorised via a decentralised procedure in December 1997.
Drug product release will be performed at ZeCare Limited, 3 Howard Road, Eaton Socon, St. Neots, Cambridgeshire PE19 8ET, UK.
Comprehensive data on drug product development is provided. It is of importance that the formulations of the different strength are not all directly dose proportional to each other. Only 16mg and 32mg strength are directly dose proportional to each other. In comparison to 16mg and 32mg strength 4mg strength differs in one excipient Data are provided which proof that the tablets can be divided into equal halves.
It is confirmed that the medicinal product used in the bioequivalence study 4mg and 32mg strength correspond in composition as well as in manufacturing with the medicinal product described in the documentation under evaluation. Furthermore, in-vitro dissolution data give evidence of the pharmaceutical equivalence of the medicinal product used in the bioequivalence study with the reference medicinal product.
In addition the applicant applies for biowaiver regarding 16mg strength (based on 32mg strength BE data). This is acceptable. For the production of the manufacturing process a standard process is used, which includes wet granulation, blending with additional binder material and tabletting. The manufacturing process described as well as the controls applied are suitable. With the response given in context with the validation of the manufacturing process an additional major objection has to be raised, since the manufacturing process applied for and validated seem to differ regarding sub-batches used.
The excipients used are well known and described in the European Pharmacopoeia except for the colorant, which is controlled in line with European food stuff regulations. The control of the excipients is sufficient.
Drug product specifications have been presented for release and shelf-life. Batch analysis results are presented and show compliance with specification.
Reference standards are suitable.
The packaging material oPA/Al/PVC-Aluminium blisters or alternatively HDPE bottles with PP
closures with desiccant is well documented.
Stability package provided included photostability, long term, accelerated testing, in-use as well as bulk stability data. A matrix approach was chosen deviating from Guideline requirements and has been justified sufficiently. The proposed shelf-life of 48 month, as well as the omission of storage conditions is justified. The in-use shelf life of 100 days after opening is acceptable.
III.2 Non-clinical aspects
Candesartan cilexetil, a prodrug that is hydrolyzed to candesartan during absorption from the gastrointestinal tract, is a nonpeptide, orally effective, potent and selective AT1 subtype angiotensin II receptor antagonist.
The main finding concerning the pharmacology of Candesartan cilexetil published within the last 10 years seems to be that candesartan is an inverse agonist at the AT1 receptor (Yasuda et al. 2008).
Candesartan crosses the blood-brain barrier poorly, but it crosses the placental barrier in rats and is distributed to the breast milk of lactating rats. Pharmacokinetic interactions via CYP3A4, CYP2C9 or P-glycoprotein are unlikely.
Detrimental effects of both ACE inhibitors and AT1 receptor antagonists administered during the second and third trimesters of pregnancy (oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, calvarial hypoplasia and neonatal death) are well known, and surviving infants may exhibit renal damage.
There is an ongoing discussion about the contraindication for the use of ACE inhibitors and AT1 receptor antagonists during the first trimester of pregnancy. The renin-angiotensin system (RAS) plays an important role in growth and development. Schütz et al. (Am. J. Pathol. 1996, 149: 2067–2079) demonstrated the presence of all components of the RAS in very early human development (30 – 35 days of gestation), and that both AT1 and AT2 receptors are expressed very early in development (24 days of gestation); angiotensin II plays a role in the growth and differentiation of the kidney, adrenal gland, heart and liver. In early embryos, AT receptors are involved in multiple aspects of the morphogenesis of the kidney and urinary tract (Miyazaki and Ichikawa 2001, Comparative Biochemistry and Physiology 128: 89–97). Chung et al. (The Lancet 2001, 357: 1620) believe that AT receptor antagonists should never be used during pregnancy or in women who are likely to become pregnant, particularly since AT receptor antagonists may lead to activation of the angiotensin II AT receptor, which is involved in vascular development and growth. Cooper et al. (N Engl J Med 2006, 354: 2443–2451) studied a cohort of 29,507 infants enrolled in Tennessee Medicaid and found that infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations of the cardiovascular system and of the central nervous system, and the authors concluded that exposure to ACE inhibitors during the first trimester cannot be considered safe and should be avoided (Editorial by Friedman, N Engl J Med 2006, 354: 2498–2500). However, the PhVWP report on ACE inhibitors and angiotensin II receptor antagonists (AIIRAs) and Recommendations on the use during the first trimester of pregnancy (EMEA/CHMP/PhVWP/474692/2007) concludes that a contraindication during the first trimester of pregnancy is not justified.
There is a discussion about the possible carcinogenic effects of AT1 receptor antagonists. AT1 receptor antagonists like Candesartan induce both an increase in plasma renin activity and in plasma Ang II concentrations. It has been suggested (Levens et al. 1992; Gasparo et al. 1995) that elevated plasma Ang II concentrations could stimulate Ang II receptors not belonging to the subtype 1 (e.g. AT2 or AT4 receptors) thereby possibly leading to undesirable (e.g. mitogenic) effects. Ang II is a mitogen, stimulating the growth of e.g. vascular smooth muscle cells and cardiomyocytes, the release of growth factors and the expression of certain proto-onkogens (Timmermans et al. 1993; Edwards and Ruffolo 1994; Edwards et al. 1995). However, these effects are blocked by AT1 receptor antagonists and, therefore, seem to be mediated by stimulation of AT1 receptors. Recently, Sipahi et al. (The Lancet 2010) have shown in a meta-analysis that AT1 receptor antagonists seem to be associated with a modestly (1.2 %) increased risk of new cancer occurrence. Therefore, both from a pre-clinical and clinical point of view the carcinogenic potential of AT1 receptor antagonists is under
discussion. The CHMP (EMEA/H/A-5(3)/1274) concluded that “the weak evidence of a small increase in the risk of new cancer occurrence associated with AT1 receptor antagonists is limited by several bias”, that “the current evidence from clinical trials and epidemiological studies do not support a signal of increased cancer risk associated with AT1 receptor antagonists” and that “preclinical studies do not provide a clear biological mechanism to support the hypothesis of an increased risk of cancer with AT1 receptor antagonists”; the conclusion of the CHMP was that “the currently available evidence does not confirm a meaningful increased risk of cancer with the use of AT1 receptor antagonists”.
Since Candesartan cilexetil is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
To support the application, the applicant has submitted two bioequivalence studies with the lowest (4 mg) and highest (32 mg) dose strength (CAN-T008 and CAN-T009):
A Comparative Randomised, Single Dose, 2-Way Crossover Open Label Study [CAN-T009] to Determine the Bioequivalence of Candesartancilexetil JCSH Pharma 4 mg Tabletten (Test) and Atacand® 4 mg Tabletten, AstraZeneca GmbH, Germany, after oral administration to healthy male volunteers under fasting conditions A Comparative Randomised, Single Dose, 2-Way Crossover Open Label Study [CAN-T008] to Determine the Bioequivalence of Candesartancilexetil JCSH Pharma 32 mg Tabletten (Test) and Atacand® 32 mg Tabletten, AstraZeneca GmbH, Germany, after oral administration to healthy male volunteers under fasting conditionsThe choice of a single dose BE study design under fasting condition is in accordance with the Guideline on the investigation of bioequivalence for an immediate-release formulation (CPMP/QWP/EWP/1401/98 Rev. 1/ corr**) since the bioavailability of candesartan is not affected by food.
Study No.: The 4-mg BE Study (CAN-T009)
A Comparative Randomized, Single Dose, Two-Way Crossover Open Label Study To Determine The Bioequivalence Of Candesartancilexetil JCSH Pharma 4 mg Tabletten (Test) and Atacand® 4 mg Tabletten, AstraZeneca GmbH, Germany, After Oral Administration To Healthy Adult Volunteers Under Fasting Conditions
Candesartan Cilexetil 4 mg tablets
Atacand® 4 mg tablets
AstraZeneca GmbH, Germany
Results
Pharmacokinetic parameters for candesartan and bioequivalence assessment are given below:
| Parameters | Test | Reference |
| AUCo-t (ng’h/ml) CTax (nq/ml) | 355.13 + 75.94 37.63 ± 10.42 | 323 09 ±79.97 34 21 ±8.36 |
| AUCo-inf (ng'h/ml) Tmax * (h) Kel (h'1) TiqbI (h) %AUCD.t/AUCDMnf | 380.69 + 81.90 4.31 ± 1.21 0.0921 ± 0.02 7.87 ± 1.82 93.41 + 3.60 | 346.97 ±82.92 4.77 + 0.72 0.0940 ± 0.02 7.65+1.76 93.04 ± 3.91 |
| Ratio T/R% | 90% confidence intervals | Intrasubject CV% | ||
| Lower limit | Upper limit | |||
| AUC0.t | 110.53 | 105.22 | 116.11 | 9.62 |
| Cmax | 109.38 | 100.69 | 118.83 | 17.27 |
Point estimates and the 90% Confidence Intervals for Candesartan transformed ratios (Test/Reference) were within the accepted limits of 80.00 % – 125.00 % for Cmax and AUC0-t. Therefore,
bioequivalence of the Test Product containing 4 mg Candesartan cilexetil with the Reference Product of AstraZeneca GmbH, Germany (Atacand 4 mg tablets) can be concluded.
The Applicant has requested a strength waiver for the 8 mg and 16 mg dose strengths using a bracketing approach.
As described in the quality section, the quantitative composition of the 16mg and 32mg strength is proportional, while the 4mg and 8mg strengths differ in one excipient and are not proportional to each other.
The conclusion of bioequivalence can be extrapolated from the Candesartan Cilexetil 32 mg dose strength to the 16 mg dose strength based on linear PK across the recommended dose range, same manufacturing process, same qualitative composition, quantitatively proportional composition and similar in vitro dissolution study results.
For the 8 mg strength, the BE study with the 4 mg strength is relevant. The biowaiver criteria according to the respective EMA guideline (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) Section 4.1.6 are fulfilled. Point c) is covered by i. and iii. (amount of active substance less than 5% of the tablet core weight and the amount of a filler is changed to account for the change in amount of active substance).
However, candesartan is not highly soluble according to the definition of the BE guideline (appendix III. 1) in particular at pH 1.0 and 4.5. Therefore, a biowaiver cannot be granted.
Study No.: The 32-mg BE Study (CAN-T008)
A Comparative Randomised, Single Dose, 2-Way Crossover Open Label Study to Determine the Bioequivalence of Candesartancilexetil JCSH Pharma 32 mg Tabletten (Test) and Atacand® 32 mg Tabletten, AstraZeneca GmbH, Germany, after oral administration to healthy male volunteers under fasting conditions
Candesartan Cilexetil 32 mg tablet
Atacand® Protect 32 mg tablets AstraZeneca GmbH, Germany
Pharmacokinetic parameters for candesartan and bioequivalence assessment are given below:
| Parameters | Test | Reference |
| AUCW (ng'h/ml) Cmax (ng/ml) | 2379.1 ±745.75 226.6 + 81.71 | 2090.5 ± 654.69 213.1 ±77.94 |
| AUCo-inf (ng«h/ml) T™ * (h) Kel (h1} T^ (h) %AUCo4/AUC0.inf | 2624.0 ± 892.94 4.63 + 1.46 0.0779 ± 0.02 9.57 + 2.72 91.59 ±6.30 | 2277.6 ± 748.41 4.14 ± 1.03 0.0767 ± 0.02 9.52 ± 2.34 92.30 ± 5.60 |
| Ratio T/R% | 90% confidence intervals | Intrasubject CV% | ||
| Lower limit | Upper limit | |||
| AUC„ | 113.19 | 105.52 | 121.41 | 14.51 |
| Cmax | 106.95 | 95.54 | 119.72 | 22.53 |
Point estimates and the 90% Confidence Intervals for Candesartan transformed ratios (Test/Reference) were within the accepted limits of 80.00 % – 125.00 % for Cmax and AUC0-t.
Therefore, bioequivalence of the Test Product containing 32 mg Candesartan cilexetil with the Reference Product of AstraZeneca GmbH, Germany (Atacand 32 mg tablets) can be concluded.
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.
Safety specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.Common renewal date is 12.06.2024.
Medicinal product subject to medical prescription.
The package leaflet for Candesartan cilexetil 4 mg, 8 mg, 16 mg and 32 mg tablets has been user tested and achieved satisfactory results; the Candesartan Cilexetil PIL user test results show that all information points can be found by all (100%) participants. This result was achieved across both sets of cohorts. Of those who could find the information points, all (100%) understood them. Therefore, the Candesartan Cilexetil PIL has passed the user test.
Bioequivalence between the Test and Reference product has been shown by the two submitted bioequivalence studies (CAN-T008 and CAN-T009) for the lowest (4 mg) and highest (32 mg) dose strength.
Based on data and justification submitted, the requested biowaiver is acceptable for the Candesartan Cilexetil 16 mg dose strength but not for the 8 mg dose strength.
The MAH decided to withdraw the 8 mg strength from this procedure and will resubmit the MAA application for the 8 mg strength once the BE study is completed. This is considered acceptable.
The Applicant provided a complete chemical pharmaceutical documentation for immediate release film-coated tablets containing 4 mg, 8 mg, 16 mg and 32 mg of the active substance Candesartan. The 8 mg product has been withdrawn.
Approval is recommended for the 4 mg, 16 mg and 32 mg dose strengths of generic Candesartan Cilexetil tablets.
The application is approved. For intermediate amendments see current product information.