Zusammenfassung der Merkmale des Arzneimittels - Cinacalcet Medice 30 mg Filmtabletten
| Proposed name of the medicinal product in the RMS | Cinacalcet Midas 30 mg; 60mg; 90mg Filmtabletten; Cinacalcet Medice 30 mg; 60mg; 90mg Filmtabletten | |
| INN (or common name) of the active substance | Cinacalcet | |
| Pharmaco-therapeutic group (ATC Code): | H05BX01 | |
| Pharmaceutical form(s) and strength(s) | Film coated tablet; 30 mg; 60mg; 90mg | |
| Reference Number(s) for the Decentralised Procedure | DE/H/4287–88/01–03/DC | |
| Reference Member State | DE | |
| Member States concerned | DE/H/4287/01–03/DC DE/H/4288/01–03/DC | LU AT; DK; FI; FR; IT; NO; PL; SE; UK |
| Marketing Authorisation Holder (name and address) | Midas Pharma GmbH Rheinstr. 49 55218 Ingelheim Germany | |
| Names and addresses of manufacturer(s) responsible for batch release in the EEA | Bluepharma – Indústria Farmacêutica SA S. Martinho do Bispo 3045–016 Coimbra Portugal or Midas Pharma GmbH Rheinstarße 49 55218 Ingelheim, Germany | |
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 Cinacalcet Midas 30 mg, 60 mg, 90 mg Filmtabletten (DE/H/4287/001–003/DC) and Cinacalcet Medice 30 mg, 60 mg, 90 mg Filmtabletten (DE/H/4288/001–003/DC), indicated for
– Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.
– Cinacalcet Midas and Cinacalcet Medice may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate.
– Reduction of hypercalcaemia in patients with:
parathyroid carcinoma. primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicatedis approved.
II.1
II.1This decentralised application concerns a generic version of cinacalcet hydrochloride, under the trade names Cinacalcet Midas 30 mg Filmtabletten, Cinacalcet Midas 60 mg Filmtabletten, Cinacalcet Midas 90 mg Filmtabletten (DE/H/4287/001–003/DC) and Cinacalcet Medice 30 mg Filmtabletten, Cinacalcet Medice 60 mg Filmtabletten, Cinacalcet Medice 90 mg Filmtabletten (DE/H/4288/001–003/DC) in the RMS. The different product names proposed during the procedure (e.g. Cinacalcet Medice) may be used interchangeably in this report. Marketed dose strengths for each product will be 30, 60 and 90 mg.
The originator product is Mimpara 90 mg Film-Coated Tablet (MA no. EU/1/04/292/009–012), Amgen Europe B.V, The Netherlands, registered centrally in the EU since 26 October 2004.
With DE as the Reference Member State in this Decentralised Procedure, Midas Pharma GmbH, Germany is applying for the Marketing Authorisations for Cinacalcet Midas Filmtabletten in the RMS and in LU, for Cinacalcet Medice Filmtabletten in the RMS and in AT, DK, ES, FI, FR, IT, NO, PL, SE and UK.
Cinacalcet is a calcimimetic agent that increases the sensitivity to extracellular calcium of the calcium-sensing receptors of the parathyroid gland, which regulate parathyroid hormone secretion; this results in a reduction in parathyroid hormone secretion as well as a decrease in serum calcium. Cinacalcet hydrochloride is given orally in the treatment of secondary hyperparathyroidism (HPT) in patients with end stage renal-disease (ESRD) on maintenance dialysis therapy. It may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. It is further indicated for the reduction of hypercalcaemia in patients with parathyroid carcinoma or primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.
Doses are expressed in terms of the base; cinacalcet hydrochloride 33 mg is equivalent to about 30 mg of cinacalcet.
In the treatment of secondary hyperparathyroidism, the initial dose is 30 mg once daily, increased at intervals of 2 to 4 weeks by 30 mg to a maximum of 180 mg daily.
For the treatment of hypercalcaemia in patients with parathyroid carcinoma or primary hyperparathyroidism, cinacalcet is given in an initial dose of 30 mg twice daily, increased sequentially at intervals of 2 to 4 weeks to a maximum of 90 mg three or four times daily.
II.2 General comments on the submitted dossier
The application is submitted under article 10 (1), generic application of Council Directive 2001/83/EC, as amended, claiming to be a generic to the reference products Mimpara 90 mg Film-Coated Tablet (MA no. EU/1/04/292/009–012), Amgen Europe B.V, The Netherlands, registered centrally in the EU since 26 October 2004.
One pivotal bioequivalence study was submitted. The reference product used in these studies was Mimpara 90 mg Film-Coated Tablet (MA no. EU/1/04/292/009–012), Amgen Europe B.V, The Netherlands, sourced from the German market. The applicant requested a biowaiver for the additional strengths of 30 mg and 60 mg. This approach is accepted, and no further clinical data are required.
The clinical overview was well written and it refers publications up to the year 2014.
Together with the submitted documentation, the information given in the submitted dossier is sufficient for this generic application.
General comments on compliance with GMP, GLP, GCP and agreed ethical principles
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
It is stated in the study report that the bioequivalence study was conducted in accordance with GCP. During the assessment, there were no indications for non-compliance with GCP.
III.1 Quality aspects
The chemical-pharmaceutical documentation of sufficient quality in view of the present European regulatory requirements.
The active ingredient of Cinacalcet 30 mg, 60 mg and 90 mg FCTs is Cinacalcet hydrochloride which is not monographed.
The active substance Cinacalcet hydrochloride is manufactured by two manufacturers. The documentation is presented as an Active Substance Master File. Additional data has been presented from the drug product manufacturer.
The synthesis is sufficiently described; all requirements of the ASMF Guideline are fulfilled.
The starting material is sufficiently described; a discussion of the carry-over of potential impurities in the drug substance is included in the closed part of the ASMF.
Cinacalcet hydrochloride and its identified impurities have been sufficiently characterised.
The possible impurity profile of drug substance has been discussed in detail.
The active substance specification is in line with the General Monograph “Substances for pharmaceutical use” 04/2013:2034 and ICH Q3A and Q6A guidelines.
The methods used are described in detail. The validation data provided are in accordance with the requirements of the relevant ICH guidelines.
The batch results presented show that all analysis data are within the proposed specification.
The information about reference standards and container closure system is considered adequate.
The stability program is carried out according to ICH guidelines on stability testing. Results of eight production batches were all within specifications and no significant changes are observed with exception of same impurity results. The re-test period of the substance 5 years (into polyethylene bag, tied with a cable and introduced into an aluminium laminated bag) is acceptable.
The goal of pharmaceutical development was to develop an immediate-release solid dosage form in three strengths which are stable and essentially similar to the reference product Mimpara® 30 mg, 60 mg and 90 mg film-coated tablets marketed by Amgen Europe B.V. The new medicinal product will be marketed in three strengths: Cinacalcet 30, 60 and 90 mg FCTs. The development work of the formulation has been shortly described.
Dissolution profiles of the reference and the test products of all strengths have been presented (speed rate 75 rpm, in 0.05 N HCl, release media at pH 4.5 and pH 6.). All dissolution profiles are comparable.
Extrapolation of the results from the bioequivalence study conducted with 90 mg strength to the lower strengths of 30 mg and 60 mg is accepted.
The composition of the drug product is satisfactorily described.
The manufacturing process of the finished product has been sufficiently described. Holding times are not set. The IPCs used are acceptable specified. The validation results presented indicate that the process is robust and reproducible.
The presented specification is suitable to control the quality of the drug product.
All methods have been described in detail. The validation data provided are in accordance with the requirements of the relevant ICH guidelines.
Satisfactory batch analyses have been presented. The batch analyses data together with the results obtained from the validation study and stability testing confirm consistency and uniformity of the product based on the parameters tested and indicate the reproducibility of the manufacturing process for the drug product.
The suitability of the working standards has been shown.
The tablets are packed in PVC/PVdC/Alu-blisters (PVC-foil: 250 μm coated with 120 g PVdC/m2, aluminium-foil: 20 μm). The applied primary packaging systems are standard for solid oral formulations. The provided specifications and information for the proposed container closure systems are considered as sufficient.
The conditions used in stability studies are according to the ICH stability guideline. Test results of stability testing at long-term conditions up to 24 months and accelerated conditions up to 6 months have been provided for the new medicinal products.
Based on the obtained results, a shelf-life of 24 months with no special storage conditions can be granted.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of Cinacalcet are well known. As Cinacalcet is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
III.3 Clinical aspects
One bioequivalence study was submitted. The study was a monocentric, open, randomized, singledose, two-stage, two-period, two-treatment, crossover bioequivalence study under fed conditions with a period of washout of at least 10 calendar days between the two periods in order to prevent a carry-over effect. A single dose study in fed condition is adequate and in line with the recommendations of the Guideline on the investigation of Bioequivalence [CPMP/EWP/QWP/1401/98 Rev. 1/Corr** (BE-GL), as the SmPC recommend intake of the reference medicinal product only in the fed state.
Beside others, subjects with presence or a history of clinically significant cardiovascular, renal, hepatic, pulmonary, metabolic, endocrine, haematological, gastrointestinal, neurological, psychiatric or other diseases have been excluded. The study population included healthy volunteers from 18 to 51 years of age, with a BMI from 18.9 to 29.7 kg/m2. Each subject received one tablet of the test product or the reference product in each study period. A period of washout of at least 10 days was left between the two periods in order to prevent a carry-over effect. The test product was Test Cinacalcet 90 mg. The reference product was Mimpara film-coated tablets, Amgen Europe B.V., The Netherlands (Source DE), approved centrally in the EU (MA no. EU/1/04/292/009–012).
A total number of 130 (1st + 2nd stage) male volunteers signed informed consent of which 25 were only screened but not included in the trail. One hundred five volunteers (1st + 2nd stage) fulfilled the inclusion criteria and met none of the exclusion criteria at entry visit and were hospitalized on day 0 study period 1 and 105 healthy volunteers were randomized on day 1 in period 1 by receiving the test or the reference IMP (Safety Set). Sixteen volunteers terminated the trial prematurely and eighty nine subjects completed the study per protocol (PPS).
The compounds (cinacalcet HCL and cincaclcet-d3 HCL as internal standard) were identified and quantified over a theoretical concentration range of 101.00 pg/mL to 50500.00 pg/mL. The validation was performed in compliance with the relevant EMA guideline. From the results of the pre- and within-validation studies it can be concluded that the method has adequate sensitivity, precision, accuracy and selectivity to determine cinacalcet in plasma at the concentration levels expected in real samples.
The main pharmacokinetic parameters of cinacalcet are displayed in the following table:
Table 1:
Pharmacokinetic parameters (n=89)
(non-transformed values; arithmetic mean ± SD, tmax median, range)
| Treatment | AUC 0–72h pg/ml/h | C max pg/ml | t max h | T 1/2 h |
| Test | 338876.07 ±120325.80 | 38839.37 ±15728.33 | 3.2 (1.00 – 8.00) | 24.55 |
| Reference | 332138.46 ±127402.90 | 38260.39 ±18887.05 | 3.3 (1.00 – 8.00) | 25.03 |
| Ratio (90.2% CI) | 102.61 (98.78 – 106.59) | 104.11 (96.08 – 112.82) | ||
| CV (%) | 15.25 | 32.84 |
AUC0–72h area under the plasma concentration-time curve from time zero to 72 hours
Cmax maximum plasma concentration
Tmax time for maximum concentration (median (min, max))
T1/2 half-life
ln-transformed values confidence interval of cinacalcet (pooled analysis after completion of 2nd stage)
With regard to submitted results of the bioequivalence study for the 90 mg strength, bioequivalence of Test 90 mg and Mimpara 90 mg can be concluded as statistical issues with regard to the applied two-stage procedure were solved.
The applicant requested a biowaiver for the additional strengths of 30 mg and 60 mg.
The Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98Rev.1/Corr**) states in section 4.1.6 “Strength to be investigated” that if several strengths of a test product are applied for, it may be sufficient to establish bioequivalence at only one or two strengths, depending on the proportionality in composition between the different strengths and other product related issues.
Extrapolation of the results from the bioequivalence study conducted with 90 mg strength to the lower strengths of 30 mg and 60 mg is acceptable from a quality point of view. The informative texts of the SmPC and PL including the therapeutic indication are in line with the originator Mimpara and they are regarded acceptable.
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.
Summary of safety concerns
| Important identified risks | – hypocalcaemia – convulsions/seizures – hypersensitivity reactions (including rash, urticaria, and angioedema) – hypotension and/or worsening heart failure – QT prolongation and ventricular arrhythmias secondary to hypocalcaemia |
| Important potential risks | – fracture – acute pancreatitis – possible drug-related hepatic disorders – myocardial ischemia – nervous system disorders (ex- cluding seizure) |
Missing information
– neoplastic events
– pregnant women
– lactating women
– paediatric patients
The Applicant has provided an RMP V.3.0 within the new format of GVP module V, which is acceptable.
Neither additional pharmacovigilance measures nor additional risk minimisation measures were proposed for the safety concerns.
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.
The common renewal date is 08.03.2021.
Medicinal product subject to medical prescription.
The User Testing has been assessed and found acceptable.
The results of this test indicate that the PIL provides a set of comprehensible information enabling the use of the medicinal product safely and appropriately.