Beipackzettel - Imatinib Pensa 400 mg Filmtabletten
TABLE OF CONTENTS
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product in the RMS | Imatinib Pensa 100 mg, 400 mg Filmtabletten |
| Name of the drug substance (INN name) | Imatinib |
| Pharmaco-therapeutic group (ATC Code) | L01XE01 |
| Pharmaceutical form(s) and strength(s) | 100 mg; 400 mg; film-coated tablets |
| Reference Number(s) for the Decentralised Procedure | DE/H/4262/001–002/DC |
| Reference Member State | DE |
| Concerned Member States | No CMS |
| Marketing Authorisation Holder (name and address) | Pensa Pharma GmbH Max-Planck-Straße 11 85716 Unterschleißheim Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | LABORATORIOS CINFA, S.A. Avda. Roncesvalles s/n 31699 Olloki (Navarra) Spain LABORATORIOS CINFA, S.A. Olaz-Chipi, 10 – Polígono Industrial Areta 31620 Huarte (Navarra) Spain |
I INTRODUCTION
Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, non-clinical, safety and efficacy, the RMS considers that the application for Imatinib Pensa 100 mg & 400 mg Filmtabletten,
is approved.
II EXECUTIVE SUMMARY
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II.1 Problem statement
For generic application this section is not applicable.
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II.2 About the product
Mode of action
Imatinib acts as a specific inhibitor of a number of tyrosine kinase (TK) enzymes and is specific for the TK domain in abl, c-kit and PDGFR (platelet-derived growth factor receptor). In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of ABL with BRC (breakpoint cluster region), termed BRC-ABL. As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity. Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of noncancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.
Pharmacological classification
ATC code: L01XE01
Pharmacotherapeutic group: protein-tyrosine kinase inhibitor
Therapeutic Indications as worded in the applicant’s SmPC:
Imatinib Pensa is indicated for the treatment of
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– paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.
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– paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase.
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– adult and paediatric patients with Ph+ CML in blast crisis.
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– adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute
lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
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– adult patients with relapsed or refractory Ph+ ALL as monotherapy.
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– adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
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– adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFR rearrangement.
The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.
Imatinib Pensa is indicated for
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– the treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
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– the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
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– the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.
In adult and paediatric patients, the effectiveness of Imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with Imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.”
Very common adverse events include neutropenia, thrombocytopenia, anaemia, nausea, diarrhea, vomiting, dyspepsia, dermatitis/eczema/rash, arthralgia and fluid retention and oedema.
Imatinib is well absorbed after oral administration (mean absolute bioavailability for imatinib is 98%) with Cmax achieved within 2–4 hours post-dose. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. Following oral administration in healthy volunteers, the t½ was approximately 18 h. There is a high between-patient variability in plasma imatinib AUC levels after an oral dose. At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95%. The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent.
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II.3 General comments on the submitted dossier
The application concerns a generic application of imatinib. The innovator is Glivec. In this DCP Germany is acting as RMS. The application concerns the following strengths:
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– Imatinib Filmtabletten 100 mg and 400 mg.
This application refers to a product which has been authorised for 10 years in at least one Member state or in the Community: Glivec (100 mg and 400 mg film-coated tablets) by Novartis, registered since November 7th 2001.
The pharmaceutical strengths of Imatinib Pensa have the same qualitative and quantitative composition in active substances and are used at the same dose(s) to treat the same disease(s) as the corresponding reference medicinal product(s) Glivec of the originator.
The application contains an adequate review of published clinical data and the bioequivalence with the reference product Glivec (400 mg film-coated tablets) has been shown for Imatinib Pensa (400 mg film-coated tablets).
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II.4 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.
According the applicant’s statement all clinical studies were performed conform with GCP and GLP standards as required.
III SCIENTIFIC OVERVIEW AND DISCUSSION
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III.1 Quality aspects
Introduction
The chemical-pharmaceutical documentation is of sufficient quality in view of the present European regulatory requirements.
Drug Substance
The active ingredient of Imatinib Pensa 100 mg and 400 mg Filmtabletten is Imatinib mesylate which is monographed in the European Pharmacopoeia.
The synthesis is sufficiently described; all requirements of the ASMF Guideline are fulfilled.
Imatinib mesylate and its identified impurities are sufficiently characterized.
The possible impurity profile of drug substance has been discussed including information about related substances and residual solvents. The specification set is in full compliance with the Ph. Eur. monograph.
The test methods used are described in detail and are conducted according to the Ph. Eur. monograph, where applicable. The validation data provided are in accordance with the requirements of the relevant ICH guidelines. Presented batch analyses (three batches) show high inter-batch consistency and very low purity level.
The information provided on the reference standards is sufficient.
The drug substance is packed in double PE bags as primary packing, placed inside a LLDPE/Al/PET/LLDPE bag and introduced into carton drum. The information about the primary packaging material is sufficient.
The presented stability data comprises three validation batches stored at long term conditions at 25°C over 36 months as well as accelerated storage at 40°C over 6 months. All test results are within the specified limits. The proposed retest period of 48 months can be granted.
The ASMF is acceptable.
Drug Product
The applications for Imatinib Pensa 100 mg and 400 mg film-coated concern generic applications for Imatinib. The drug product relates to two strengths of film-coated tablets, containing Imatinib mesylate in an amount equivalent to 100 mg and 400 mg of Imatinib base.
The qualitative composition of the film-coated tablets of both strengths is the same and the composition is quantitatively proportional.
Imatinib film-coated tablets are packed in aluminium – PVC/PVDC blisters.
The drug products have been developed as generic medicinal products with respect to the originator product Glivec to ensure similarity in qualitative composition as marketed in Europe, manufactured by Novartis Europharm Limited. The development of the product has been sufficiently described, the choice of excipients justified and their functions explained. The excipients are well-known, generally used for this kind of dosage form and of Ph. Eur. quality.
The manufacturing process for the presented medicinal products is considered as a standard process. The various steps of the manufacturing process with indication of the IPC have been described. Three batches
of strengths 100 mg and 400 mg in industrial scale each were produced in accordance with the described manufacturing process. Process validation data of these batches have been provided.
The product specifications cover relevant parameters for this dosage form. They are in accordance with the relevant guidelines.
The applied methods are in accordance with current technical and scientific requirements and have been adequately described.
Validations of the analytical methods have been presented and are in accordance with the requirements of the relevant ICH guidelines. The stability indicating nature of the assay and purity methods are discussed.
Satisfactory batch analyses have been presented. The results presented together with the results obtained from the validation study and stability testing confirms consistency and uniformity of the product and indicates the reproducibility of the manufacturing process for the drug product.
Sufficient information on the reference standards is given.
The packaging material is commonly used for oral preparations and the stability studies demonstrate that the containers do not interact physically or chemically with the drug product.
The conditions used in the stability studies are according to the ICH stability guideline. The drug product control tests and specifications are set adequately. The proposed shelf-life of 30 months can be granted. As the tablets should be stored protected from light and the film coated tablets are stored in transparent blisters the storage condition “Please store protected from light in the cardbox carton” have been added.
Biowaiver
The applicant requested a biowaiver for the lower strength (i.e. 100 mg film-coated tablets).
According to Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1) waiver of an in vivo bioequivalence study for additional strengths were applied because following conditions according to the guideline have met:
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– The pharmaceutical products are manufactured by the same manufacturer and process;
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– The drug input is linear over the therapeutic dose range;
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– The qualitative composition of the different strengths is the same;
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– The ratio between amounts of active substance and excipients is the same;
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– The dissolution profiles are similar under identical conditions for the additional strengths
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III.2 Non clinical aspects
The pharmacodynamic, pharmacokinetic and toxicological properties of imatinib are well known.
As imatinib is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are generally not required. A non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology was provided which was acceptable.
Environmental Risk Assessment (ERA)
Since the applied Imatinib products are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
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III.3 Clinical aspects
Bioequivalence study
To support the application, the applicant has submitted one bioequivalence study (study No. CFA-822).
Methods
Study No. CFA-822 was designed as an open label, 2-period, 2-sequences, cross-over, controlled, block randomized, single dose bioequivalence study on 36 healthy adult male volunteers (aged 18–55) under fed conditions.
The study started July 4th 2013 and ended August 15th 2013.
The study protocol was approved by The National Ethics Committee for Drugs Clinical Trials (on January 21st 2013) and The Medicine Agency (on January 2nd 2013).
The final protocol dated on November 19th 2012.
Final Study report dated September 18th 2013.
The study was performed in compliance with the Helsinki Declaration, ICH-GCP, EC rules concerning human experimentation (91/507/EEC) and Directive 2001/20/EC (confirmed on September 19th 2013 by Anda Neatu, Quality Assurence Responsible).
For reference the medicinal product Glivec (400 mg, film-coated tablets) was selected, for which a marketing authorisation has been granted, and the corresponding dosage of 400 mg as available on the market has been used.
The study medication consisted of one film-coated tablet of Imatinib 400mg (TEST) or one film-coated tablet of Glivec 400 mg (REFERENCE) administered PO with 200 ml of still bottled water at room temperature.
- Test Product: Imatinib, film-coated tablet, 400mg.
- Reference Product: Glivec, film-coated tablet, 400mg, Novartis Pharma GmbH Germany, Batch no.: S0019B; Expiry Date: 2014/12; Country of purchase: Germany.
Healthy male volunteers, non- or ex-smokers, between 18 and 55 years of age, with a body mass index within 18.5 and 30.0 kg/m2, and a minimum weight of 70 kg were included in the study. The absence of hypersensitivity reactions, renal insufficiency, hepatic insufficiency, cardiovascular and severe respiratory diseases, any acute or chronic infectious disease, and the absence of clinically significant deviations from normal hematology, clinical chemistry and urinalysis was required.
In order to account for potential cases of dropouts, a total of 36 healthy male volunteers were enrolled in the study.
All volunteers completed the study.
Thirty (30) minutes after a standardized high-fat, high-calorie breakfast a single oral dose of the medicinal product (TEST or REFERENCE, as per Treatment Randomization Table) was administered.
The identification and quantification of Imatinib in plasma was performed by a Liquid Chromatography/Mass Spectrometry (HPLC/MS/MS) method.
Parameters considered for bioequivalence assessment
For the parameters considered for bioequivalence assessment (AUC0-t and Cmax) a confidence interval of 90% for the ratio of the population geometric least square means (TEST/REFERENCE) has been chosen.
These pharmacokinetic parameters were analyzed using ANOVA, after the data had been transformed (ln-transformation).
To demonstrate bioequivalence the 90% confidence interval of the mean (TEST/REFERENCE) ratios obtained for AUC0-t and Cmax primary parameters (ln-transformed data) must lay within an acceptance interval of 80.00–125.00%.
Results
Table 1: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD,
tmax mean ± SD)
| Treatment | AUC 0-t xg/ml/h | AUC 0-∞ xg/ml/h | C max xg/ml | t max h |
| Test | 25026.183±8294.373 | 25781.371±8590.614 | 1498.251±421.439 | 3.368±1.315 |
| Reference | 26983.618±9398.760 | 27673.971±9783.741 | 1613.096±513.127 | 3.061±1.187 |
| Ratio (90% CI) | 89.040–96.691 | 89.427– 97.137 | 88.674–98.129 |
AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h can be
reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products
AUC0-∞ Area under the plasma concentration curve extrapolated to infinite time.
AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t
Cmax Maximum plasma concentration
tmax Time until Cmax is reached
*ln-transformed values
The 90% confidence interval of the mean extrapolation for AUC0–1 and Cmax were within the requested range to show bioequivalence.
Only four adverse events (of mild intensity) occurred in four volunteers. One volunteer completely recovered before the end of the study. Three volunteers had laboratory parameters (CPK increased in two subjects, WBC increased in one subject) outside the normal range at follow up. Since these three subjects did not return for repetition of these parameters, high laboratory values were considered as adverse events with unknown outcome. The clinical investigator considered the laboratory values outside the normal range found at screening of no clinical relevance. No death or serious adverse events have been reported.
Pharmacokinetic conclusion on BE study CFA-822
Bioequivalence between the test and reference products (Imatinib, film-coated tablet, 400mg versus Glivec, film-coated tablet, 400mg) seems to be demonstrated in accordance with the recommendation given in the GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr) regarding the mean ratios of the 90%CI for AUC0-t and Cmax in the submitted bioequivalence study CFA-822 after a standardized high-fat, high-calorie meal.
The results of study CFA-822 with 400 mg formulation can be extrapolated to the other strength 100 mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr, section 4.1.6.
The justification for BCS (Biopharmaceutics Classification System) – based strength biowaiver can be accepted.
Pharmacovigilance system (DDPS)
The RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.
Risk Management Plan
The MAH proposed the following updated summary of safety concerns:
| Important identified risks | Myelosuppression Oedema and fluid Retention Cerebral and gastrointestinal haemorrhage Gastrointestinal obstruction, perforation or ulceration Hepatotoxicity Skin Rashes and Severe Cutaneous Adverse Reactions (SCARs) Hypothyroidism Hypophosphatemia Cardiac Failure Renal Failure Acute respiratory failure/pulmonary hypertension/pulmonary fibrosis Rhabdomyolysis and Myopathy Ovarian haemorrhage and haemorrhagic ovarian cyst Tumour Iysis syndrome Growth retardation in children |
| Important potential risks | Treatment-related secondary malignancies Disseminated intravascular coagulation Hypoglycaemia Suicidality Tolerability during pregnancy and pregnancy outcomes |
| Missing information | Long-term follow-up in paediatric patients Paediatric patients below 2 years of age Patients with renal impairment Patients with hepatic impairment Elderly patients |
| Important identified interactions | Concomitant strong CYP3A4 inhibitors Concomitant strong CYP3A4 inducers Concomitant drugs eliminated by CYP3A4 |
| Important potential interactions | Concomitant drugs eliminated by CYP2C9, CYP2C19 and CYP2D6 Concomitant acetaminophen/paracetamol (no dosage adjustments required) |
The corrected RMP is now approvable.
Periodic Safety Update Report (PSUR)
PSURs should 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.
Common renewal date
The common renewal date of 5 years after the finalisation of the procedure is endorsed.
Legal status
Medicinal product subject to medical prescription.
User Test
According to the “consultation summary outcome report” provided by the applicant, the user test took place in Stockholm (Sweden) and was performed in a Swedish target test population using a Swedish package leaflet. Unfortunately, it is neither possible to assess whether the Swedish package leaflet (attached to the a.m. report) reflects the applicant’s package leaflet nor whether the results given in the “consultation summary outcome report” really reflect the outcome of the user test. Therefore, the “user test” is not assessable.
However, the RMS wants to point out, that the package leaflets provided by the applicant is in line with the originator’s modified package leaflets for generic application and a readability test is therefore not essentially necessary.
IV BENEFIT RISK ASSESSMENT
From the quality point of view, the application now contains sufficient data on quality aspects and also regarding the drug substance in the ASMF.
The application contains an adequate review of published non clinical and clinical data.
Bioequivalence with respect to the applied 400 mg formulation was shown in the bioequivalence trial CFA-822 with the reference drug Glivec.
The justification given for a BCS (Biopharmaceutics Classification System) – based strength biowaiver for the applied 100 mg formulation is also acceptable.
In conclusion, as all issues raised during the procedure have been sufficiently resolved, the risk/benefit for the applied products is positive. Approval can be recommended from the quality, non-clinical and clinical point of view.
The application is approved. For intermediate amendments see current product information.
Imatinib Pensa 100 mg, 400 mg Filmtabletten
DE/H/4262/01–02/DC
Public Assessment Report
11/11