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PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Gadothek

Procedure Number: DE/H/3378/001/DC

Gadopent

Procedure Number: DE/H/3379/0001/DC

Gadomed

Procedure Number: DE/H/3380/001/DC

Gadopur

Procedure Number: DE/H/3441/001/DC

Gadosan

Procedure Number: DE/H/3442/001/DC

Gadolan

Procedure Number: DE/H/3443/001/DC

Active Substance:

Gadopentetate Dimeglumine

Dosage Form:

Solution for injection / 0.5 mmol/ml

Marketing Authorisation Holder in the RMS, Germany:

medithek GmbH

Publication:

10.12.2021

This module reflects the scientific discussion for the approval of Gadothek; Gaodpent; Gadomed; Gadopur; Gadosan; Gadolan. The procedure was finalised on 23.01.2013.

TABLE OF CONTENTS

• I. INTRODUCTION.­.............­.............­.............­.............­.............. Fehler! Textmarke nicht definiert.

ADMINISTRATIVE INFORMATION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for the a.m. generics of gadopentetate dimeglumine, a paramagnetic contrast agent for magnetic resonance imaging, indicated for

Cranial and spinal magnetic resonance imaging (MRI) and whole body MRI.

is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

This Decentralised Procedure application concerns a generic version of gadopentetate dimeglumine, under the several different trade names as mentioned above.

The originator product is Magnevist® 0,5 mmol/ml, Solution for injection by Bayer Vital GmbH, registered in Germany since 5th February 1988.

With Germany as Reference Member State in this Decentralised Procedure, medithek GmbH applied for the Marketing Authorisations for gadopentetate dimeglumine in DE and LU.

• II.2 About the product

Gadopentetate dimeglumine is a paramagnetic contrast agent for magnetic resonance imaging. The Contrast enhancing effect is mediated by the di-N-methylglucamine salt of gadopentetate – the gadolinium complex of pentetic acid (diethylene triamine pentaacetic acid = DTPA). When a suitable scanning sequence (e.g. T1-weighted spin-echo technique) is used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

The compound is used as a paramagnetic contrast medium in cranial, spinal and whole body magnetic resonance imaging (MRI) and for magnetic resonance angiography and its use for these indication is well-established.

The adverse effects associated with the use of gadopentetate dimeglimine are well known and they are usually mild and transient. As with other comparable contrast media serious, life-threatening and fatal adverse effects have nevertheless been reported.

The originator product is marketed in numerous European countries and has been proved to be safe and effective for 18 years.

• II.3 General comments on the submitted dossier

The clinical overview was sufficiently amended according to RMSs proposals.

The active substance is not considered a new active substance.

• II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

GCP

Due to their rather old publication date some of the studies referred to in the Clinical Overview were not performed according to good clinical practice (GCP). However, the quality of the clinical trials corresponds to those of other drugs evaluated in the same time period. Additional studies conducted according to GCP would not provide further information and are not planned by the applicant.

GMP

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.

For company Baccinex S.A. (Switzerland) – as a subcontractor for cleaning of empty vials/bottles prior to filling – the applicant has submitted a new GMP certificate of the Swiss authorities.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

• I II.1 Quality aspects

Drug substance

The chemical-pharmaceutical documentation and Expert Report in relation to the medicinal products are of sufficient quality in view of the present European regulatory requirements.

The active substance gadopentetate dimeglumine is not isolated but formed ‘in-situ’ during the manufacture of the drug product (solution for injection).

The impurity profile is determined by the quality of the three starting materials gadolinium (III) oxide, pentetic acid and meglumine.

For meglumine an EDQM certificate of suitability has been provided.

The proposed retest periods of gadolinium (III) oxide, pentetic acid (DTPA) and of meglumine are justified.

Drug Product

The drug products are solutions for injection containing the active substance gadopentetate dimeglumine with a strength of 0.5 mmol (gadolinium)/ml.

The development of the product has been described, the choice of excipients is justified and their functions is explained. The presented formulation is an aqueous solution for injection containing meglumine for adjustment to pH 7.0 – 8.0 and an appropriate amount of free pentetic acid to ensure complexation of gadolinium ions.

The description of the analytical methods used to analyse the drug products are adequate, the validation results are plausible.

The claimed shelf life of 36 months is acceptable.

All questions regarding the drug substance and the drug products have been solved.

• I II.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of Gadopentetate dimeglumine are well known. As Gadopentetate dimeglumine is a widely used, well-known active substance, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate.

The nonclinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

• I II.3 Clinical aspects

Pharmacokinetics

Pharmacokinetic properties of gadopentetate dimeglumine are well known. As gadopentetate dimeglumine is a widely used, well-known active substance, no further pharmacokinetic studies are required

Pharmacodynamics

Pharmacodynamic properties of gadopentetate dimeglumine are well known. As gadopentetate dimeglumine is a widely used, well-known active substance, no further Pharmacodynamic studies are required and the applicant provides none.

Clinical efficacy

Gadopentetate dimeglumine may be the best studied extracellular gadolinium containing contrast agent, as the efficacy of the compound has been demonstrated in numerous clinical studies.

The applicant now claims the indications proposed by the RMS:.

Gadothek; Gaodpent; Gadomed; Gadopur; Gadosan; Gadolan is a contrast medium for cranial and spinal magnetic resonance imaging (MRI).

Gadothek; Gaodpent; Gadomed; Gadopur; Gadosan; Gadolan is also indicated for whole body MRI including head and neck region, thoracic space including the heart, female breast, abdomen (pancreas and liver), retroperitoneal space (kidney), pelvis (prostate, bladder and uterus) and musculoskeletal system by intravenous administration.

Gadopentetate dimeglumine facilitates visualisation of abnormal structures or lesions and helps in the differentiation between healthy and pathological tissue.

Gadopentetate dimeglumine can also be used in MR angiography (except for coronary arteries) for the assessment of stenoses, occlusions and collaterals.

Specific applications in the heart include measurement of myocardial perfusion under pharmacological stress conditions and viability diagnostics („delayed enhancement“).

The clinical overview was amended concerning presentation of the efficacy studies and discussion of clinical usefulness of the compound in general. Concerning clinical usefulness, the RMS has given the following hints: (a) in many instances patients undergo some other diagnostic procedures prior to contrast enhanced MRI, e.g. ultrasound of the target body region or contrast enhanced CT, but increasingly contrast enhanced MRI with extracellular Gd-contrast agents is also performed as the primary imaging modality1, 2. (b) Contrast enhanced MRI is considered to be state-of-the-art imaging for the assessment of parenchymal disease e.g. in liver and kidneys3, 4, 5. © The use of Gd-based contrast agents is considered to be standard in the clinical setting, because both detection and classification of lesions are known to be improved by administration of extracellular contrast agents6, 7.

SPC and PIL

The SPC and PIL were amended according to the RMSs proposal.

• 1 Reiser M, Semmler W. Magnetresonan­ztomographie. Springer Verlag, Berlin – Heidelberg (2002): pp. 678 ff.

• 2 Reimer P et al. Clinical MR Imaging – A Practical Approach. Spinger Verlag Berlin – Heidelberg – New York (2003): pp. 272 ff.

• 3 Reimer P, Parizel PM, Stichnoth FA (Eds.). Clinical MR Imaging. A Practical Approach. Berlin: Springer; 2003 (2nd edition): Preface

• 4 Semelka R, Helmberger KG. Contrast Agents for MR Imaging of the Liver. Radiology (2001); 218:27–38

• 5 Krestin GP. Kidneys and adrenal glands. In: Magnevist Monograph. Edited by Felix R, Heshiki A, Hricak H, Chang KH. Berlin: Blackwell Science; 2001 (4th edition); 147–153

• 6 Reiser M, Semmler W. Magnetresonan­ztomographie. Berlin, Heidelberg: Springer; 2002: 2.7 Kontrastmittel (pp 111 – 132)

• 7 Krestin GP. Kidneys and adrenal glands. In: Magnevist Monograph. Edited by Felix R, Heshiki A, Hricak H, Chang KH.

Berlin: Blackwell Science; 2001 (4th edition); 147–153

The MAH has commited himself to amend his SmPC/PL in case an European Core SPC will be available.

Clinical safety

No post-marketing data is available as the applicant has not marketed the product elsewhere.

The section Undesirable effects of the SPC was checked by the RMS under consideration of the PSURs of the originator.

Gd-DTPA dimeglumine has an excellent and well-established safety profile after i.v. injection, irrespective of age. Bolus injections, high dosage or repeated Gd-DTPA-enhanced MRI studies showed no increased safety risk. The overall incidence of AEs – irrespective of their drug relationship – after i.v. administration of 0.1 or 0.2 mmol Gd-DTPA/kg of body weight was found to be approximately 12%.

Adverse events (AEs) with the administration of Gd-DTPA include nausea, emesis, headache and local injections site symptoms as irritation or focal burning.

Particular attention should be given to patients with a history of allergy or asthma and especially with previous reaction to MRI contrast agents. Very rarely anaphylactoid reactions, including anaphylactic shock, may occur after i.v. administration of Gd-DTPA dimeglumine. Vary rarely, seizures have been reported after the administration of Gd-DTPA dimeglumine.

During the last years evidence has been growing for a causal association between the development of nephrogenic systemic fibrosis (NSF) and exposure to gadolinium containing contrast agents used for MRA in patients with severe renal impairment. NSF was first diagnosed in 1997. It is an acquired, idiopathic disorder that is observed in patients with renal failure. Most patients with NSF have undergone dialysis for renal failure. Among other triggers an association of NSF with coagulation abnormalities, recent vascular surgery or presence of antiphospholipid antibodies has been discussed so far. Nevertheless the origin of NSF is still unknown. The clinical picture imposes with thickening and induration of the skin with a possible involvement of the other organs (e.g. lungs, liver,muscles and the heart). Diagnosis is confirmed in a skin biopsy by certain specific histopathologic features. Most of these cases were associated with the use of gadodiamide (Omniscan®) but NSF cases have also been reported with the use of Gd-DTPA. The patients developed NSF within 3 months (range 2 weeks to 3 months) after having received the gadolinium-containing contrast agent.

All amendments proposed by the CHMP pharmacovigilance working party were implemented in the SPC proposed by the RMS for this procedure.

Pharmacovigilance system

The applicant has submitted a signed Summary of the Applicant’s Phar­macovigilance System and asked the RMS to replace the previously submitted DDPS with the new Summary of the applicant’s phar­macovigilance system. Provided that the corresponding Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation (EU) No 520/2012 and as detailed in the GVP module II, the RMS accepts this substitution.

Risk Management Plan

not required

Periodic Safety Update Report (PSUR)

The applicant has not requested a different PSUR cycle upon approval. The PSUR submission scheme will follow Volume 9A of The Rules Governing Medicinal Products in the European Union starting with 6-monthly PSUR. The RMS considers the submission of 6-monthly PSURs not necessary and recommends PSUR submissions to be aligned with the EU Harmonised Birthday and related Data Lock Points as published on the HMA website or and recommends submission of 3 yearly PSURs.

Common renewal date:

A proposed common renewal date of 5 years after finalisation of the procedure was accepted.

User Test

The results demonstrate a high level of comprehension of product related information. A further modification and following study round was not necessary.

Legal Status

Medicinal product subject to medical prescription.

• IV. BENEFIT RISK ASSESSMENT