Decentralised Procedure. Public Assessment Report. Gadojaco Handvist Gadopentetat Dimeglumin Jacobsen 500 Mikromol/ml Injektionslösung

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Gadojaco Handvist Gadopentetat Dimeglumin Jacobsen 500 Mikromol/ml Injektionslösung Gadopentetate dimeglumine DE/H/1678/001/DC DE/H/1679/001/DC DE/H/1680/001/DC Applicant: Jacobsen Pharma AS Nørre Havnegade Sønderborg Denmark Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

2 TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..4 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Nonclinical aspects... 5 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT /7 Public AR

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number for the Decentralised Procedure 1. Gadojaco 2. Handvist 3. Gadopentetat Dimeglumin Jacobsen 500 Mikromol/ml Injektionslösung Gadopentetate dimeglumine V08C A01 Solution for injection, 500 micromole/ml [0,5 mmol/ml] DE/H/1678/001/DC DE/H/1679/001/DC DE/H/1680/001/DC Reference Member State: Member States concerned: Applicant (name and address) Germany (DE) AT, CZ, ES, HU, IT, NL, PL, PT, SE, NO, FI, DK, UK Jacobsen Pharma AS Nørre Havnegade 108 DK-6400 Sønderborg Denmark Names and addresses of manufacturers responsible for batch release in the EEA Helm Pharmaceuticals GmbH Nordkanalstr. 28 D Hamburg Germany 3/7 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Gadopentetat Dimeglumin (various names) a paramagnetic contrast agent for magnetic resonance imaging is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This Decentralised Procedure application concerns a generic version of gadopentetate dimeglumine, under the trade names Gadojaco It is an abridged marketing authorisation application under Article 10(1) of Directive 2001/83/EC claiming that the product is essentially similar to Magnevist mg/ml (Bayer Schering). The originator product is Magnevist (469 mg/ml, Solution for injection) by Schering, registered in Germany since 5 th February With Germany as Reference Member State in this Decentralised Procedure, Jacobsen Pharma and Bowmed are applying for the Marketing Authorisations in AT, CZ, ES, HU, IT, NL, PL, PT, SE, NO, FI, DK. 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 indications is well-established. The adverse effects associated with the use of gadopentetate dimeglumine 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 SPC is considered adequate. The originator product is marketed in numerous European countries and has been proven to be safe and effective for 20 years. II.3 General comments on the submitted dossier The clinical overview is considered to be acceptable. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 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. 4/7 Public AR

5 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. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance 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 oxide, pentetic acid and meglumine. All starting materials and the manufacture are adequately described. 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 presented formulation is an aqueous solution for injection containing meglumine for adjustment to ph and an appropriate amount of free pentetic acid to ensure complexation of gadolinium ions. Pentetic acid also serves as buffer and UV-stabiliser. Due to the high content of active ingredient (469.0 mg/ml) and other excipients the formulation represents a hyper-osmotic product ( Osm/kg H 2 O). The description of the analytical methods used to analyse the drug products are adequate, the validation results are plausible. A shelf life of 36 months is acceptable. III.2 Nonclinical aspects Pharmacology Gadopentetate dimeglumine is pharmacologically inert and has no known pharmacological effects in vitro and in vivo. When placed in a magnetic field, gadopentetate dimeglumine shortens the T1and T2 relaxation times in tissues where it accumulates. Pharmacokinetics The pharmacokinetics of gadopentetate dimeglumine were widely investigated in preclinical studies. Data obtained from studies in mice, rats and rabbits show rapid renal clearance and no dissociation or retention of the complex in the body. Toxicology Pre-clinical data reveal no special hazards for humans based on conventional studies of single dose toxicity, repeated dose toxicity and genotoxicity. However, developmental retardation was observed after repeated administration of gadopentetate dimeglumine in pregnant rabbits. Therefore and because no adequate data in pregnant women are available gadopentetate dimeglumine should be administered during pregnancy only after a careful benefit-risk consideration. Discussion on the non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of gadopentetate dimeglumine are well known. This product has been shown to be essentially similar and refer to a product approved in many countries. No new preclinical data have been submitted or are considered necessary. 5/7 Public AR

6 Reference is made to the SPC (section 4.6 and 5.3) where all the current knowledge of gadopentetate dimeglumine is well described. III.3 Clinical aspects Pharmacokinetics The 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. Bioequivalence: as Gadopentetat Dimeglumin and Magnevist are essentially similar from a quality point of view and the product is given i.v., no formal bioequivalence studies are required. Pharmacodynamics The 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 The clinical indications of Gadopentetat Dimeglumin are in line with those of the originator Magnevist and have been sufficiently documented in the clinical overview. Clinical safety No post-marketing data is available from the applicant as the applicant has not marketed the product anywhere. In clinical studies adverse events (AEs), irrespective of their drug relationship, were observed in approximately 1-2% of the patients who received 0.1 or 0.2 mmol/kg gadopentetate dimeglumine. Some studies reported higher incidence rates of adverse events which might be due to different reporting methods adopted for different studies. Common adverse events are headache, dizziness and nausea; most adverse events are mild and transient. There was no correlation between patient age and the incidence of AEs. In patients with a known history of allergy the incidence of AEs increased slightly. In pediatric use no added risk was observed. Gadopentetate dimeglumine showed good renal tolerance in patients with and without preexisting impairment of renal function. Gadopentetate dimeglumine can be considered at least as safe as non-ionic X-ray contrast media. Caution is warranted in patients with a history of asthma or allergies, especially if allergic reaction occurred to a contrast agent. However, the literature reviewed suggests that the risk of a lifethreatening anaphylactoid reaction to gadopentetate dimeglumine is remote. Post-marketing surveillance data supported the good safety profile after i.v. administration of diagnostic doses to patients of all age groups, irrespective of the injection speed and pre-existing renal impairment. Bolus injections, high dosage or repeated Gd-DTPA-enhanced MRI studies showed no increased safety risk. Pharmacovigilance system 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 Not applicable 6/7 Public AR

7 IV. BENEFIT RISK ASSESSMENT Based on the review of the submitted data Gadopentetat Dimeglumin is essentially similar to the orginator Magnevist, and the benefit/risk-ratio is positive. The application is approved. 7/7 Public AR