Public Assessment Report

Scientific discussion

Montek

Radionuclide generator, 10-40 GBq

Sodium (99Mo) molybdate/sodium pertechnetate (99mTc)

DK/H/1741/001/DC

Date: 17 June 2013

This module reflects the scientific discussion for the approval of Montek. The procedure was finalised on 13 April 2011. For information on changes after this date please refer to the module ‘Update’.

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Montek radionuclide generator, 10-40 GBq, from Monrol Europe S.R.L.

The eluate from the generator (sodium pertechnetate (99mTc) injection Ph. Eur.), may be used as a reagent for labelling of various carrier compounds supplied as kits or administered directly in-vivo.

When administered intravenously, the sterile sodium (99mTc) pertechnetate solution is used as a diagnostic aid in the following:  Thyroid scintigraphy: Direct imaging and measurement of thyroid uptake to give information on the size, position, nodularity and function of the gland in thyroid disease.  Salivary gland scintigraphy: To assess salivary gland function and duct patency.  Location of ectopic gastric mucosa: Meckel’s diverticulum.  Cerebral scintigraphy: To identify breaches in the blood-brain barrier caused by tumour, infarction, haemorrhage and oedema, when no other methods are available. Following instillation of sterile sodium pertechnetate (99mTc) solution into the eye, the product may be used for Lacrimal duct scintigraphy to assess patency of tear ducts.

A comprehensive description of the indications and posology is given in the SmPC.

This decentralised procedure concerns a generic application claiming essential similarity with the reference product Drytec which has been registered in Denmark by GE Healthcare Limited since 1995.

The marketing authorisation has been granted pursuant to Article 10.3 of Directive 2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

The mother nuclide is sodium (99Mo) molybdate 10-40 GBq/generator (no carrier added) at the activity reference date. The daughter nuclide is sodium (99mTc) pertechnetate 8.3-33.9 GBq.

The quantity of sodium pertechnetate (99mTc) injection, Ph. Eur. that may be eluted from the generator at any one time is dependent on the quantity of sodium (99Mo) molybdate present, the volume of eluate obtained and the elapsed time since the previous elution.

Technetium-99m is produced by means of a (99Mo/99mTc) generator and decays with the emission of gamma radiation with a mean energy of 140 keV and a half-life of 6 hours to 99mTc which, in view of its long half-life of 2.13 x 105 years can be regarded as quasi stable.

The radionuclide generator is a blue colour plastic covered cylindrical body and closure, attached to the body with 2 clamps, with a holder on top.

The radionuclide generator is supplied in a type I, colourless, natural glass column with bromobutyl rubber stopper and aluminium cap. The evacuated vial is a 20 ml colourless, type I natural glass vial with bromobutyl rubber stopper and aluminium cap. The sodium chloride 9 mg/ml (0.9%) solution for injection is supplied in colourless, 20 ml, type I natural glass vials and bromobutyl rubber stoppers with aluminium caps.

The outer container consists of a tin bucket with the aid of styrofoam filling material and contains: Radionuclide generator: Lead shield in plastic outer container. Evacuated vial: Cardboard box Sodium chloride 9 mg/ml (0.9%) solution for injection of 5 ml, 10 ml: Cardboard box.

The sodium chloride 9 mg/ml (0.9%) solution for injection eluent is available in 2 different volumes giving elution volumes of 5 ml and 10 ml to allow the generator eluate to be collected at varying radioactive concentrations. Packs of 5 vials containing 5 ml and 5 vials containing 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

Packs of 10 vials containing 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 10 vials containing 10 ml sodium chloride 9 mg/ml (0.9%) solution for injection are available for custom order. Vials are packed in 5 vial cartons. Evacuated elution vials are available in packs of 10 vials. Vials are packed in 5 vial cartons. However, not all pack sizes may be available.

The excipients are: Aluminium oxide; Molybdenum trioxide; Sodium hydroxide; Hydrogen peroxide 30%; Sodium hydroxide 1 M (pH adjustment); Hydrochloric acid 4 M (pH adjustment); Hydrochloric acid 1 M (pH adjustment); Sodium chloride 9 mg/ml (0.9%) solution for injection and Water for injections.

Compliance wih Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation.

II.2 Drug Substance

The generator contains sodium molybdate (99Mo) sourced from two suppliers. The documentation from the two suppliers is presented as European Drug Master Files (EDMF) in CTD format. In both cases the molybdenum (99Mo) is extracted from fission products of uranium. Since the filing of the two DMFs an EP monograph on sodium molybdate (99Mo) solution (fission) has been published.

On the basis of the current drug master files and the documentation submitted during the procedure sodium molybdate (99Mo) complies with the Ph.Eur. monograph 01/2008:1923, sodium molybdate 99Mo solution (fission).

The manufacture and control of the drug substances are in accordance with guidelines and described adequately. Stability studies have been performed with the drug substances. No significant changes in any parameters were observed. Appropriate retest periods have been set.

II.3 Medicinal Product

The product is a sodium molybdate (99Mo)/sodium pertechnetate (99mTc) generator, under the trade name Montek radionuclide generator, 10-40 GBq; the daughter nuclide in the form of sodium pertechnetate (99mTc) is obtained from molybdenum extracted from fission products of uranium.

The documentation provided complies with relevant EU guidelines and directives. Manufacture is performed in accordance with cGMP and specifications for sodium pertechnetate (99mTc) injection eluated from Montek (99Mo) generator comply with Ph.Eur. monograph 01/2008:0124, sodium pertechnetate (99mTc) injection (fission). Sodium chloride 9 mg/ml (0.9%) solution for injection is controlled adequately in accordance with Ph.Eur. methods.

The following shelf-lives and storage conditions have been set:

Montek generator: 21 days from the date of manufacture. Store the generator below 25°C in the original package. Do not freeze. Eluate: 8 hours from elution. Store the eluate, sodium pertechnetate (99mTc) injection below 25°C in the original package. Do not freeze. Evacuated vials: 12 months without storage conditions. Sodium chloride 9 mg/ml (0.9%) solution for injection: 12 months.

III. NON-CLINICAL ASPECTS

This product is a generic formulation of Drytec, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application.

Overview based on literature review is, thus, appropriate. The non-clinical overview on the pre- clinical pharmacology, pharmacokinetics and toxicology is adequate.

IV. CLINICAL ASPECTS

This product is a generic formulation of Drytec, which is available on the European market. No new clinical data have been submitted, and therefore the application has not undergone clinical assessment. This is acceptable for this type of application.

The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

IV.1 Risk management plan & Pharmacovigilance system

99Mo/99mTc (Tc generator) was first approved in 1983, and there is now more than 10 years post- authorisation experience with the use of 99Mo/99mTc (Tc generator). The safety profile of 99Mo/99mTc can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation.

The Pharmacovigilance system described 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 identification and notification of any a potential risks occurring either in the Community or in a third country.

V. PRODUCT INFORMATION

SmPC and Package leaflet The content of the SmPC and package leaflet approved during the decentralised procedure is in accordance with the EU Core Safety Profile for technetium.

User consultation The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The test consisted of: A pilot test with 3 participants, followed by one round with 17 participants.

The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Montek radionuclide generator, 10-40 GBq has a proven chemical-pharmaceutical quality and is a generic form of Drytec. Drytec is a well-known medicinal product with an established favourable efficacy and safety profile.

The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations.

The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with the EU Core Safety Profile for technetium.

Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Montek with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 13 April 2011. Montek was authorised in Denmark on 27 September 2011.

A European harmonised birth date has been allocated (1983-06-01) and subsequently the next data lock point is 2012-05, after which the PSUR submission cycle is 3 years.

The date for the first renewal will be: 13 April 2016.

The following post-approval commitments have been made during the procedure:

 MAH commits not to bring the finished medicinal product onto the market before Riso DTU National Laboratory for Sustainable Energy gets authorisation which assures the capability of Riso DTU National Laboratory for Sustainable Energy towards testing on the impurities 89Sr, 90Sr, other gamma emitting impurities and alpha emitting impurities.

 MAH commits to submit to the RMS and the CMSs the GMP certificate of the contract laboratory Risø DTU National Laboratory for Sustainable Energy when issued.

 MAH commits to provide information on the reference standards 89Sr, 90Sr and 90Y which are used for the determination of the radionuclidic impurities 89Sr and 90Sr, not later than one month after end of procedure.

 MAH commits to submit to the RMS Certificates of Analysis of the 3 first production batches, issued by the EU batch releaser Institute of Isotopes Co. Ltd., Hungary.

 For sodium chloride 9 mg/ml (0.9%) solution for injection: Since the stability studies were performed on one production batch of 10 mL volume and one production batch of 5 mL volume MAH commits to place additional batches to a total three production batches of each volume and to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months according to the ICH guidelines. For these additional stability studies the identical stability protocol will be used and stability study results will be provided whenever available.

Furthermore, MAH commits that in the case of any out-of-specification event in the stability studies the authorities will be informed in time.