Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

TABLE OF CONTENTS

ADMINISTRATIVE INFORMATION

Name of the medicinal product in the RMS:	Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung
Name of the drug substance (INN name):	Vecuronium bromide
Pharmaco-therapeutic group (ATC Code):	M03AC03
Pharmaceutical form(s) and strength(s):	Powder for solution for injection; # 10 mg/vial
Reference Number(s) for the Decentralised Procedure:	DE/H/6024/001/DC (former UK/H/5693/001/DC)
Reference Member State:	DE (former UK)
Concerned Member States:	PT
Applicant (name and address):	BRADEX S.A., Pharmaceutical Products 27 Asklipiou str. 14568 Krioneri, Attiki Greece

• I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung (PL 43946/0002; UK/H/5693/001/DC) could be approved. The product is a prescription-only medicine (POM) and is indicated as an adjunct to general anaesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery in adults, neonates, infants, children and adolescents.

The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Germany and Portugal as Concerned Member States (CMS). The application was submitted under Article 10.1 of Directive 2001/83/EC, as amended, as a generic application. The reference medicinal product for this application is Norcuron 10 mg, powder for solution for injection (PL 05003/0044; N. V Organon, The Netherlands) which has been registered in the UK since 04 October 1991.

Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung (vecuronium bromide) is a non-depolarising neuromuscular blocking agent, chemically designated as the aminosteroid 1-(3α, 17β-diacetoxy-2β piperidino-5α -androstan-16β-yl)- 1 methylpiperi­dinium bromide. Vecuronium bromide blocks the transmission process between the motor nerve-ending and striated muscle by binding competitively with acetylcholine to the nicotinic receptors located in the motor endplate region of striated muscle.

Unlike depolarising neuromuscular blocking agents, such as suxamethonium, vecuronium bromide does not cause muscle fasciculations. Within the clinical dosage range, vecuronium does not block the sympathetic nicotinic receptors, and thus exerts no ganglion blocking activity. In addition, in this dose range vecuronium does not block the parasympathetic muscarinic receptors, and thus exerts no vagolytic activity.

No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been licensed for over 10 years. No new clinical data have been submitted and none are required for applications of this type. A bioequivalence study was not necessary to support this application as both test and reference products are aqueous intravenous solutions at the time of administration.

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release 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 ce1tification that acceptable standards of GMP are in place at those sites.

The RMS and CMS considered that the application could be approved at the end of procedure (Day 209) on 06 January 2016. After a. subsequent national phase, a licence was granted in the UK on 03 February 2016.

After changing the RMS, Germany is the new RMS. The former procedure number was UK/H/5693/001/DC.

• II. QUALITY ASPECTS

  • II.1 Introduction

One vial contains 10 mg vecuronium bromide (as a freeze dried powder), which on reconstitution as recommended in 5ml of water for injections corresponds to 2 mg vecuronium bromide per ml. Other ingredients consist of the pharmaceutical excipients citric acid monohydrate, disodium phosphate dihydrate, mannitol, sodium hydroxide (for pH correction) and phosphoric acid (for pH correction). The finished product is packed into clear, colourless glass (Type D vials closed with a rubber closure and sealed with an aluminium cap and is available in pack sizes of 1, 10, 20, 20 (2×10) and 100 vials. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components.

Vecuronium bromide

Piperidinium, 1-[(2β, 3α, 5α, 16β, 17β)-3,17– bis(acetyloxy) –2-(1 –

piperidinyl) androstan-16– yl] –1-methyl-bromide

C34H57BrN2O4

637.75

White or cream white crystals or a crystalline powder.

Freely soluble in alcohol and chloroform, slightly soluble in acetone, forms a gel with water which at 1% concentration is fluid.

Vecuronium bromide is the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate inprocess controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the active substance. All potential known impurities have been identified and characterised. Satisfactory certificates of analysis have been provided for all working standards. Batch analysis data are provided that comply with the proposed specification. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging.

• II.3 Medicinal product

Pharmaceutical Development

The objective of the development programme was to formulate a safe, efficacious, powder for solution for injection containing 10 mg vecuronium bromide (as a freeze dried powder) which on reconstitution in 5ml of water for injections (as recommended) corresponds to 2 mg vecuronium bromide per ml, that was comparable to the originator product Norcuron 10 mg, powder for solution for injection (N. V Organon, The Netherlands). A satisfactory account of the pharmaceutical development has been provided.

All excipients comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. None of the excipients contains materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product.

Manufacture of the product

A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial-scale batch size and shown satisfactory results.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years for the unopened vial with no special storage conditions.

Chemical and physical in-use (i.e. following reconstitution) stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. Do not use Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung when the solution after reconstitution contains particles or is not clear. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product.

• II.4 Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of this application from a pharmaceutical viewpoint.

• III. NON-CLINICAL ASPECTS

  • III.1 Introduc­tion

As the pharmacodynamic, pharmacokinetic and toxicological properties of vecuronium bromide are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The Applicant's non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology.

• III.2 Pharmaco­logy

Not applicable for this product type. Refer to section ' III.1; Introduction' detailed above.

• III.3 Pharmaco­kinetics

Not applicable for this product type. Refer to section ' III.1; Introduction' detailed above.

• III.4 Toxicology

Not applicable for this product type. Refer to section ' III.1; Introduction' detailed above.

• III.5 Environ­mental Risk Assessment (ERA)

Since Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

• III.6 Discussion on the non-clinical aspects

No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been licensed for over 10 years. There are no objections to the approval of this application from a non-clinical viewpoint.

• IV. CLINICAL ASPECTS

• IV. 1 Introduction

The Applicant has provided a justification for not submitting new clinical data. The proposed product is intended for intravenous administration. It contains the same active substance as the reference product. According to the current ‚Guideline on the Investigation of Bioequivalence‘ (CPMP/EWP/QWP/1401/98 Rev. 1/Con), bioequivalence studies are generally not required if the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product. There are no excipient interactions which might affect the pharmacokinetics of the active substance.

No new efficacy or safety studies have been perfom1ed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pha1macology, efficacy and safety of Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung. Based on the data provided, Vecuronium BRADEX

• 10 mg Pulver zur Herstellung einer Injektionslösung can be considered a generic of Norcuron 10 mg, powder for solution for injection (N. V Organon, The Netherlands).

IV.2 Pharmaco­kinetics

In line with the guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Con), the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product. No bioequivalence study has been submitted with this application and none is required.

IV.3 Pharmaco­dynamics

No new pharmacodynamic data were submitted and none were required for an application of this type.

IV.4 Clinical efficacy

No new efficacy data were submitted and none were required for an application of this type.

IV.5 Clinical safety

No new safety data were submitted and none were required for an application of this type.

IV.6 Risk Management Plan

The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), in accordance with the requirements of Directive 2001/83/EC as amended, describing the pha1macovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below.

Summary table of safety concerns:

Summary of safety concerns
Important identified risks	Residual neuromuscular block Hypersensitivity reactions (including anaphylaxis) Prolonged paralysis with long term use of neuromuscular blocking agents in the Intensive Care Unit Myopathy after long term administration of nondepolarizing neuromuscular blocking agents in the Intensive Care Unit in combination with corticosteroid therapy Altered responses in patients with: neuromuscular diseases, including previous poliomyelitis and neuromuscular junction disorders; obesity; burns; hypothermia; electrolyte and metabolic disturbances; prolonged circulation time; dehydration
Important potential risks	Safety in hepatic disease Safety in renal disease Drug interactions
Missing information	Safety in pregnancy and lactation Safety in preterm newborn infants

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

IV.7 Discussion on the clinical aspects

No new clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been licensed for over 10 years. A bioequivalence study was not necessary to support this application as both test and reference products are aqueous intravenous solutions at the time of administration.

The grant of a marketing authorisation is recommended for this application.

V. 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 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

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with vecuronium bromide is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.

The application is approved. For intermediate amendments see current product information.

Vecuronium BRADEX 10 mg Pulver zur Herstellung einer Injektionslösung, DE/H/6024/001/DC

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