Public Assessment Report. Scientific discussion. Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion. (rocuronium bromide)

Transcription

1 Public Assessment Report Scientific discussion Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion (rocuronium bromide) NL/H/2812/001/DC Date: 21 July 2014 This module reflects the scientific discussion for the approval of Rocuroniumbromide Hospira 10 mg/ml. The procedure was finalised on 22 December For information on changes after this date please refer to the module Update. This report includes a summary, on pages 8-10.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion from Hospira Benelux BVBA. The product is indicated in adults and paediatric patients (from term neonates to adolescents 0 to 18 years) as an adjunct to general anaesthesia to facilitate tracheal intubation during routine sequence induction and to provide skeletal muscle relaxation during surgery. In adults, rocuronium bromide is also indicated to facilitate tracheal intubation during rapid sequence induction and as an adjunct in the intensive care unit (ICU) to facilitate intubation and mechanical ventilation for short term use. A comprehensive description of the indications and posology is given in the SmPC. Rocuronium bromide is an intermediate acting non-depolarising neuromuscular blocking agent with a fast onset, possessing all of the characteristic pharmacological actions of this class of medicinal products (curariform). It acts by competing for nicotinic cholinoceptors at the motor end-plate. This action is antagonised by acetylcholinesterase inhibitors. This decentralised procedure concerns a generic application claiming essential similarity with the innovator product Esmeron (NL License RVG 16946) which has been registered in the Netherlands by N.V. Organon since In addition, reference is made to Esmeron authorisations in the individual member states (reference product). The concerned member states (CMS) involved in this procedure were Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Italy, Norway, Poland, Portugal, Slovakia, Spain, Sweden and the United Kingdom. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Rocuroniumbromide Hospira 10 mg/ml is a clear, colorless to yellow or orange solution with ph 3.8 to 4.2 and osmolality between 256 and 312 mosmol/kg. Each ml of solution for injection or infusion contains 10 mg rocuronium bromide. The solution is packed in 5 ml or 10 ml glass vials (type I), bromobutyl rubber stopper and aluminium flip-off seal. Each vial contains 5 ml of solution with 50 mg rocuronium bromide or 10 ml of solution with 100 mg rocuronium bromide. The excipients are: sodium acetate anhydrous (E262), sodium chloride, glacial acetic acid (for ph adjustment) (E260), sodium hydroxide (for ph adjustment) (E524), water for injections. II.2 Drug Substance Rocuronium bromide is a well known, established active substance, described in the European Pharmacopeia (Ph.Eur.). The substance is an almost white to pale yellow powder, which is freely soluble in water and in anhydrous ethanol. The substance is a slightly hygroscopic powder. Rocuronium bromide exhibits isomerism. The drug substance manufacturer produces a single (+) enantiomer. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general 2/10

3 monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The drug substance specification is in line with Ph.Eur. and the additional parameters as mentioned on the CEP. The specifications are acceptable in view of the route of synthesis and the various European guidelines. Batch analytical data demonstrating compliance with the drug substance specification have been provided for two batches. Stability of drug substance Three batches were stored for accelerated testing at 5 C±3 C for 6 months. Three batches were stored at -20 C for 60 months and 4 more batches were stored at -20 C for up to 48 months. Based on the provided data a retest period of 3 years is acceptable, when stored at -20 C. II.3 Medicinal Product Pharmaceutical development The development of the product has been described, the choice of excipients is justified and their functions explained. The following studies were performed as part of the development: pharmaceutical equivalence testing (in terms of comparisons of the innovator product with the proposed product), choice of sterilisation cycle studies, hold time studies during manufacturing, material contact study, selection of filtration media, extractable studies, container closure integrity studies and compatibility studies. The choice of terminal sterilization is justified. No overages are used. Equivalence with respect to chemical-pharmaceutical properties has been demonstrated. The pharmaceutical development of the proposed product has been adequately performed. Manufacturing process During the manufacturing process, the excipients and active substance are compounded and mixed. The solution is pre-filtered, filtered and filled into vials. The filled vials are stoppered and capped. An overfill of 18% of the nominated fill volume is justified and acceptable. The sealed vials are autoclaved and visually inspected for fill volume and visible particulates. Suitable in-process controls are defined. Process validation has been performed for three batches filled into 5 ml vials, according to relevant European guidelines. The MAH will conduct process validation studies with the first three productionscale batches and for the 10 ml presentation. Control of excipients The MAH states that analytical procedures for all the excipients, are performed as per the requirements specified in the Ph.Eur. and per the USP for sodium acetate. Quality control of drug product The product specification includes tests for clarity, volume, colour, particulate matter, sterility, bacterial endotoxins, assay, total acetate, total sodium, ph, degradation products, identification, osmolarity and residual solvents. The specifications and corresponding limits, are considered to be suitable for the control of the drug product. The analytical methods have been adequately described and validated. Batch analytical data from four pilot-scale (two of each presentation) and three commercial-scale batches (5 ml) have been provided. All batches comply with the specification. Stability of drug product Stability data on the product has been provided for three full-scale batches of 5 ml vials and four pilotscale batches (two of each presentation) stored at 2-8 C (6 months) in inverted and upright position. Furthermore the four pilot-scale batches were stored at 25 C/60% RH (6 months) in inverted and upright position. The batches were stored in the proposed marketing packaging. At both conditions and in both presentations increases were observed in one impurity. All other parameters tested remained relatively stable throughout the test period at both conditions. All results remained within specification limits. Based on the stability data provided a shelf life 36 months is acceptable with the following storage conditions: Store in a refrigerator (2 C - 8 C). Furthermore a sequential shelf life of 12 weeks when stored below 30 C can be granted. 3/10

4 An in-use study was conducted after dilution to 0.5 mg/ml and 2.0 mg/ml, in line with the innovator s claim. The results of this study demonstrate that Rocuroniumbromide Hospira is chemically and physically stable for 72 hours at 30 C in the following infusion fluids: - 0.9% Sodium Chloride Injection - 5% Dextrose Injection - 5% Dextrose and 0.9% Sodium Chloride Injection - Sterile Water for Injection - Lactated Ringer s Injection An in-use storage time of 72 hours is acceptable. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Rocuroniumbromide Hospira 10 mg/ml has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Rocuroniumbromide Hospira 10 mg/ml 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.2 Discussion on the non-clinical aspects This product is a generic formulation of Esmeron, which is available on the European market. Reference is made tot the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-todate and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Rocuronium bromide is a well-known active substance with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. IV.2 Pharmacokinetics Rocuroniumbromide Hospira 10 mg/ml aqueous solution for injection or infusion is a parenteral formulation and therefore fulfils the exemption mentioned in the Note for Guidance on bioequivalence parenteral solutions, which states that a bioequivalence study is not required if the product is administered as an aqueous intravenous solution containing the same active substance in the same concentration as the currently authorized reference medicinal product (NfG CPMP/EWP/QWP 1401/98). The qualitative composition of excipients of Rocuroniumbromide Hospira 10 mg/ml solution for injection or infusion is comparable to the originator. Therefore, it may be considered as therapeutic 4/10

5 equivalent, with the same efficacy/safety profile as known for the active substance of the reference medicinal product. The current product can be used instead of its reference product. IV.3 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Rocuroniumbromide Hospira 10 mg/ml. Summary table of safety concerns as approved in RMP Important identified risks - Prolonged neuromuscular block - Hypersensitivity including anaphylactic and anaphylactoid reactions - Local injection site reactions Important potential risks - Cardiovascular events (including cardiac arrest and bradycardia) - Rhabdomyolysis - interaction between theophyllin and rocuronium bromide Important missing information -- The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The member states agree that routine minimisation measures are considered sufficient for the important identified and potential risks and missing information associated with this product. IV.4 Discussion on the clinical aspects For this authorisation, reference is made to the clinical studies and experience with the innovator product Esmeron. No new clinical studies were conducted. A bioequivalence study was not required. Equivalence to the innovator product has been sufficiently demonstrated based on the chemicalpharmaceutical properties. Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product. 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 test consisted of a pilot test with 4 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. It was determined whether the respondents were able to find the information and whether they understood the information and could act upon it. 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 Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion has a proven chemicalpharmaceutical quality and is a generic form of Esmeron 10 mg/ml. Esmeron 10 mg/ml is a well-known medicinal product with an established favourable efficacy and safety profile. Since both the reference and current product are intended for parenteral use, no bioequivalence study is deemed necessary. The Board followed the advice of the assessors. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Rocuroniumbromide Hospira 10 mg/ml with the reference 5/10

6 product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 22 December /10

7 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Variation to reduce the lower range of the batch size. Minor changes to an approved test procedure. Procedure number NL/H/2812/ 001/IB/001 NL/H/2812/ 001/IB/002 Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached IB Approval N IB Approval N 7/10

8 Summary Public Assessment Report Generics Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion rocuronium bromide NL/H/2812/001/DC Date: 21 July /10

9 Summary Public Assessment Report Generics Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion Active substance: rocuronium bromide This is a summary of the public assessment report (PAR) for Rocuroniumbromide Hospira 10 mg/ml. It explains how this medicine was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Rocuroniumbromide Hospira. For practical information about using this medicine, patients should read the package leaflet or contact their doctor or pharmacist. What is Rocuroniumbromide Hospira 10 mg/ml and what is it used for? Rocuroniumbromide Hospira is a generic medicine. This means that it is similar to a reference medicine already authorised in the European Union (EU) called Esmeron 10 mg/ml solution for injection or infusion. In adults and children, this medicine is used under general anaesthesia, to ease the insertion of a tube into the windpipe (trachea), to help with mechanical assistance of breathing and to ensure that the patient s muscles are relaxed during surgery. In adults only, the doctor may also use this medicine for a short time as an additional medicine in the intensive care unit (ICU) (e.g. to ease the insertion of a tube into the windpipe when the patient is to receive mechanical breathing). This medicine can also be administered in an emergency situation when a patient needs to receive a tube into his windpipe very quickly. How is this medicine used? The medicine can only be obtained with a prescription. The dose of Rocuroniumbromide Hospira is determined by an anaesthetist, based on: the type of anaesthetic the expected length of the operation other medicines a patient is taking the patient s state of health. The normal dose is 0.6 mg per kg body weight and the effect will last minutes. The medicine is given intravenously (into a vein), either as single injections or as a continuous infusion (a drip). How does this medicine work? Rocuronium bromide belongs to a group of medicines called muscle relaxants. Under normal circumstances our nerves send messages to the muscles by impulses. This medicine acts by blocking these impulses so that the muscles become relaxed. During an operation the muscles must be completely relaxed. This makes it easier for the surgeon to perform the operation. How has this medicine been studied? The company provided data from the published literature on rocuronium bromide. No additional studies were needed as Rocuroniumbromide Hospira is a generic medicine that is given by infusion or intravenous injection and contains the same active substance in the same concentration as the reference medicine, Esmeron. What are the benefits and risks of this medicine? Because this is a generic medicine, its benefits and risks are taken as being the same as the reference medicine. Why is this medicine approved? It was concluded that, in accordance with EU requirements, Rocuroniumbromide Hospira 10 mg/ml has been shown to have comparable quality and to be comparable to Esmeron 10 mg/ml. Therefore, the view was that, as for Esmeron, the benefit outweighs the identified risk. 9/10

10 What measures are being taken to ensure the safe and effective use of this medicine? A risk management plan has been developed to ensure that this medicine is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Rocuroniumbromide Hospira, including the appropriate precautions to be followed by healthcare professionals and patients. Other information about this medicine In the Netherlands, the marketing authorisation for Rocuroniumbromide Hospira 10 mg/ml, solution for injection/infusion was granted on 23 April The full PAR for this medicine can be found on the website For more information about treatment with this medicine, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in July /10