Public Assessment Report Decentralised Procedure - GOV.UK · (remifentanil hydrochloride, powder...

Public Assessment Report

Decentralised Procedure Remifentanil Noridem 1 mg Powder for Concentrate for

Solution for Injection or Infusion

Remifentanil Noridem 2 mg Powder for Concentrate for Solution for Injection or Infusion

Remifentanil Noridem 5 mg Powder for Concentrate for

Solution for Injection or Infusion

UK licence no: PL 24598/0025-27

UK/H/2861/01-03/DC

Applicant: Noridem Enterprises Limited

PAR Remifentanil Nor idem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion

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LAY SUMMARY


Remifentanil Noridem 2 mg Powder for Concentrate for Solution for Injection or

Infusion


(remifentanil hydrochloride, powder for concentrate for solution for injection or

infusion, 1mg, 2mg and 5 mg)

This is a summary of the Public Assessment Report (PAR) for Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion (PL 24598/0025-27; UK/H/2861/01-03/DC). It explains how Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion. The products will be collectively referred to as Remifentanil throughout the remainder of this public assessment report (PAR). For practical information about using Remifentanil, patients should read the package leaflet or contact their doctor or pharmacist. What is Remifentanil and what is it used for? Remifentanil is a ‘generic medicine’. This means that Remifentanil is similar to a ‘reference medicine’ already authorised in the European Union (EU) called Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited). Remifentanil is used:

• to help put the patient to sleep before an operation • to keep the patient asleep and stop them feeling pain during an operation • to make the patient feel sleepy and stop them feeling pain while they receive

treatment in an Intensive Care Unit. How does Remifentanil work? Remifentanil belongs to a group of medicines known as opioids. It works by acting on the body’s central nervous system (CNS) or brain to relieve pain. How is Remifentanil used? The pharmaceutical form of this medicine is a powder for concentrate for solution for injection or infusion, and the route of administration is into the patient’s vein (intravenously). The patient will never be expected to give themselves this medicine. It will always be given to them by a person who is qualified to do so.


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Remifentanil can be given: • as a single injection into the patient’s vein • as a continuous infusion into the patient’s vein. This is where the drug is

slowly given to the patient over a longer period of time. The way the patient is given the drug and the dose they receive will depend on:

• the operation they have • how much pain they will be in • how sleepy the medical staff want the patient to be in the Intensive Care Unit.

The dose varies from one patient to another. After the patient’s operation The patient should tell their doctor or nurse if they are in pain. If they are in pain after their procedure, the patient’s doctor or nurse will be able to give them other painkillers. Please read section 3 of the package leaflet for detailed dosing recommendations, the route of administration, and the duration of treatment. For further information on how Remifentanil is used, refer to the package leaflet and Summary of Product Characteristics available on the Medicines and Healthcare products Regulatory Agency (MHRA) website. This medicine can only be obtained with a prescription. What benefits of Remifentanil have been shown in studies? No additional studies were needed as Remifentanil is a generic medicine that is given intravenously and contains the same active substance as the reference medicine, Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited). What are the possible side effects of Remifentanil? Because Remifentanil is a generic medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with Remifentanil see section 4 of the package leaflet available on the MHRA website. Why was Remifentanil approved? It was concluded that, in accordance with EU requirements, Remifentanil has been shown to be comparable to Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited). Therefore, the MHRA decided that, as for Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited); the benefits are greater than the risks and recommended that it can be approved for use.


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What measures are being taken to ensure the safe and effective use of Remifentanil? Safety information has been included in the Summaries of Product Characteristics (SmPCs) and the package leaflet for Remifentanil including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Remifentanil Austria, Greece, Ireland, Spain and the UK agreed to grant Marketing Authorisations for Remifentanil on 24 October 2011. Marketing Authorisations were granted in the UK on 6 December 2011. The full PAR for Remifentanil follows this summary. For more information about treatment with Remifentanil, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in September 2016.


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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 8 III Non-clinical aspects Page 11 IV Clinical aspects Page 11 V User consultation Page 13

VI Overall conclusion, benefit/risk assessment and Page 13 Recommendation

Summary of steps taken after authorisation Page 18


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I INTRODUCTION On 24 October 2011, Austria, Germany, Greece, Ireland, Spain and the UK agreed to grant Marketing Authorisations (MAs) to Ranbaxy (UK) Limited for the medicinal products Noridem Enterprises Limited Remifentanil/Noridem 1 mg, 2mg and 5 mg Powder for Injection or Infusion. The MAs were granted via a Decentralised Procedure (DCP), with the UK as Reference Member State (RMS UK/H/2861/01-3/DC). After the national phase, MAs were granted in the UK on 6 December 2011 (PL 24598/0025-27). These products are prescription-only medicines. These are generic applications for Remifentanil/Noridem 1 mg, 2mg and 5 mg Powder for Injection submitted under Article 10(1) of Directive 2001/83/EC, as amended. The applications refer to the EEA reference products Ultiva for Injection 1, 2 and 5 mg, which were first authorised in the UK on 30 October 1996 to Glaxo Group Limited (PL 14213/0002 - 4). Following a change of marketing authorisation holder, the product was authorised on 3 April 2000 to Elan Pharma International Limited (PL 16804/0009 – 11). After a second change of marketing authorisation holder, the product was authorised on 1 May 2004 to GlaxoSmithKline UK Limited (PL 194949/0026 – 28).The reference products have been registered in the EEA for more than 10 years, hence the period of data exclusivity has expired. Remifentanil is a selective μ-opioid agonist with a rapid onset and very short duration of action. The μ-opioid activity, of remifentanil, is antagonised by narcotic antagonists, such as naloxone. Remifentanil is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia. Remifentanil is indicated for provision of analgesia in mechanically ventilated intensive care patients 18 years of age and over. The indications applied for are identical to the indications approved for the reference product. No new non-clinical or clinical efficacy studies were conducted for this application, which is acceptable given that the applications were for generic versions of products that have been licensed for over 10 years. A bioequivalence study is not necessary to support these applications for parenteral products. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture and assembly of these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. 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 or 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


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Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS considers that the pharmacovigilance system, as described by the MAH, fulfils the requirements and provides adequate evidence that the MAH 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. The Marketing Authorisation Holder has provided adequate justification for not submitting a Risk Management Plan (RMP). As the application is for a generic version of an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profile of the active is well established. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). This was an application for a generic product and there is no reason to conclude that marketing of this product will change the overall use pattern of the existing market.


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II QUALITY ASPECTS II.1 Introduction The proposed product is presented as a sterile, endotoxin-free, preservative-free, white to off-white, powder for concentrate for solution tor injection or infusion. The medicinal product is supplied in a lyophilised form in a glass vial containing, 1 mg, 2mg or 5 mg of remifentanil base (as remifentanil hydrochloride). When reconstituted as directed, solutions of the proposed product are clear and colourless and contain 1 mg/mL remifentanil hydrochloride.

Other ingredients consist of, glycine and hydrochloride acid (for pH adjustments). Both the excipients comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for both excipients. Appropriate justification for the inclusion of each excipient has been provided. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in, or used in the manufacturing process for the proposed product. Furthermore, no genetically modified organisms are used in the manufacture of glycine and hydrochloride acid. The finished products are licensed for marketing in colourless, glass vials (Ph.Eur, type I) vials, closed with bromobutyl rubber (Ph.Eur, type I) stoppers and sealed with aluminium caps which have a plastic flip-off cover. The vials are placed with the Patient Information Leaflet (PIL) into cardboard outer cartons and are packaged in pack sizes of 5 vials. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. The glass vials and rubber stoppers comply with Ph Eur requirements and are suitable for contact with parenteral solution products. II.2 Drug Substance Remifentanil Hydrochloride rINN name: Remifentanil Hydrochloride Chemical name: 3-(4-Methoxycarbonyl-4-((1-oxopropyl)phenylamino)-1-piperidine)propanoic acid, methyl ester hydrochloride Molecular formula: C20H28N2 O5HCl Molecular weight: 412.9 Structure


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General properties Description: White to off-white crystalline solid Solubility: Freely soluble in water, sparingly soluble in ethanol, very

slightly soluble in methyl isobutyl ketone and slightly soluble in isopropyl alcohol.

The active substance, remifentanil hydrochloride, is the subject of a European Pharmacopoeia (EP) monograph. Manufacture Synthesis of the drug substance from the designated starting materials has been adequately described and appropriate in-process 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. Appropriate proof-of-structure data have been supplied for the active pharmaceutical ingredient. All potential known impurities have been identified and characterised. 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. Batch analysis data are provided and comply with the proposed specification. Satisfactory certificates of analysis have been provided for all working standards. 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 aim of the pharmaceutical development programme was to produce a stable, robust, reproducible lyophilised finished product that could be considered a generic medicinal product of Ultiva for Injection 1 mg, 2 mg and 5 mg (GlaxoSmithKline UK Limited). Suitable pharmaceutical development data have been provided for this application. The physico-chemical properties of the drug product have been compared with the reference product. These data demonstrate that the proposed product can be considered a generic medicinal product of Ultiva for Injection 1 mg, 2 mg and 5 mg (PL 19494/0026-28) licensed to GlaxoSmithKline UK Limited. Impurity Profiles Comparative impurity data were provided for the test and reference products. The impurity profiles were found to be similar, with all impurities within the specification limits.


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Manufacture of the product A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted on three batches of each strength and are satisfactory. The validation data demonstrated consistency of the manufacturing process. All results comply with the process validation protocol and presented specifications. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Stability of the Product Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life for Remifentanil/Noridem 1, 2 and 5 mg Powder for Solution for Injection or Infusion of 18 months, 2 years and 3 years respectively has been approved. Storage conditions are “Do not store above 25oC. Keep the vial in the outer carton protected from light”. Finished product stability studies have been carried out after reconstitution in water as well as after dilution in an appropriate diluent. For storage conditions in both cases see Section 6.3 of the Summary Product Characteristics (SmPC). Bioequivalence Study The product is formulated for administration as a solution by the intravenous route. Hence there is no requirement for a bioequivalence study. Quality Overall Summary A satisfactory quality overall summary is provided and has been prepared by an appropriately qualified expert. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the labelling and PIL have been provided. The labelling is satisfactory and fulfils the statutory requirements for Braille. MAA Forms The MAA forms are pharmaceutically satisfactory. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion from a quality point of view.


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III NON-CLINICAL ASPECTS III.1 Introduction The pharmacodynamic, pharmacokinetic and toxicological properties of remifentanil are well-known. Therefore, no further studies are required and the applicant has provided none. The non-clinical overall summary was written by a suitably qualified person and is satisfactory. The curriculum vitae of the expert has been provided. 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 Ecotoxicity/environmental risk assessment (ERA) No formal Environmental Risk Assessment has been provided. The applicant has justified the absence adequately. As a generic product, the use of this product is not expected to increase the overall use of remifentanil and so no additional increase in environmental risk has been identified. SUMMARY OF PRODUCT CHARACTERISTICS (SmPCs) The SmPCs are satisfactory from a non-clinical viewpoint and is consistent with that for the reference products. III.6 Discussion on the non-clinical aspects There are no objections to the approval of Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion from a non-clinical point of view. IV CLINICAL ASPECTS IV.1 Introduction Remifentanil is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia. Remifentanil is indicated for provision of analgesia in mechanically ventilated intensive care patients 18 years of age and over.

POSOLOGY AND METHOD OF ADMINISTRATION Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and


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management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

Full details concerning the posology are provided in the SmPC. The posology is consistent with that for the reference products and is satisfactory.

TOXICOLOGY The toxicology of remifentanil is well-known. No new data have been submitted and none are required for these types of applications. CLINICAL PHARMACOLOGY The clinical pharmacology of remifentanil is well-known. No novel pharmacodynamic or pharmacokinetic data are supplied or required for these applications. IV.2 Pharmacokinetics Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion are generic versions of Ultiva for Injection 1, 2 and 5 mg. The use of the reference products is well-established in the UK. Both the reference and proposed products contain the same quantitative and qualitative composition of the active ingredient, remifentanil According to CPMP guidelines, the applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous intravenous solution containing the same active substance, in the same concentration as the currently authorised product (CPMP/EWP/1401/98, subpoint 5.1.6, Parenteral solutions). IV.3 Pharmacodynamics No new data have been submitted and none are required for an application of this type. IV.4 Clinical efficacy No new data have been submitted and none are required for an application of this type. IV.5 Clinical safety No new safety data have been submitted or required for this generic application. As remifentanil is a well-known product with an acceptable adverse event profile, this is satisfactory. Expert Report A satisfactory clinical overall summary is provided, and has been prepared by an appropriately qualified physician. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels


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The SmPCs and PIL are medically acceptable, and consistent with those for the reference product. The labelling is medically acceptable and in-line with current requirements. MAA form The MAA forms are medically satisfactory. IV.7 Discussion on the clinical aspects There are no objections to approval of Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion from a clinical point of view. 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 package leaflet 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 QUALITY The important quality characteristics of Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY The applicant’s Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion has been demonstrated to be generic versions of the reference products Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited). No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The SmPCs and PILs are acceptable, and consistent with those for the reference product. The labelling is acceptable and in-line with current requirements. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The qualitative and quantitative assessment supports the claim that the applicant’s Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion and the reference products Ultiva for Injection 1, 2 and 5 mg (GlaxoSmithKline UK Limited), are interchangeable.


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Extensive clinical experience with remifentanil is considered to have demonstrated the therapeutic value of the active substance. The benefit/risk is, therefore, considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for the original grant of this medicine is presented below:


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STEPS TAKEN AFTER INITIAL PROCEDURE – SUMMARY

The following table lists non-urgent safety updates to the Marketing Authorisations for these products that have been approved by the MHRA since the products were first licensed. The table includes updates that have been added as an annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to these Marketing Authorisations. Scope Procedure

number Product Information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached

To update section 4.8 of the SmPC In line with the QRD template. Consequently the leaflet has been updated.

UK/H/2861/01-03/IB/002

SmPC and leaflet

11/07/2016 10/08/2016 Approved on 16/08/2016

Yes-see Annex 1


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ANNEX 1 Our Reference: PL 24598/0025-0009 PL 24598/0026-0009 PL 24598/0027-0009 Product: Remifentanil Noridem 1 mg, 2 mg and 5 mg Powder for Concentrate for Solution for Injection or Infusion Marketing Authorisation Holder: Noridem Enterprises Limited Active Ingredient(s): Remifentanil hydrochloride Type of Procedure: Mutual Recogniton Submission Type: Variation Submission Category: Type IB Submission Complexity: Standard EU Procedure Number (if applicable): UK/H/2861/001-002/IB/002 Reason: To update section 4.8 of the SmPC in line with the QRD template. Consequently the leaflet has been updated. Supporting Evidence Revised SmPC fragments and PIL. Evaluation The proposed changes to the SmPC and PIL are acceptable. The updated SmPC fragments and PIL have been incorporated into the Marketing Authorisations. Conclusion Approved on 16 August 2016.

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