Public Assessment Report UK National Procedure Nefopam ... · Nefopam Hydrochloride 30mg...

Nefopam Hydrochloride 30mg Film-coated Tablets PL 41830/0014 and PL 41830/0034

1

Public Assessment Report

UK National Procedure

Nefopam Hydrochloride 30mg Film-coated Tablets

PL 41830/0014

PL 41830/0034

NRIM Limited


2

LAY SUMMARY This is a summary of the public assessment report (PAR) for Nefopam Hydrochloride 30mg Film-coated Tablets. It explains how Nefopam Hydrochloride 30mg Film-coated Tablets 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 Nefopam Hydrochloride 30mg Film-coated Tablets. For practical information about using Nefopam Hydrochloride 30mg Film-coated Tablets, patients should read the package leaflet or contact their doctor or pharmacist. What are Nefopam Hydrochloride 30mg Film-coated Tablets and what are they used for? Nefopam Hydrochloride 30mg Film-coated Tablets is a generic medicine. This means that Nefopam Hydrochloride 30mg Film-coated Tablets are similar to a reference medicine already authorised in the European Union (EU) called Acupan 30mg Tablets. Nefopam is used to relieve acute and chronic pain (for example pain after an operation, dental pain, joint or muscle pain, pain after an injury, or pain caused by cancer). Nefopam should not be used to treat the pain from a heart attack. How do Nefopam Hydrochloride 30mg Film-coated Tablets work? Nefopam belongs to a group of medicines called analgesics, commonly known as pain killers or pain relievers. Nefopam interrupts the pain messages being sent to the brain and also acts in the brain to stop pain messages being felt. This means that Nefopam does not stop the pain from happening but patients will not be able to feel the pain as much. How are Nefopam Hydrochloride 30mg Film-coated Tablets used? Nefopam Hydrochloride 30mg Film-coated Tablets should be swallowed with water. The usual initial dose in adults is two tablets taken three times a day. A doctor may increase this dose up to a maximum of three tablets taken three times a day according to their patient’s needs. Children over 12 years should take the same dose as adults. Nefopam should not be taken by children under 12. In elderly patients the doctor may reduce the number of tablets that are taken. The dosage for patients with kidney and/or liver problems may be adjusted by a doctor, depending upon their patient’s condition. Nefopam Hydrochloride 30mg Film-coated Tablets can only be obtained with a prescription. What benefits of Nefopam Hydrochloride 30mg Film-coated Tablets have been shown in studies? Because Nefopam Hydrochloride 30mg Film-coated Tablets is a generic medicine, studies in patients have been limited to tests to determine that this medicine is bioequivalent to the reference medicine, Acupan 30mg Tablets. Two medicines are bioequivalent when they produce the same levels of the active substance in the body.


3

What are the possible side effects of Nefopam Hydrochloride 30mg Film-coated Tablets? Because Nefopam Hydrochloride 30mg Film-coated Tablets is a generic medicine its possible side effects are taken as being the same as those of the reference medicine, Acupan 30mg Tablets. For the full list of all side effects reported with Nefopam Hydrochloride 30mg Film-coated Tablets see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why are Nefopam Hydrochloride 30mg Film-coated Tablets approved? It was considered that the benefits of using Nefopam Hydrochloride 30mg Film-coated Tablets to relieve acute and chronic pain outweigh the risks and the grant of Marketing Authorisations was recommended. What measures are being taken to ensure the safe and effective use of Nefopam Hydrochloride 30mg Film-coated Tablets? A Risk Management Plan has been developed to ensure that Nefopam Hydrochloride 30mg Film-coated Tablets are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics and the package leaflet for Nefopam Hydrochloride 30mg Film-coated Tablets, 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 and reviewed continuously. Other information about Nefopam Hydrochloride 30mg Film-coated Tablets The MHRA agreed to grant Marketing Authorisations for Nefopam Hydrochloride 30mg Film-coated Tablets on 9 February 2015. For more information about treatment with Nefopam Hydrochloride 30mg Film-coated Tablets, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in April 2015.

The full PAR for Nefopam Hydrochloride 30mg Film-coated Tablets follows this summary.


4

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 9 IV Clinical aspects Page 9

V User consultation Page 12

VI Overall conclusion, benefit/risk assessment and recommendation Page 12 VII Steps taken for assessment Page 13 VIII Steps taken after initial authorisation Page 13


5

I Introduction Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) considered that the applications for Nefopam Hydrochloride 30mg Film-coated Tablets could be approved. This prescription only medicine (POM) is used for the relief of acute and chronic pain, including post-operative pain, dental pain, musculo-skeletal pain, acute traumatic pain and cancer pain. The applications for Nefopam Hydrochloride 30mg Film-coated Tablets were made under Article 10(1) of Directive 2001/83/EC, as amended, as so-called generic applications. The reference medicinal product for these applications is Acupan 30 mg Tablets, which was first authorised to 3M Heath Care Limited (authorisation number: PL 00068/0061) on 2 March 1978. The Marketing Authorisation was transferred to Valeant Pharmaceuticals Ltd (PL 19166/0088) on 30 October 2007 and then to Meda Pharmaceuticals Ltd (PL 15142/0109) on 2 February 2010. As this reference product has been authorised in the EEA for at least 10 years the legal basis of these applications is acceptable. Nefopam is a potent and rapidly-acting analgesic. It is totally distinct from other centrally-acting analgesics such as morphine, codeine, pentazocine and propoxyphene. Unlike the narcotic agents, nefopam has been shown not to cause respiratory depression. There is no evidence from pre-clinical research of habituation occurring with nefopam. A bioequivalence study comparing Nefopam Hydrochloride 30mg Film-coated Tablets to Acupan 30 mg Tablets (PL 19166/0088) was submitted with the applications. Assurance has been provided that the study has been conducted according to the principles of Good Clinical Practice (GCP). No new non-clinical data were submitted, which is acceptable given that the applications are for generic versions of an originator product that has been in clinical use for over 10 years. 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. 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 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 MA holder, fulfils the requirements and provides adequate evidence that the MA holder 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 MA holder has provided a Risk Management Plan (RMP).

Since Nefopam Hydrochloride 30mg Film-coated Tablets are intended for generic substitution, their use will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. The MHRA considered that the applications could be approved and Marketing Authorisations were granted on 9 February 2015.


6

II Quality aspects II.1 Introduction Each coated tablet contains 30 mg nefopam hydrochloride and the excipients calcium hydrogen phosphate dihydrate, microcrystalline cellulose, pregelatinized starch, hydrogenated vegetable oil, colloidal anhydrous silica, and magnesium stearate (which make up the tablet core) and hypromellose (HPMC 2910), titanium dioxide (E171), and macrogol/PEG (which make up the tablet coating). The film coated tablets are white to off white, round and biconvex with 'NFP' debossed on one side and plain on the other side. The tablets are presented in either an ALU-ALU blister pack (consisting of ALU/OPA/PVC (50/25/60 microns) and aluminium foil 25 microns) or a PVC–ALU blister pack (consisting of PVC 250 micron and aluminium foil 20 microns). Each pack contains three blisters of 30 tablets, hence a total pack size of 90 tablets. II.2 Drug Substance INN: Nefopam Chemical name: 3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine

hydrochloride or 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine hydrochloride

Structure:

Molecular formula: C17H20 Cl.NO Molecular weight: 289.80 Synthesis of the active 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. 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 that 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 foodstuff. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging.


7

II.3 Medicinal Product

Pharmaceutical development The aim of the pharmaceutical development of Nefopam Hydrochloride 30mg Film-coated Tablets was to develop a generic version of the innovator product, Acupan 30mg Tablets. The proposed and the reference products were tested for a number of parameters to support the claim that the products were comparable. All excipients comply with their European Pharmacopoeia monographs, with the exception of hydrogenated vegetable oil, which is controlled in line with the British Pharmacopoeia monograph. In the absence of a European Pharmacopoeia monograph for this excipient this is satisfactory. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. None of the excipients are of animal or human origin. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results.

Finished Product Specification The finished product specifications proposed for the products are acceptable. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided that comply with the release specification. Certificates of analysis have been provided for any working standards used. Stability of the product Stability studies were performed in accordance with current guidelines, on batches of the finished product stored in the packaging proposed for marketing. The data from these studies support a shelf-life of 24 months. These medicinal products do not require any special storage conditions. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of marketing authorisations is recommended.

II.5 SmPCs, PIL and labelling 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 following product labelling was approved for use in the UK:


8

Blister:

Carton:


9

III Non-clinical aspects III.1 Introduction No new non-clinical data have been submitted and none are required for applications of this type. The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory. III.2 Pharmacology No new pharmacology data are required for these applications and none have been submitted. III.3 Pharmacokinetics No new pharmacokinetic data are required for these applications and none have been submitted. III.4 Toxicology No new toxicology data are required for these applications and none have been submitted. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Nefopam Hydrochloride 30mg Film-coated Tablets are intended for generic substitution, they 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 The grant of marketing authorisations is recommended. IV Clinical aspects IV.1 Introduction The applicant has submitted a report of a bioequivalence study in support of these applications. The applicant’s clinical overview has been written by an appropriately qualified expert and is considered acceptable. IV.2 Pharmacokinetics Bioequivalence study Study design An open label, randomised, two-period, two-treatment, two-sequence, crossover, balanced, single dose oral bioequivalence study comparing Nefopam Hydrochloride 30mg Film-coated Tablets (NRIM Limited) with Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd). The study was conducted with 30 healthy, adult, male human subjects. Twenty-seven subjects completed the study. In each study period, a single 30 mg oral dose was administered to the subjects after an overnight fasting of at least 10 hours. There was an interval of 7 days between treatments. Blood samples were collected at pre-dose (0.0 hours) and at intervals over 48.00 hours after administration of each dose. The main pharmacokinetic parameters are summarised in Table1.


10

Table 1: Test & Reference Geometric mean, Ratio, 90% Confidence Intervals, Intra- Subject CV (%) and Power based on Log-transformed data for Nefopam (n=27)

The 90% confidence intervals for AUC and Cmax were within the acceptance range of 80.00 to 125.00 %. Bioequivalence between the test product and the reference product has been adequately demonstrated. Assessor’s Comment/Conclusion Based on these results, it was concluded that the proposed product, Nefopam Hydrochloride 30 mg Tablets,(NRIM Limited, UK, Rubicon Research Pvt. Ltd., India) and AcupanTM (Nefopam Hydrochloride) 30 mg Tablets, (Meda Pharmaceuticals Ltd., Skyway House, Parsonage Road, Takeley, Bishop's Stortford, CM22 6PU, UK) are bioequivalent under fasting conditions. IV.3 Pharmacodynamics No new pharmacodynamic data are required for these applications and none have been submitted. IV.4 Clinical efficacy No new clinical efficacy data are required for these applications and none have been submitted. IV.5 Clinical safety With the exception of the data generated during the bioequivalence study, no new safety data are presented for these applications and none are required. No new or unexpected safety issues arose during the bioequivalence study. IV.6 Risk Management Plan The applicant has submitted an RMP, 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 Nefopam Hydrochloride 30mg Film-coated Tablets. Routine pharmacovigilance activities and risk minimisation measures should be adequate for this product, which contains a widely used active substance with a well-established safety profile. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is listed below:


11


12

IV.7 Discussion on the clinical aspects The grant of Marketing Authorisations is recommended for these applications. 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 The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with nefopam is considered to have demonstrated the therapeutic value of the compound. The benefit/risk balance is, therefore, considered to be positive.


13

VII Steps taken for assessment

VIII Steps taken after initial authorisation

Date submitted

Application type

Scope Outcome

1 The MHRA received the Marketing Authorisation applications on 11/02/2014. 2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 17 March 2014. 3 Following assessment of the applications the MHRA requested further

information relating to the dossier on 26 June 2014. 4 The applicant responded to the MHRA’s requests, providing further information

on 25 September 2014. 5 Following assessment of the response the MHRA requested further information

relating to the dossier on 26 November 2014. 6 The applicant responded to the MHRA’s requests, providing further information

on 17 December 2014. 7 The applications were granted on 9 February 2015.

Date post:	25-Jul-2018
Category:	Documents
Upload:	phamcong
View:	526 times
Download:	22 times

Public Assessment Report UK National Procedure Nefopam ... · Nefopam Hydrochloride 30mg...

Documents