Nefopam 30mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Nefopam hydrochloride
Available from:
DE Pharmaceuticals
ATC code:
N02BG06
INN (International Name):
Nefopam hydrochloride
Dosage:
30mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04070100
Authorization number:
; PL 15184/0907

Read all of this leaflet carefully before you start using this medicine because it contains important information for you

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same

as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Nefopam Hydrochloride is and what it is used for

2. What you need to know before you use Nefopam Hydrochloride

3. How to use Nefopam Hydrochloride

4. Possible side effects

5. How to store Nefopam Hydrochloride

6. Contents of the pack and other information

What Nefopam Hydrochloride is and what it is used for

The name of your medicine is Nefopam Hydrochloride 30mg Tablets (referred to as Nefopam Hydrochloride throughout this leaflet).

Nefopam Hydrochloride includes the active substance nefopam hydrochloride.

Nefopam Hydrochloride belongs to a group of medicines called analgesics, commonly known as pain killers or pain relievers. The active

substance, nefopam hydrochloride, interrupts the pain messages being sent to your brain, and it also acts in your brain to stop pain messages

being felt. This means that Nefopam Hydrochloride does not stop the pain from happening, but you will not be able to feel the pain as much.

Nefopam Hydrochloride is used to relieve of acute and chronic pain (for example pain after an operation, dental pain, joint or muscle pain, after

an injury, or pain caused by cancer). Nefopam Hydrochloride should not be used to treat the pain from a heart attack.

2. What you need to know before you use Nefopam Hydrochloride

Do not take Nefopam Hydrochloride:

◆ if you are a child under 12 years old

◆ if you are allergic to nefopam hydrochloride or any of the other ingredients of this medicine (listed in section 6)

◆ if you are taking monoamine oxidase inhibitors (MAOIs) to treat your depression

◆ if you have, or have ever had, epilepsy (fits).

◆ if you are pregnant or breast-feeding

Warnings and precautions

Talk to you doctor or pharmacist before using Nefopam

Hydrochloride.

If the answer to any of the following is ‘yes’, you must tell your doctor – your doctor may decide to alter your treatment.

Are you pregnant or breast feeding?

Do you have severe problems with your liver or kidneys?

Do you have, or have you had in the past difficulty passing urine?

Are you taking other medicines?

Have you previously been diagnosed with glaucoma (increased pressure in the eye)?

Children

Do not give this medicine to children between the ages of 0 to 12 years as the safety has not yet been established

Other medicines and Nefopam Hydrochloride

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Tell your doctor, dentist or pharmacist if you are taking or have recently taken the medicines listed below:

Monoamine oxidase inhibitors (known as MAOIs) for depression. You must tell your doctor if you are taking this medicine.

Tricyclic antidepressants for depression

Anticholinergics

Sympathomimetics

Pregnancy, breast-feeding and fertility

Nefopam Hydrochloride should not be taken during pregnancy or while breast-feeding.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice

before taking this medicine. Please contact your doctor if you become pregnant during your treatment.

Driving and using machines

Nefopam Hydrochloride can cause drowsiness. Do not drive or operate heavy machinery unless you know how Nefopam

Hydrochloride affects you.

3. How to take Nefopam Hydrochloride

Dosage for adults

Always take this medicine exactly as your doctor or pharmacist has told you. Check with you doctor or pharmacist if you are not sure.

The recommended dose is two tablets taken three times a day. Your doctor many increase this dose up to a maximum of three tablets taken

three times a day according to your needs.

Ask your doctor or pharmacist if:

you are not sure how many tablets to take or when to take them

you think the effect is too strong or too weak

Swallow your tablets with water.

Use in children and adolescents:

Over 12 years – as per above.

Under 12 years – Nefopam Hydrochloride 30mg Tablets should not be taken by children under 12.

Use in older patients:

In older patients the doctor may reduce the number of tablets that are taken.

Package Leaflet: Information for the user

Nefopam Hydrochloride 30mg Tablets

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Use in patients with kidney and/or liver problems:

Your doctor may adjust the dose of Nefopam Hydrochloride depending upon your condition.

If you take more Nefopam Hydrochloride than you should

If you accidentally take more tablets than your prescribed dose, tell your doctor or pharmacist immediately and if necessary contact your

nearest hospital casualty department. Remember to take the pack and any remaining medicines with you.

If you forget to take Nefopam Hydrochloride

If you forget to take Nefopam Hydrochloride, take it as soon as you remember.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Nefopam Hydrochloride

Do not stop taking Nefopam Hydrochloride without first checking with your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Please stop taking this medicine and contact

your doctor as soon as possible if you experience the following rare reactions:

swelling of the skin and soft tissue around the eyes, nose and throat (angioedema), or allergic reactions (anaphylaxis).

Side-effects which may occur most frequently include:

feeling sick

feeling light-headed, dizzy or nervous, or fainting

a decrease in blood pressure

numbness or tingling in the extremities

a dry mouth

having difficulty passing urine

convulsions, tremor

confusion

hallucinations (seeing things that aren’t there).

Other side-effects which may occur less frequently include:

being sick

abdominal pain or diarrhoea

blurred vision

drowsiness

sweating

trouble sleeping

headaches

awareness of your heartbeat (palpitations), or a fast heartbeat (tachycardia).

coma

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Nefopam Hydrochloride

Keep this medicine out of the sight and reach of children.

Keep your tablets in the original package.

Do not store above 30 °C.

Do not use this medicine after the expiry date which is stated on the carton.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use.

These measures will help protect the environment.

6. Contents of the pack and other information

What Nefopam Hydrochloride contains

The active substance in Nefopam Hydrochloride 30mg Tablets is nefopam hydrochloride 30mg.

The other ingredients are dibasic calcium phosphate dihydrate, microcrystalline cellulose, pregelatinised maize starch, magnesium stearate,

hydrogenated vegetable oil, colloidal silicone dioxide, hydroxypropylmethylcellulose, titanium dioxide.

What Nefopam Hydrochloride looks like and contents of the pack

Nefopam Hydrochloride 30mg Tablets are round, white and marked ‘APN’ on one side. The tablets are packaged in blister packs of 90 tablets.

Market Authorisation Holder:

Mylan,

Potters Bar,

Hertfordshire,

EN6 1TL, UK

Manufacturer

3M Health Care Limited

Derby Road,

Loughborough,

Leicestershire.

LE11 5SF, UK

This leaflet was last revised in May 2018.

Other sources of information

Is this leaflet hard to see or read? Please contact the MA holder at the address above.

3100 0128 01

56UK2260110-02

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Nefopam Hydrochloride 30 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Nefopam Hydrochloride 30 mg.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film coated, white, round tablet and marked APN on one side

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Nefopam Hydrochloride is indicated for the relief of acute and chronic pain,

including post-operative pain, dental pain, musculo-skeletal pain, acute

traumatic pain and cancer pain.

4.2

Posology and method of administration

Posology

ADULTS: Dosage may range from 1 to 3 tablets three times daily depending

on response. The recommended starting dosage is 2 tablets three times daily.

OLDER PEOPLE: Older patients may require reduced dosage due to slower

metabolism.

It is strongly recommended that the starting dose does not exceed one tablet

three times daily as older people appear more susceptible to, in particular, the

CNS side effects of Nefopam Hydrochloride and some cases of hallucinations

and confusion have been reported in this age group.

PAEDIATRIC POPULATION: The safety and efficacy of Nefopam

Hydrochloride in children under 12 years has not yet been established. No

dosage recommendation can be given for patients under 12 years.

Patients with end stage renal disease might experience increased serum peak

concentrations during treatment with Nefopam Hydrochloride. In order to

avoid that, it is recommended the daily dose should be reduced not only for the

elderly, but also for patients with terminal renal insufficiency.

Method of administration

Oral use.

4.3

Contraindications

Nefopam Hydrochloride is contra-indicated in patients with a history of

convulsive disorders and should not be given to patients taking mono-amine-

oxidase (MAO) inhibitors. Nefopam Hydrochloride is contraindicated in

patients with known hypersensitivity to any of the ingredients.

4.4

Special warnings and precautions for use

The side effects of Nefopam Hydrochloride may be additive to those of other

agents with anticholinergic or sympathomimetic activity. It should not be used

in the treatment of myocardial infarction since there is no clinical experience

in this indication. Hepatic and renal insufficiency may interfere with the

metabolism and excretion of Nefopam Hydrochloride.

Nefopam should be used with caution in patients with angle closure glaucoma.

Cases of nefopam dependence and abuse have been reported with nefopam

use.

Nefopam Hydrochloride should be used with caution in patients with, or at

risk of, urinary retention.

Rarely a temporary, harmless pink discolouration of the urine has occurred.

4.5

Interaction with other medicinal products and other forms of interaction

Caution should be exercised when Nefopam Hydrochloride is administered

concurrently with tricyclic antidepressants.

It should be noted that Nefopam Hydrochloride may interfere with some

screening tests for benzodiazepines and opioids. These tests for

benzodiazepines and opioids may give false positive results for patients taking

Nefopam Hydrochloride.

4.6

Fertility, Pregnancy and lactation

There is no evidence as to the drug safety in human pregnancy, nor is there

evidence from animal work that it is free from hazard. Avoid in pregnancy

unless there is no safer treatment.

4.7

Effects on ability to drive and use machines

Not applicable

4.8

Undesirable effects

Nausea, nervousness, dry mouth and light-headedness, urinary retention,

hypotension, syncope, palpitations, gastrointestinal disturbances (including

abdominal pain and diarrhoea), dizziness, paraesthesia, convulsions, tremor,

confusion, hallucination, angioedema, and allergic reactions may occur. Less

frequently, anaphylactic reactions, coma, vomiting, blurred vision, drowsiness,

sweating, insomnia, headache and tachycardia have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via the Yellow Card Scheme

at: www.mhra.gov.uk/yellowcard.

4.9

Overdose

The clinical pattern of Nefopam Hydrochloride toxicity in overdose is on the

neurological (coma, convulsions, hallucinations and agitation) and

cardiovascular systems (tachycardia with a hyperdynamic circulation). Routine

supportive measures should be taken and prompt removal of ingested drug by

gastric Lavage or induced vomiting with Syrup of Ipecacuanha should be

carried out. Oral administration of activated charcoal may help prevent

absorption.

Convulsions and hallucinations should be controlled (eg with intravenously or

rectally administered diazepam). Beta-adrenergic blockers may help control

the cardiovascular complications.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: 4.7.1 Non-opioid analgesics and compound

analgesic preparations

ATC code: N02BG06

Nefopam Hydrochloride 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 Hydrochloride has been shown not to

cause respiratory depression. There is no evidence from pre-clinical research

of habituation occurring with Nefopam Hydrochloride.

5.2

Pharmacokinetic properties

Nefopam Hydrochloride is absorbed from the gastro-intestinal tract. Peak

plasma concentrations occur about 1-3 hours after oral administration. About

73% is bound to plasma proteins. It has an elimination half-life of about 4

hours. It is extensively metabolised and excreted mainly in urine. Less than

5% of a dose is excreted unchanged in the urine. About 8% of a dose is

excreted via the faeces.

5.3

Preclinical safety data

Not applicable

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dibasic calcium phosphate dihydrate

Microcrystalline cellulose

Pregelatinised maize starch

Magnesium stearate

Hydrogenated vegetable oil

Colloidal silicon dioxide

These tablets are film coated using an aqueous solution containing:

hydroxypropyl methylcellulose 2910, titanium dioxide E171.

6.2

Incompatibilities

None known

6.3

Shelf life

5 years

6.4

Special precautions for storage

Store below 30ºC.

6.5

Nature and contents of container

20 micron aluminium foil and 250 micron UPVC.

Blister pack of 90 tablets

6.6

Special precautions for disposal

None

7

MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 04569/1783

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

29/09/2015

10

DATE OF REVISION OF THE TEXT

29/06/2018

1

Public Assessment Report

UKPAR

Nefopam hydrochloride 30mg film-coated tablets

(Nefopam hydrochloride)

UK Licence Number: PL 27827/0038

Galen Limited.

PAR Nefopam hydrochloride 30mg film-coated tablets

PL 27827/0038

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LAY SUMMARY

Nefopam hydrochloride 30mg film-coated tablets

This is a summary of the Public Assessment Report (PAR) for Nefopam hydrochloride 30mg film-

coated tablets (PL 27827/0038). 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.

The product will be referred to as Nefopam tablets throughout the remainder of this public assessment

report (PAR).

For practical information about using Nefopam tablets, patients should read the package leaflet or

contact their doctor or pharmacist.

What are Nefopam tablets and what are they used for?

Nefopam tablets are a ‘generic medicine’. This means that Nefopam tablets are similar to a ‘reference

medicine’ already authorised in the European Union (EU) called Acupan 30 mg Tablets (Meda

Pharmaceuticals Ltd, UK).

Nefopam tablets are used to relieve acute and chronic pain (for example pain after an operation, dental

pain, joint or muscle pain, after an injury, or pain caused by cancer). Nefopam tablets should not be used

to treat the pain from a heart attack.

How do Nefopam tablets work?

Nefopam tablets belong to a group of medicines called analgesics, commonly known as pain killers or

pain relievers. The active substance, nefopam hydrochloride, interrupts the pain messages being sent to

the brain, and it also acts in the patient’s brain to stop pain being felt. This means that Nefopam tablets

do not stop the pain from happening, but the patient will not be able to feel the pain as much.

How are Nefopam tablets used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of administration is oral

(by mouth).

The patient should always take this medicine exactly as their doctor has told them. The patient should

check with their doctor or pharmacist if they are not sure.

Adults

The recommended initial dose is two tablets taken three times a day. The patient’s doctor may increase

this dose up to a maximum of three tablets taken three times a day according to their needs.

The patient should ask their doctor or pharmacist if:

they are not sure how many tablets to take or when to take them

they think the effect is too strong or too weak.

Swallow the tablets with water.

Use in children and adolescents

Over 12 years - as per adults (see above).

Under 12 years -

Nefopam tablets should not be taken by children under 12.

PAR Nefopam hydrochloride 30mg film-coated tablets

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Elderly

In older patients, the doctor may reduce the number of tablets that are taken.

Patients with kidney and/or liver problems

The patient’s doctor may adjust the dose of Nefopam tablets depending upon their condition.

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 Nefopam tablets are 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 Nefopam tablets have been shown in studies?

Because Nefopam tablets are a generic medicine, studies in patients have been limited to tests to

determine that they are bioequivalent to the reference medicine

Acupan 30 mg Tablets (Meda

Pharmaceuticals Ltd, UK). Two medicines are bioequivalent when they produce the same levels of the

active substance in the body.

What are the possible side effects of Nefopam tablets?

Because Nefopam tablets are a generic medicine and as the tablets are bioequivalent to the reference

medicine Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd, UK), the benefits and possible side effects

are taken as being the same as for the reference medicine.

For the full list of restrictions, see the package leaflet.

For the full list of all side effects reported with Nefopam tablets, see section 4 of the package leaflet

available on the MHRA website.

Why were Nefopam tablets approved?

It was concluded that, in accordance with EU requirements, Nefopam tablets have been shown to have

comparable quality and to be bioequivalent to Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd, UK).

Therefore, the MHRA decided that, as for Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd, UK); the

benefits are greater than the risks and recommended that it can be approved for use.

What measures are being taken to ensure the safe and effective use of Nefopam tablets?

A risk management plan (RMP) has been developed to ensure that Nefopam tablets are used as safely as

possible. Based on this plan, safety information has been included in the Summary of Product

Characteristics (SmPC) and the package leaflet for Nefopam 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/reviewed continuously.

Other information about Nefopam tablets

A Marketing Authorisation was granted in the UK on 20 July 2017.

The full PAR for Nefopam tablets follows this summary.

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For more information about treatment with Nefopam tablets, read the package leaflet, or contact your

doctor or pharmacist.

This summary was last updated in August 2017.

PAR Nefopam hydrochloride 30mg film-coated tablets

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TABLE OF CONTENTS

Introduction

Page 6

Quality aspects

Page 7

Non-clinical aspects

Page 9

Clinical aspects

Page 9

User consultation

Page 11

Overall conclusion, benefit/risk assessment and

recommendation

Table of content of the PAR update

Page 11

Page 14

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I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products

Regulatory Agency (MHRA) granted Galen Limited, a marketing authorisation for the medicinal

product Nefopam tablets (PL 27827/0038). The product is a prescription only medicine (POM) indicated

in adults, including the elderly, and children aged 12 years and older for the relief of acute and chronic

pain, including post-operative pain, dental pain, musculoskeletal pain, acute traumatic pain and cancer

pain.

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 Acupan 30 mg Tablets which were

first authorised in the UK to 3M Healthcare Limited (PL 00068/0061) on 02 March 1978 and

subsequently underwent several changes of ownership procedures the most recent of which was to the

current marketing authorisation holder (MAH), Meda Pharmaceuticals Ltd, UK (PL 15142/0109) on 02

February 2010.

Nefopam hydrochloride 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.

One bioequivalence study (conducted under fasting conditions) was submitted to support this

application. The applicant has stated that the bioequivalence study was conducted in accordance with

Good Clinical Practice (GCP).

With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted,

which is acceptable given that this is a generic medicinal product of an originator product that has been

in clinical use for over 10 years.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place for this product type at all sites responsible for the manufacture and assembly of this product.

No new or unexpected safety concerns arose during the review of information provided by the

Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Nefopam tablets

outweigh the risks and a Marketing Authorisation was granted.

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II

QUALITY ASPECTS

II.1

Introduction

Each film-coated tablet contains 30 mg nefopam hydrochloride, as the active ingredient. Other

ingredients consist of the pharmaceutical excipients:

Tablet core:

Calcium hydrogen phosphate dihydrate, microcrystalline cellulose, pregelatinised starch, magnesium

stearate, hydrogenated vegetable oil and colloidal anhydrous silica.

Film-coating:

Hypromellose (E464), titanium dioxide (E171), lactose monohydrate, macrogol 3000 and triacetin.

The finished product is packed into polyvinyl chloride (PVC)/aluminium blisters in a pack size of 90

film-coated tablets.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components.

II.2

Drug Substance

INN:

Nefopam hydrochloride

Chemical name:

3,4,5,6-tetrahydro-5-méthyl-1-phenyl-1H-2,5-benzoxazocine hydrochloride

Structure:

Molecular formula:

ClNO

Molecular weight:

289.80 g/mol

Description:

White crystalline powder.

Solubility:

Soluble in water and methanol. Slightly soluble in chloroform.

Nefopam hydrochloride is the subject of an active substance masterfile (ASMF).

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 for the active substance. 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.

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Batch analyses data are provided that comply with the proposed specification.

Satisfactory Certificates of Analysis have been provided for all working standards used.

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 safe, efficacious film-coated tablets

containing 30 mg nefopam hydrochloride per tablet, that are a generic version of the reference product

Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd, UK). A satisfactory account of the pharmaceutical

development has been provided.

Comparative

in vitro

dissolution profiles have been provided for the proposed and originator products.

All excipients comply with their respective European Pharmacopoeia monographs with the exception of

hydrogenated vegetable oil which is compliant with the British Pharmacopoeia (BP) monograph.

Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data

have been provided for each excipient.

With the exception of lactose monohydrate none of the excipients used contain material of animal or

human origin. The supplier of lactose monohydrate has confirmed that it is sourced from healthy animals

under the same conditions as milk for human consumption.

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 pilot

scale batch size and has 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 which comply with the release specification.

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

the finished product in the packaging proposed for marketing. The data from these studies support a

shelf life of 3 years with no special storage conditions.

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.

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III

NON-CLINICAL ASPECTS

III.1

Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of nefopam hydrochloride 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

Ecotoxicity/environmental risk assessment (ERA)

Since Nefopam tablets are 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

There are no objections to the approval of this application from a non-clinical viewpoint.

IV

CLINICAL ASPECTS

IV.1

Introduction

The clinical pharmacology of nefopam hydrochloride is well-known. With the exception of data from

the bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are

provided or are required for this application.

No new efficacy or safety studies have been performed 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 pharmacology, efficacy and safety of nefopam hydrochloride.

Based on the data provided, Nefopam tablets can be considered bioequivalent to Acupan 30 mg Tablets

(Meda Pharmaceuticals Ltd, UK).

IV.2

Pharmacokinetics

In support of this application, the applicant submitted the following bioequivalence study:

STUDY

An open label, randomised, two-treatment, two period, two-sequence, single oral dose, crossover,

bioequivalence study of the applicant’s test product Nefopam hydrochloride 30mg film-coated

tablets (Galen Limited) versus the reference product Acupan 30 mg Tablets (Meda

Pharmaceuticals Ltd, UK) in healthy, adult, subjects under fasting conditions.

Following a fast of at least 8 hours, subjects were administered a single dose (1 x 30 mg film-coated

tablet) of the test or the reference product. Subjects continued to fast for at least 4 hours post dose.

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PL 27827/0038

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Blood samples were collected for plasma levels before dosing and up to and including 48 hours after

each administration. The washout period between the treatment phases was 7 days. The pharmacokinetic

results are presented below:

Table: Summary of pharmacokinetic data for nefopam (ratio and 90% confidence interval of the

test product versus the reference product):

area under the plasma concentration-time curve from zero to t hours

maximum plasma concentration

Conclusion

The 90% confidence intervals of the test/reference ratio for AUC and C

values for nefopam lie within

the acceptable limits of 80.00% to 125.00%, in line with the guideline on the investigation of

bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the

applicant’s test product, Nefopam hydrochloride 30mg film-coated tablets (Galen Limited)

bioequivalent to the reference product, Acupan 30 mg Tablets (Meda Pharmaceuticals Ltd, UK).

IV.3

Pharmacodynamics

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

IV.4

Clinical efficacy

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

IV.5

Clinical safety

No new safety data were submitted and none are required.

IV.6

Risk Management Plan (RMP) and Pharmacovigilance System

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 pharmacovigilance activities

and interventions designed to identify, characterise, prevent or minimise risks relating to nefopam

hydrochloride.

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

listed below:

PAR Nefopam hydrochloride 30mg film-coated tablets

PL 27827/0038

11

Summary table of safety concerns:

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

IV.7

Discussion on the clinical aspects

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

V

User consultation

A user consultation with target patient groups on the package information leaflet (PIL) has been

performed on the basis of a bridging report making reference to Acupan 30mg Tablets (Meda

Pharmaceuticals Limited; PL 15142/0109). The bridging report submitted by the applicant is acceptable.

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 nefopam hydrochloride is considered to have demonstrated

the therapeutic value of the compound. The product is bioequivalent to the marketed reference product

and its benefit/risk balance is considered similar and positive.

PAR Nefopam hydrochloride 30mg film-coated tablets

PL 27827/0038

12

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for this medicine is presented below:

PAR Nefopam hydrochloride 30mg film-coated tablets

PL 27827/0038

13

PAR Nefopam hydrochloride 30mg film-coated tablets

PL 27827/0038

14

Annex 1

Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Date submitted

Application

type

Scope

Outcome

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