galpharm period pain relief 250mg gastro- resistant ... galpharm period pain relief 250mg gastro-...

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Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets

PL 16028/0144

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 2

Scientific Discussion

Page 4

Steps Taken After Initial Authorisation

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Summary of Product Characteristics

Page 11

Patient Information Leaflet

Page 12

Labelling

Page 13

Annex 1 Page 15

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GALPHARM PERIOD PAIN RELIEF 250MG GASTRO-RESISTANT TABLETS

PL 16028/0144

LAY SUMMARY

This is a summary of the public assessment report (PAR) for Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets (PL 16028/0144). It explains how Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets 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 Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets. This medicinal product will be referred to as Galpharm Period Pain Relief in the remainder of this summary. For practical information about using Galpharm Period Pain Relief, patients should read the package leaflet or contact their doctor or pharmacist. What is Galpharm Period Pain Relief and what is it used for? Galpharm Period Pain Relief is a ‘General Sales List’ product (legal status ‘GSL’) containing the active ingredient naproxen. It is used for the treatment of period pain (menstrual pain or dysmenorrhoea). How does Galpharm Period Pain Relief work? Galpharm Period Pain Relief contains 250 mg naproxen. Naproxen belongs to a group of painkillers called non-steroidal anti-inflammatory drugs (also called NSAIDs). NSAIDs work by blocking the COX-1 and COX-2 enzymes which, in turn, stops the body from making as many prostaglandins. This results in less swelling and less pain How is Galpharm Period Pain Relief used? The tablets should be swallowed whole with water. The lowest effective dose should be taken and no more than three tablets should be taken in a day. The tablets should not be taken for more than 3 days in any one month (menstrual cycle). What benefits of Galpharm Period Pain Relief have been shown in studies? With the exception of the reclassification of the legal status of this product from pharmacy medicine (legal status P) to a general sales list medicine (GSL), this product is identical to the reference product Naproxen 250mg enteric coated tablets (PL 00289/0699), which was licensed for use in the UK on 12 September 2007 to Teva UK Limited. Therefore, no new studies have been provided but reference is made to the Marketing Authorisation owned by Teva UK Limited.

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What are the possible side effects from Galpharm Period Pain Relief? Like all medicines Galpharm Period Pain Relief can cause side effects, although not everybody gets them. For the full list of all side effects reported with Galpharm Period Pain Relief, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why is Galpharm Period Pain Relief approved? It was concluded that, in accordance with EU requirements, Galpharm Period Pain Relief is identical to the reference product that has been granted in the UK. Additionally, the product has been authorised as a GSL medicine following advice from the Commission of Human Medicines (CHM) and a period of consultation. The benefit-risk profile for this product available without the supervision of a pharmacist was considered to be favourable and a Marketing Authorisation was granted. What measures are being taken to ensure the safe and effective use of Galpharm Period Pain Relief? A Risk Management Plan has been developed to ensure Galpharm Period Pain Relief 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 Galpharm Period Pain Relief, 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 Galpharm Period Pain Relief A Marketing Authorisation was granted in the UK on 7 January 2010. This summary was last updated in October 2016. The full PAR for Galpharm Period Pain Relief follows this summary.

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GALPHARM PERIOD PAIN RELIEF 250MG GASTRO-RESISTANT TABLETS

PL 16028/0144

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 5

Pharmaceutical Assessment

Page 6

Preclinical Assessment

Page 7

Clinical Assessment

Page 8

Overall Conclusion and Benefit/Risk Assessment Page 9

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INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted a marketing authorisation for the medicinal product Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets to Galpharm Healthcare Limited on 7 January 2010. Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets is indicated for the treatment of primary dysmenorrhoea in women aged 15 to 50 years. The abridged application for Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets was submitted under Article 10(c) of EC Directive 2001/83, as amended, claiming identicality to Naproxen 250mg enteric coated tablets (PL 00289/0699), which was licensed for use in the UK on 12 September 2007 to Teva UK Limited. Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets was subsequently reclassified as a GSL medicine.

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PHARMACEUTICAL ASSESSMENT

INTRODUCTION An appropriate letter of consent from Teva UK Limited has been submitted. Galpharm Healthcare Limited have indicated that they hold a copy of Module 3 of the dossier and the manufacturer of the reference product has indicated that it will manufacture the proposed product for Galpharm Healthcare Limited. NAPROXEN The naproxen used in this product is controlled by a suitable certificate of suitability and is, therefore, satisfactory. The naproxen complies with the Ph Eur monograph. DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT The product is a white biconvex coated tablet with“3N3” printed in black. Each table contains 250 mg naproxen and the excipients lactose monohydrate, maize starch, polyvidone, sodium starch glycollate (type A), magnesium stearate (E572), hydroxypropyl methylcellulose (E464), colloidal silicon dioxide, polyethylene glycol, polyvinyl acetate phthalate, purified stearic acid (E570), purified talc (E553(b)), sodium alginate (E401), sodium bicarbonate (E500), triethyl citrate, titanium dioxide (E171), shellac (E904), soya lecithin (E322), antifoam agent and black iron oxide (E172). The product is stored in blister strips in packs of 3, 6, 8 or 9 tablets. There is no difference between the composition of the proposed product and that of the already licensed cross reference product. ADDITIONAL DATA REQUIREMENTS The manufacturing process, finished product specification and active ingredient specification are in line with those for the reference product and are satisfactory. The applicant has provided TSE appropriate declarations from the manufacturers/suppliers of all excipients used in the manufacture of the finished. EXPERT REPORTS Satisfactory expert reports in the form of quality, non-clinical and clinical overall summaries are provided, with signed declarations from each expert confirming that the applicant’s product is identical to the reference product in all particulars. Expert CVs are also submitted and are acceptable. PRODUCT LITERATURE The proposed SmPC, PIL and labels are consistent with the detailed registered for the reference product, with the exception of revisions associated with the difference in the products’ legal status. The package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. ASSESSOR’S OVERALL CONCLUSIONS A product licence may be granted for this product.

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PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with this application and none are required for an application of this type.

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CLINICAL ASSESSMENT

OVERVIEW A statement has been provided confirming that the clinical particulars for Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets are identical to those for the already licensed product; Naproxen 250mg enteric coated tablets (PL 00289/0699). This is satisfactory.

BIOAVAILABILITY AND BIOEQUIVALENCE No bioequivalence study has been performed to support this application and none is needed. PRODUCT LITERATURE All product literature is medically satisfactory. ASSESSOR’S OVERALL CONCLUSIONS It is recommended that a Marketing Authorisation can be granted.

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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets (PL 16028/0144) is identical to the already licensed reference product. This product is, therefore, pharmaceutically satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY The efficacy of naproxen is well established. The SmPC, PIL and labelling are satisfactory and consistent with those for the cross-reference product, with the exception of revisions associated with the difference in the products’ legal status. RISK BENEFIT ASSESSMENT The quality of the product is acceptable, no significant preclinical or clinical safety concerns were identified, and benefit has been shown to be associated with naproxen. The risk benefit ratio is therefore considered to be acceptable.

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STEPS TAKEN AFTER INITIAL AUTHORISATION

Date submitted

Application type Scope Outcome

26/09/2014 Type IA variation To register introduction of a summary of pharmacovigilance system.

24/10/2014 - granted

16/02/2016 Type IA variation 1) To register a change in address of MA holder- Galpharm Healthcare Limited, from Hugh House, Galpharm Way, Upper Cliffe Road, Dodworth Business Park, Dodworth, Barnsley, S75 3SP to Wrafton, Braunton, Devon, EX33 2DL, the marketing authorisation holder shall remain the same legal entity. 2) To implement the ADR reporting statement into the Summary of Product Characteristics and the Patient Information Leaflet. Consequentially, the PIL, label and sections 4.8 and 7 of the SmPC have been updated.

04/03/2016 - granted

10/12/2009 Type II variation reclassification

To change the legal status of the drug product from Pharmacy (P) to General Sale List (GSL). See Annex 1 for further details

07/10/2016 - granted

01/06/2015 PIU Leaflet This application is submitted under Article 61(3) change code P2 to re-user test the patient information leaflet for Galpharm Period Pain Relief 250mg Gastro-resistant Tablets in association with the ongoing reclassification procedure

07/10/2016 - granted

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SUMMARY OF PRODUCT CHARACTERISTICS

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.

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PATIENT INFORMATION LEAFLET

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.

UKPAR Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets, PL 16028/0144

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LABELLING

Blister:


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Carton:


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Annex 1

Public Assessment Report

Pharmacy to General Sales List Reclassification

Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets

PL 16028/0144 – 0002

TABLE OF CONTENTS

Introduction Page 14 Background Page 14 Proposed terms of reclassification General Sales List criterion Page 15 Assessment of Suitability for General Sales List availability

Page 15

Advice from Expert Advisory Groups and the Commission on Human Medicines

Page 17

Consultation on GSL availability of naproxen Page 17 Conclusion Page 18


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1. Introduction

Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets is a medicine to be taken by mouth for the treatment of primary dysmennorrhoea (period pain) in women aged 15-50 years. The active ingredient in the product is naproxen, which is in the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). The licence holder Galpharm Healthcare Limited applied to make this product available as a General Sale List medicine (GSL) for sale through general retail outlets. The Medicines and Healthcare product Regulatory Agency (MHRA) considers this product is safe enough to be sold on general sale. This report outlines the evidence that the MHRA reviewed which led to the decision to approve the application.

2. Background Naproxen is a non-steroidal anti-inflammatory drug (NSAID) which has been licensed in the UK since 1973. It is currently marketed in the form of tablets by several companies. Typical indications for when it is available on prescription are: pain and inflammation in rheumatic disease and other musculoskeletal disorders; dysmenorrhoea; acute gout. Naproxen was first reclassified from a prescription medicine to a medicine that is available in pharmacies (as a Pharmacy (P) medicine) in February 2008 as Feminax Ultra (Galpharm) for the treatment of primary dysmenorrhoea in women between 15 and 50 years only. The conditions for P supply are: 1 CONDITIONS FOR PHARMACY SUPPLY Product will be Prescription Only Medicine unless the following conditions are met: For internal use, in the form of enteric coated tablets For the treatment of primary dysmenorrhoea in women aged between 15 and 50 years Maximum strength: 250mg Maximum dose: 500mg Maximum daily dose: 750mg Maximum duration of treatment: 3 days Maximum pack size: 9 tablets

This is the first application for General Sales List availability for this product in the UK. The proposed dosage regimen for GSL supply is the currently authorised dosage regimen for P supply: starting dose of 2 x 250mg followed 6-8 hours later with a subsequent dose of 250mg, subsequently on days 2 and 3 taking one tablet every 6-8 hours, max 3 tablets each day. 2.1 Treatment of dysmenorrhoea Dysmenorrhoea (also known as period pain) is painful cramping, usually in the lower abdomen, sometimes radiating to the lower back or the thighs and occurring prior to and/or during menstruation (periods). Dysmenorrhoea is divided into two categories: • Primary dysmenorrhoea is the onset of painful cramping, in the absence of any identifiable

pelvic complication. • Secondary dysmenorrhoea is associated with an underlying pelvic condition such as

endometriosis, fibroids (myomas), endometrial polyps, adenomyosis, pelvic inflammatory disease or the use of an intrauterine contraceptive device.


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Most patients self treat for dysmennorhoea, either using medicines available in pharmacies or on general sales. These include aspirin, paracetamol and ibuprofen as well as combination analgesics (painkillers) which may contain codeine. There are many such analgesics available which are licensed for a range of short term self limiting painful conditions such as headache, toothache, backache and flu, as well as dysmennorhoea. 2.2 Legal status of naproxen Naproxen has been available as a prescription medicine since 1973, and from pharmacies without prescription since 2008. 2.3 Legal status of other dysmenorrhoea treatments Other types of product are available as GSL in the UK for the treatment of self limiting painful conditions, including dysmonorrhoea. These include aspirin, paracetamol and ibuprofen.

3. Proposed terms of reclassification The applicant proposes the following conditions for GSL supply of Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets:

- For oral use - Strength: 250mg Naproxen - For the relief of primary dysmenorrhoea - Women aged 15 to 50 years - Maximum dose: 500mg naproxen - Maximum daily dose: 750mg naproxen - Maximum duration of treatment 3 days - Maximum pack size: 9 tablets (containing 2.25g naproxen)

4. General Sales List criterion

Under the provisions of The Human Medicines Regulations 2012, regulation 62(5), General Sales List is appropriate for medicines which can, with reasonable safety, be sold or supplied without prescription by someone other than a pharmacist. The term “with reasonable safety” has been defined as: “where the hazard to health, the risk of misuse, or the need to take special precautions in handling is small and where wider sale would be a convenience to the purchaser."

5. Assessment of suitability for general sales list availability The MHRA assessed the application against the General Sales List criterion, stated in Section 4.

5.1 Hazard to health 5.1.1. Safety profile

Naproxen has been in use for a considerable number of years and has a well-established safety profile. The safety and tolerability of naproxen is supported in particular by post-marketing experience from the over 6 million naproxen tablets that have been supplied since March 2008, when naproxen became available as a Pharmacy medicine. The main concerns regarding the safety of naproxen are the gastrointestinal and cardiovascular safety. It has been shown that the risks of these adverse effects are less in the younger population targeted by this product and also when naproxen is used for only a short period of time. As the proposed pack size is 9 tablets, which gives 3 days supply Galpharm Period Pain Relief 250mg Gastro-Resistant Tablets can only be used for a short course. The indication of dysmenorrhoea also means that the tablets will only be needed for one course per month, which will also decrease the risks of serious adverse effects.


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Adequate warnings of possible side effects are included in the Patient Information Leaflet to alert the consumer to seek medical advice should they experience side effects. Also, there are adequate warnings to alert the patient not to take naproxen if they are taking other NSAIDs, have kidney, liver, heart or stomach problems or are taking other interacting medicines. The applicant has submitted a PSUR covering the period from when these were reclassified to a Pharmacy medicine (February 2008), which focuses on naproxen used in the non-prescription environment. Adverse events described in the PSUR do not raise any new or unexpected safety issues related to OTC use of naproxen. The low numbers of reported adverse reactions discussed by the applicant are reassuring The Expert Working Group on the Review of Non-prescrtiption Analgesics considered the data relating to the cardiovascular risk of naproxen from the Coxib and traditional NSAID Trialists’ (CNT) Collaboration meta-analyses of NSAID trials. They concluded that the benefits continue to outweigh the risks for naproxen. Data suggest that the use of naproxen at prescription doses may be associated with a lower cardiovascular risk than other NSAIDS. There are insufficient data regarding the effects of low dose naproxen (up to 750 mg) daily to draw firm conclusions. This expert working group was set up by the CHM in 2013 in the light of evidence about the cardiovascular risks associated with diclofenac and ibuprofen. Overall, the safety profile of naproxen is considered acceptable for GSL availability.

5.1.2 Drug interactions Drug interactions involving naproxen (and other NSAIDs) are well established. A complete list of interacting medicines is provided in the leaflet, and this is in line with the MHRA Minimum Clinical Particulars for GSL NSAIDs which have been applied to GSL ibuprofen since 2007. To minimise the risk, the outer carton states “If you are taking any other medicines please read the leaflet carefully.” Those patients on other medication should therefore be directed to the Patient Informaiton Leaflet (PIL) to ensure they take the product appropriately.

5.2 Risk of misuse 5.2.1 Misuse and abuse

The risk of intentional/unintentional overdose or prolonged treatment is considered to be low. Naproxen can be considered to be similar to ibuprofen in its toxic effects and management; it is considered to have a low toxicity in overdose with drowsiness and abdominal discomfort being the main symptoms. There is no evidence of naproxen as a drug of abuse.

5.2.2 Misdiagnosis Dysmenorrhoea has been safely and effectively self treated using general sale analgesics such as ibuprofen for decades. Naproxen is no more likely to mask an underlying condition than any existing GSL period pain reliever. The applicant’s up to date and specifically targeted labelling and small pack size can be expected to ensure appropriate use and quickly refer patients with underlying conditions to their GP, by including a section on symptoms which warrant a discussion with a pharmacist or doctor. For example the labelling will state that women who first get period pain more than a year after starting their periods should first discuss this with their health professional before taking naproxen. This is because a delay in onset of period pain after periods start may be an indication of secondary dysmenorrhoea. Similarly, the patient information leaflet for this medicine gives instruction for the patient to talk to their doctor or pharmacist if the medication is ineffective or if they have any side effect. Direct referencing to the MHRA Yellow Card scheme is also given within the leaflet. The Yellow Card Scheme enables patients to report a suspected side effect to a medicine, which helps the MHRA identify issues which might not have been previsouly known about. Reports can be made online here: https://yellowcard.mhra.gov.uk


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5.3 Special precautions in handling

There are no special precaution in handling Galpharm Period Pain Relief.

5.4 Wider sale would be a convenience Dysmenorrhoea is a well-established GSL indication within the UK environment. Occasionally it may be necessary to purchase a medicine for relief of period pains at an inconvenient time when many pharmacies are closed. Therefore the availability of Galpharm Period Pain Relief Tablets at outlets other than pharmacies may afford some increased convenience to the consumer.

6. Advice from Expert Advisory Groups and the Commission on Human Medicines The Medicines for Womens Health Expert Advisory Group recommended that Galpharm Period Pain Relief could be safety supplied as a GSL medicine under the following conditions:

• For oral use • Strength: 250mg Naproxen • For the relief of primary dysmenorrhoea • Women aged 15 to 50 years • Maximum dose: 500mg naproxen • Maximum daily dose: 750mg naproxen • Maximum duration of treatment 3 days • Maximum pack size: 9 tablets (containing 2.25g naproxen)

The Commission on Human Medicines also considered the available evidence and advised in favour of GSL availability of Galpharm Period Pain relief under the above conditions.

7. Consultation on GSL availability of naproxen Consultation document ARM 87, which summarises the proposals on the Pharmacy (P) to General Sales List (GSL) reclassification of Galpharm Period Pain Relief 250mg Tablets, was posted on the gov.uk website on 17 February 2014. The deadline for comments was given as 17 March 2014. ARM 87 can be accessed via the following link: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/281218/Classification_of_Galpharm_Period_Pain_Releif_250mg_gastro-resistant_tablets.pdf Ten responses were received. All responses were opposed to the proposal for various reasons. Overall, no new key issues of concern have been raised in relation to GSL availability of naproxen as the responses reflect concerns which had previously been considered and addressed by CHM when giving their advice in favour of GSL supply. Respondents did note a number of concerns that were addressed by improving the patient information leaflet and label following the consultation period. The patient information leaflet text and design have been revised and user-tested to ensure that patients can make an informed decision about this medicine. The following is a summary of the key issues raised. Concerns about side effect profile and gastro-intestinal risks - The limited duration of use of this product and the limitation of use to women of 50 years and younger will minimise the risks of adverse reactions that are generally associated with longer term use of NSAIDs and particularly in the older population. This is also in line with the advice to use NSAIDs at the lowest effective dose for the shortest duration necessary. The leaflet advises patients always to take the lowest effective dose, and not to take the product for longer than three days in any one month. The leaflet instructs the patient not to take the product if they have ever experienced stomach ulcer, perforation or gastro-intestinal bleeding.

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/281218/Classification_of_Galpharm_Period_Pain_Releif_250mg_gastro-resistant_tablets.pdf�

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/281218/Classification_of_Galpharm_Period_Pain_Releif_250mg_gastro-resistant_tablets.pdf�


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Concerns about patients’ ability to self-diagnose dysmenorrhoea - It is accepted that the pharmacist’s advice is not needed for women to self-diagnose period pain, and a range of general sale products (e.g. ibuprofen) have been used for many years to self-medicate. There is a risk that taking naproxen will mask the pain of secondary dysmenorrhoea, e.g. endometriosis, pelvic inflammatory disease, fibroids, dyspareunia. However, the package leaflet clearly alerts women to the possibility that menstrual pain may indicate the possible presence of significant disease and provides advice on symptoms that warrant further investigation. The leaflet text is now considered sufficient for the patient to identify any symptoms that may require referral. Concerns about patients not being advised about interactions – A complete list of interacting medicines is provided in the leaflet, and this is in line with the MHRA Minimum Clinical Particulars for GSL NSAIDs which have been applied to GSL ibuprofen since 2007. This is not an issue that is specific to the proposed GSL naproxen and it is considered that the text in the leaflet and label adequately address this concern. Concerns about more than one oral NSAID being available as GSL – There are already two oral NSAIDs available as GSL (ibuprofen, aspirin) and the risks of them being taken together are already addressed through the patient information of these products. In the same way, in relation to this product, as well as the list of interacting medicines in the leaflet, the label provides specific warnings that the patient should not take this medicine if they “are taking other NSAID painkillers (e.g. aspirin, ibuprofen). Concerns about whether naproxen was required as an additional GSL analgesic as ibuprofen and paracetamol are already indicated for dysmenorrhoea – It has been demonstrated that this product meets the criteria for GSL supply, women should be allowed wider access to it and increased choice of treatments for this condition. The product information advises patients not to take more than one non-steroidal anti-inflammotory medicine concurrently.

8. Conclusion Assessment of the responses to consultation on the application for Galpharm Period Pain Relief has revealed no new issues of concern in addition to those already considered by CHM and on which CHM were reassured. Specific issues raised in response to the public consultation have been addressed by amendments to the patient information. In light of the advice from the CHM the Licensing Authority has taken the decision to approve GSL legal status for Galpharm Period Pain Relief. MHRA October 2016

galpharm period pain relief 250mg gastro- resistant ... galpharm period pain relief 250mg gastro-...

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