warfarin 1 mg, 3 mg and 5 mg tablets - gov.uk · pdf filethis is a summary of the public...

WARFARIN 1 MG, 3 MG AND 5 MG TABLETS

(warfarin sodium clathrate)

PL 36390/0136 - 0138

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 4

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics

Product Information Leaflet

Labelling

Page 11 Page 12 Page 12 Page 13

UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets PL 36390/0136 - 0138

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LAY SUMMARY Warfarin 1 mg, 3 mg and 5 mg Tablets

(warfarin sodium clathrate) This is a summary of the public assessment report (PAR) for Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 36390/0136-0138). It explains how Warfarin 1 mg, 3 mg and 5 mg Tablets were assessed and their authorisations recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Warfarin 1 mg, 3 mg and 5 mg Tablets. For practical information about using Warfarin 1 mg, 3 mg and 5 mg Tablets, patients should read the package leaflet or contact their doctor or pharmacist. What are Warfarin 1 mg, 3 mg and 5 mg Tablets and what are they used for? Warfarin 1 mg, 3 mg and 5 mg Tablets belong to a group of medicines called anticaogulants. They are used to reduce the clotting ability of the blood. Warfarin 1 mg, 3 mg and 5 mg Tablets are used to treat and prevent blood clots from forming in the legs, lungs, brain and heart. These medicines are identical to Warfarin 1 mg, 3 mg and 5 mg Tablets, which were originally authorised in the UK to Neolab Limited on 11 March 2004 (PL 08137/0093-0095). Following subsequent changes of ownership, the current marketing authorisation holder since 17 October 2012 is Aptil Pharma Ltd (PL 40378/0168-0170). Aptil Pharma Ltd has agreed that scientific data presented for Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 40378/0168-0170) can be used for these applications for Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 36390/0136-0138).

How are Warfarin 1 mg, 3 mg and 5 mg Tablets used?

Warfarin 1 mg, 3 mg and 5 mg Tablets are for oral use only and cannot be obtained without a prescription. Regular blood tests will need to be performed to see how long it takes the blood to clot. These blood tests are very important to ensure that the correct dose has been prescribed. It is recommended that the anticoagulation card is carried at all times. The tablets come in three strengths and colours: 1 mg strength comes in the form of a brown tablet, 3 mg strength comes in the form of a blue tablet and the 5 mg strength comes in the form of a pink tablet. It is recommended that the medicines should be taken at the same time each day. The usual maintenance dose for Warfarin Tablets is between 3-9 mg. Due to the risk of bleeding, the dose of warfarin may need to be lowered before an operation or removal of teeth. If the risk of severe bleeding is likely, warfarin intake must be stopped 72 hours before and after surgery.

How do Warfarin 1 mg, 3 mg and 5 mg Tablets work?

Warfarin 1 mg, 3 mg and 5 mg Tablets contain the active ingredient warfarin sodium clathrate. Warfarin 1 mg, 3 mg and 5 mg Tablets are known as anticoagulants. They work by preventing the formation of blood clots in the legs, lungs, brain and heart by reducing the clotting ability of the blood. The clotting ability of Warfarin 1 mg, 3 mg and 5 mg Tablets can be affected by many other medicines, including non-prescription medicines, herbal remedies, vitamins and food supplements, as these


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medicines can increase the effect of warfarin sodium clathrate and increase the amount of bleeding.

How have Warfarin 1 mg, 3 mg and 5 mg Tablets been studied?

These applications are identical to the previously granted applications for Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 40378/0168-0170; Aptil Pharma Ltd). The applicant (Cipla (EU) Limited) referred to data provided by Aptil Pharma Ltd for the grant of Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 40378/0168-0170) as a basis for the grant of identical licences for Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 36390/0136-0138).

What are the benefits and risks of Warfarin 1 mg, 3 mg and 5 mg Tablets?

Warfarin 1 mg, 3 mg and 5 mg Tablets are considered identical to previously authorised Warfarin 1 mg, 3 mg and 5 mg Tablets (Aptil Pharma Ltd), with the same benefits and risks.

Why are Warfarin 1 mg, 3 mg and 5 mg Tablets approved?

No new or unexpected safety concerns arose from these applications. It was, therefore, considered that the benefits of Warfarin 1 mg, 3 mg and 5 mg Tablets outweigh their risks; and the grant of Marketing Authorisations was recommended.

What measures are being taken to ensure the safe and effective use of Warfarin 1 mg, 3 mg and 5 mg Tablets?

A risk management plan has been developed to ensure that Warfarin 1 mg, 3 mg and 5 mg Tablets are used as safely as possible. Based upon this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Warfarin 1 mg, 3 mg and 5 mg Tablets, including the appropriate precautions to be followed by healthcare professionals and patients.

Other information about Warfarin 1 mg, 3 mg and 5 mg Tablets

Marketing Authorisations were granted in the UK on 22 January 2014. For more information about treatment with Warfarin 1 mg, 3 mg and 5 mg Tablets, read the package leaflet, or contact your doctor or pharmacist.

This summary was last updated in March 2014. The full PAR for Warfarin 1 mg, 3 mg and 5 mg Tablets follows this summary.


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(PL 36390/0136-0138)

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 5

Pharmaceutical assessment

Page 6

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions 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 Marketing Authorisations for the medicinal products Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 36390/0136-0138) on 22 January 2014 to Cipla (EU) Limited. These applications for Warfarin 1 mg, 3 mg and 5 mg Tablets were submitted as abridged simple applications, according to Article 10c of Directive 2001/83/EC, as amended, cross-referring to Warfarin 1 mg, 3 mg and 5 mg Tablets, which were authorised in the UK to Neolab Limited on 11 March 2004 (PL 08137/0093-0095). Following subsequent changes of ownership, the current marketing authorisation holder since 17 October 2012 is Aptil Pharma Ltd (PL 40378/0168-0170). These medicines are prescription only medicines (legal status POM). Warfarin 1 mg, 3 mg and 5 mg Tablets contain the active ingredient warfarin sodium clathrate and are indicated for:

• prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation

• prophylaxis after insertion of prosthetic heart valves

• prophylaxis and treatment of venous thrombosis and pulmonary embolism and transient attacks of cerebral ischaemia.

Warfarin is a synthetic anticoagulant of the coumarin series. It acts by inhibiting the formation of active clotting factors II, VII, IX and X.


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PHARMACEUTICAL ASSESSMENT

LICENCE NO: PL 36390/0136-0138 PROPRIETARY NAME: Warfarin 1 mg, 3 mg and 5 mg Tablets ACTIVE(S): Warfarin sodium clathrate COMPANY NAME: Cipla (EU) Limited E.C. ARTICLE: Article 10c of Directive 2001/83/EC, as amended LEGAL STATUS: POM 1. INTRODUCTION These are simple, piggyback applications for Warfarin 1 mg, 3 mg and 5 mg Tablets submitted under Article 10c of Directive 2001/83/EC, as amended. The proposed MA holder is Cipla (EU) Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW United Kingdom. The applications cross-refer to Warfarin 1 mg, 3 mg and 5 mg Tablets (PL 40378/0168-0170), which are currently authorised in the UK to Aptil Pharma Ltd. The current applications are considered valid. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 NAME(S) The proposed names of the products are Warfarin 1 mg, 3 mg and 5 mg Tablets. The products have been named in-line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes Each tablet contains the active substance warfarin sodium clathrate, which is equivalent to warfarin sodium as follows: Each Warfarin 1 mg Tablet contains 1.10 mg of the active substance warfarin sodium clathrate, which is equivalent to 1.0 mg of warfarin sodium. Each Warfarin 3 mg Tablet contains 3.30 mg the active substance warfarin sodium clathrate, which is equivalent to 3.0 mg of warfarin sodium. Each Warfarin 5 mg Tablet contains 5.46 mg the active substance warfarin sodium clathrate, which is equivalent to 5.0 mg of warfarin sodium. The finished products are packaged in either:

1. high-density polyethylene (HDPE) containers with low-density polyethylene (LDPE) wad and tamper-evident, child-resistant HDPE lids containing 28, 56, 100, 112 or 500 tablets

2. polyvinylchloride (PVC)/polyvinylidene chloride (PVdC)/aluminium blister packs containing 28, 56 or 112 tablets.

The Marketing Authorisation Holder has stated that not all pack sizes are intended for marketing. However, they have committed to providing the relevant licensing authority with the mock-ups for any pack size before marketing it in that country.


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The proposed shelf-life of 2 years for product in either packaging, with the storage conditions “Do not store above 25°C, keep blisters in the outer carton, store in original packaging” for the blister packs and “Do not store above 25°C, keep the container tightly closed” for the HDPE containers are consistent with the details registered for the cross-reference products. 2.3 Legal status On approval, the products are only available with a prescription from a healthcare professional (legal status POM). 2.4 Marketing authorisation holder/Contact Persons/Company Cipla (EU) Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW United Kingdom The QP responsible for pharmacovigilance is stated and his CV is included. 2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference products and evidence of Good Manufacturing Practice (GMP) compliance has been provided. 2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the cross-reference products. 2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference products and the maximum batch sizes are stated. 2.8 Finished product/shelf-life specification The proposed finished product specifications are in line with the details registered for the cross-reference products. 2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross-reference products. 2.10 TSE Compliance With the exception of lactose anhydrous and magnesium stearate, none of the excipients contain materials of animal or human origin. This is consistent with the details for the reference products. It is stated that lactose anhydrous is produced from milk fit for human consumption. The suppliers of magnesium stearate have provided Certificates of Suitability from the European Directorate for the Quality of Medicines and Healthcare (EDQM) to show that it is manufactured in line with the current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE).


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No materials of human origin are included in these products. This is consistent with the cross-reference products. 3. EXPERT REPORTS The applicant has included detailed expert reports in Module 2 of the application. Signed declarations and copies of the experts’ CVs are enclosed in Module 1.4 for the quality, non-clinical and clinical experts. All are considered to have sufficient experience for their responsibilities. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product names. The appearances of the products are identical to the cross-reference products. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The proposed SmPCs are consistent with the details registered for the cross-reference products. 6. PATIENT INFORMATION LEAFLET (PIL)/CARTON

The patient information leaflet has been prepared in-line with the details registered for the cross-reference products.

PIL

The proposed artwork is comparable to the artwork registered for the cross-reference products and complies with statutory requirements. In-line with current legislation, the applicant has also included the name of the products in Braille on the outer packaging and has included sufficient space for a standard UK pharmacy dispensing label.

Carton and blister

7. CONCLUSIONS The data submitted with these applications are acceptable. From a quality perspective, Marketing Authorisations should be granted.

NON-CLINICAL ASSESSMENT

No new non-clinical data have been supplied with these applications and none are required for applications of this type.


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CLINICAL ASSESSMENT

No new clinical data have been supplied with these applications and none are required for applications of this type.

OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Warfarin 1 mg, 3 mg and 5 mg Tablets are identical to those of the already granted reference products. 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. CLINICAL PHARMACOLOGY/EFFICACY No new clinical pharmacology/efficacy data have been submitted with these applications and none are required for applications of this type. SAFETY No new safety data have been submitted with these applications and none are required for applications of this type. No new or unexpected safety concerns arise from these applications. The SmPCs, PIL and labels are satisfactory. Pharmacovigilance System and Risk Management Plan The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant 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. A risk management plan has been developed to ensure that Warfarin 1 mg, 3 mg and 5 mg Tablets are used as safely as possible. Based upon this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Warfarin 1 mg, 3 mg and 5 mg Tablets, including the appropriate precautions to be followed by healthcare professionals and patients. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with Warfarin 1 mg, 3 mg and 5 mg Tablets is considered to have demonstrated the therapeutic value of the products. The benefit/risk is, therefore, considered to be positive.


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(PLs 36390/0136-0138)

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation applications on 31 December

2012

2 Following standard checks and communication with the applicant, the MHRA considered the applications valid on 31 January 2013

3 Following assessment of the applications, the MHRA requested further information relating to the dossiers on 01 May 2013, 05 September 2013 and 31 October 2013

4 The applicant responded to the MHRA’s requests, providing further information on 25 July 2013, 30 September 2013 and 17 December 2013.

5 The applications were determined on 22 January 2014


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(PL 36390/0136-0138) STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome


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Summary of Product Characteristics and Patient Information Leaflet The current approved UK versions of the Summary of Product Characteristics (SmPCs) and Patient Information Leaflet (PILs) for these products is available on the MHRA website.


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Labelling


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