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
Page 10
Steps taken after authorisation – summary
Page 11
Summary of Product Characteristics
Page 12
Product Information Leaflet
Page 12
Labelling
Page 13
UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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 nonprescription medicines, herbal remedies, vitamins and food supplements, as these
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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
WARFARIN 1 MG, 3 MG AND 5 MG TABLETS
(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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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
PIL
The patient information leaflet has been prepared in-line with the details registered for
the cross-reference products.
Carton and blister
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.
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
WARFARIN 1 MG, 3 MG AND 5 MG TABLETS
(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
The applicant responded to the MHRA’s requests, providing further information
on 25 July 2013, 30 September 2013 and 17 December 2013.
The applications were determined on 22 January 2014
4
5
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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
WARFARIN 1 MG, 3 MG AND 5 MG TABLETS
(PL 36390/0136-0138)
STEPS TAKEN AFTER AUTHORISATION - SUMMARY
Date
Application
submitted type
Scope
Outcome
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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
Labelling
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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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UKPAR Warfarin 1 mg, 3 mg and 5 mg Tablets
PL 36390/0136 - 0138
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