PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
1
Public Assessment Report
UKPAR
Metformin Hydrochloride 500 mg and 850 mg film-coated
tablets
(Metformin hydrochloride)
UK Licence No: PL 42289/0003-4
Wave Pharma Limited
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
2
LAY SUMMARY Metformin Hydrochloride 500 mg and 850 mg film-coated tablets
(Metformin hydrochloride)
This is a summary of the Public Assessment Report (PAR) for Metformin Hydrochloride 500 mg and
850 mg film-coated tablets (PL 42289/0003-4). For Ease of reading, these medicinal products will be
referred to as Metformin Tablets in this Lay Summary.
This summary explains how Metformin Tablets were assessed and their authorisations recommended, as
well as their conditions of use. It is not intended to provide practical advice on how to use these
products.
For practical information about using Metformin Tablets, patients should read the package leaflet or
contact their doctor or pharmacist.
What are Metformin Tablets and what are they used for?
This medicine is the same as Metformin 500 mg and 850 mg tablets (PL 36722/0030-0031; Special
Concept Development Ltd), which are already authorised in the UK. The licence holder (Special
Concept Development Ltd) for Metformin 500 mg and 850 mg tablets (PL 36722/0030-0031) has agreed
that its own scientific data can be used as a basis for the grant of identical licences for Metformin
Hydrochloride 500 mg and 850 mg film-coated tablets (PL 42289/0003-4).
Metformin tablets are used for the treatment of type II diabetes (a condition in which the body does not
make enough insulin or where the insulin that the body produces does not work as well as it should) not
controlled by diet and exercise alone. A doctor may prescribe Metformin tablets for a patient to take on
its own or in combination with other oral anti-diabetic medicines called sulphonylureas, or insulin.
How do Metformin Tablets work?
Metformin Tablets contain the active ingredient metformin hydrochloride. Metformin is one of a group
of medicines called oral hypoglycaemics, which works by reducing the level of sugar in the blood.
How are Metformin Tablets used?
Metformin Tablets are taken orally. The tablets should be swallowed whole with a glass of water during
or after meals.
Patients should always take Metformin Tablets exactly as a doctor has told them. Patients must check
with a doctor or pharmacist if they are not sure.
If a patient is taking Metformin tablets continuously, she/he should have regular blood tests to check the
blood glucose levels and kidney function.
The recommended dose for adults is one or two 500 mg tablets, or one 850 mg tablet each day. The dose
will be gradually increased by a doctor until the right dose to control patient’s symptoms is found. In
most cases symptoms can be eventually controlled with three 500 mg tablets or two 850 mg tablets each
day in divided doses. The maximum daily doses are six 500 mg tablets or three 850 mg tablets.
A lower dose may be prescribed in patients with reduced kidney function.
The usual dose in children 10 years and over and adolescents start with 500 mg or 850 mg Metformin
tablet once a day. The maximum daily dose is 2000 mg taken as 2 or 3 divided doses. Treatment of
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
3
children between 10 and 12 years of age is only recommended on specific advice from a doctor, as
experience in this age group is limited.
This medicine can only be obtained with a prescription.
For further information on how Metformin Tablets are used, please see the Summaries of Product
Characteristics or the package leaflet available on the MHRA website.
What benefits of Metformin Tablets have been shown in studies?
As Metformin Hydrochloride 500 mg and 850 mg film-coated tablets (PL 42289/0003-4) are considered
to be identical to the reference products, Metformin 500 mg and 850 mg tablets (PL 36722/0030-0031),
their benefits and risks are taken as being the same as those for the reference products.
What are the possible side effects from Metformin Tablets?
Like all medicines, Metformin Tablets can cause side effects, although not everybody gets them.
The most common side effects (usually when you first start taking metformin) are nausea, vomiting,
abdominal pain, diarrhoea, loss of appetite or a metallic taste.
For the full list of all side effects reported with Metformin Tablets, see section 4 of the package leaflet.
For the full list of restrictions, see the package leaflet.
Why are Metformin Tablets approved?
No new or unexpected safety concerns arose from these applications. It was, therefore, considered that
the benefits of Metformin Tablets outweigh the risks, and the grant of Marketing Authorisations was
recommended.
What measures are being taken to ensure the safe and effective use of Metformin Tablets?
A risk management plan (RMP) has been developed to ensure that Metformin Tablets are used as safely
as possible. Based on this plan, safety information has been included in the Summaries of Product
Characteristics and the patient information leaflet for Metformin Tablets including the appropriate
precautions to be followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore, new safety signals reported by
patients/healthcare professionals will be monitored and reviewed continuously.
Other information about Metformin Tablets
Marketing Authorisations were granted in the UK on 02 January 2018.
The full PAR for Metformin Tablets follows this summary.
This summary was last updated in February 2018.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
4
TABLE OF CONTENTS
I Introduction Page 5
II Quality aspects Page 6
III Non-clinical aspects Page 7
IV Clinical aspects Page 7
V User consultation Page 10
VI Overall conclusion, benefit/risk assessment and
recommendation
Page 11
Table of content of the PAR update Page 15
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
5
I INTRODUCTION
The Medicines and Healthcare products Regulatory Agency (MHRA) granted Wave Pharma Limited
Marketing Authorisations for the medicinal products Metformin Hydrochloride 500 mg and 850 mg
film-coated tablets (PL 42289/0003-4) on 02 January 2018.
These are prescription only medicines (POM), and are indicated for non-insulin-dependent diabetes
(NIDDM, type II) and, in particular, in obese patients, when adequate dietary treatment has failed.
-Metformin can be given alone as initial therapy, or can be administered in combination with
sulphonylureas after careful assessment of the contra-indications.
• In adults, Metformin may be used as monotherapy or in combination with other oral antidiabetic agents
or with insulin.
• In children from 10 years of age and adolescents, Metformin may be used as monotherapy or in
combination with insulin.
A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients
treated with metformin as first-line therapy after diet failure.
These applications were submitted as abridged simple applications, according to Article 10c of Directive
2001/83/EC, as amended. The applicant has cross-referred to Metformin Hydrochloride 500 mg and 850
mg tablets, which were originally authorised to Auden Mckenzie Limited (PL 17507/0007-8) on 04
January 2001. These licenses underwent changes of ownership procedures to the current Marketing
Authorisation Holder (MAH), Special Concept Development Ltd (PL 36722/0030-0031), on 19 June
2014.
Metformin is a biguanide oral anti-hyperglycaemic agent and reduces elevated blood glucose levels only
in patients with non-insulin-dependent diabetes (NIDDM), but does not increase insulin secretion and
does not cause hypoglycaemia or increased weight gain. Its mode of action is multifactorial and not yet
completely understood. However, the augmentation of glucose uptake into peripheral tissues may
influence glucose utilisation. Furthermore, the effects of metformin include reduced hepatic
gluconeogenesis and delayed intestinal glucose absorption which may explain the blood glucose-
lowering effect. The efficacy of metformin is dependent on a minimum concentration of insulin. A slight
influence of the insulin secretion by metformin is possible but a clinical relevance is not very likely.
Metformin seems to potentiate insulin action by enhancing insulin binding to its receptors and by
facilitating steps in the post-receptor pathways of insulin-action. Apart from the glucose-lowering effect,
metformin reduces the serum triglyceride level and possesses antithrombotic properties.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs)
known to date.
No new data were submitted nor were they necessary for these simple applications, as the data are
identical to those of the previously granted cross-reference products.
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 these product.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
6
II QUALITY ASPECTS
II.1 Introduction
These are simple (informed consent) applications for Metformin Hydrochloride 500 mg and 850 mg
film-coated tablets (PL 42289/0003-4), submitted under Article 10c of Directive 2001/83/EC, as
amended. The applicant has cross-referred to Metformin Hydrochloride 500 mg and 850 mg tablets,
which were originally authorised to Auden Mckenzie Limited (PL 17507/0007-8) on 04 January 2001.
These licenses underwent changes of ownership procedures to the current Marketing Authorisation
Holder (MAH), Special Concept Development Ltd (PL 36722/0030-0031) on 19 June 2014. The current
applications are considered valid.
II.2. Drug Substance
Drug substance specification
The proposed drug substance specification is consistent with the details registered for the cross-reference
products.
II.3. Medicinal Product
Name
The proposed product names are Metformin Hydrochloride 500 mg and 850 mg film-coated tablets. The
products have been named in line with current requirements.
Strength, pharmaceutical form, route of administration, container and pack size
Each film-coated tablet contains 500 or 850 mg of metformin hydrochloride, as active ingredient. The
route of administration is oral.
The finished product is packed in blister pack of 28, 56 or 84 (500mg formulation) and 28, 42, 56 or 84
film-coated tablets (850 mg formulation).
Not all pack sizes may be marketed.
The proposed shelf-life is 3 years with a special storage condition “Do not store above 25C”.
The proposed packaging, shelf-life and storage condition are consistent with the details registered for the
cross-reference products.
Marketing Authorisation Holder/Contact Persons/Company
Wave Pharma Limited, 4th Floor Cavendish House, 369 Burnt Oak Broadway, Edgeware, HA8 5AW,
United Kingdom
The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory Curriculum
Vitae (CV) has been provided.
Manufacturer
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.
Qualitative and quantitative composition
The proposed composition is consistent with the details registered for the cross-reference products.
Manufacturing process
The proposed manufacturing process is consistent with the details registered for the cross-reference
products and the maximum batch size is stated.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
7
Finished product/shelf-life specification
The proposed finished product specifications are in line with the details registered for the cross-reference
products.
Bioequivalence
No bioequivalence data are required to support these simple abridged applications as the proposed
products are manufactured to the same formula utilising the same process as the cross-reference
products, Metformin 500 mg and 850 mg tablets (PL 36722/0030-0031).
Expert Report
The applicant cross-refers to the data for Metformin 500 mg and 850 mg tablets (PL 36722/0030-0031),
to which these applications are claimed to be identical. This is acceptable. The applicant has included
expert reports of the applications. Signed declarations and copies of the experts’ CVs are enclosed for
the quality, non-clinical and clinical experts. All are considered to have sufficient experience for their
responsibilities.
II.4 Discussion on chemical, pharmaceutical and biological aspects
The quality data for these applications are consistent with those approved for Metformin 500 mg and
850 mg tablets (PL 36722/0030-0031) and, as such, have been judged to be satisfactory. The grant of
Marketing Authorisations is recommended.
III NON-CLINICAL ASPECTS
As these are abridged simple applications submitted under Article 10c of Directive 2001/83/EC, as
amended, no new non-clinical data has been supplied and none are required.
A suitable justification has been provided for not submitting an environmental risk assessment.
The grant of Marketing Authorisations is recommended.
IV CLINICAL ASPECTS
As these are abridged simple applications submitted under Article 10c of Directive 2001/83/EC, as
amended, no new clinical data have been supplied and none are required.
Risk Management Plan (RMP)
The Marketing Authorisation Holder (MAH) has submitted a risk management plan, 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 Metformin
Hydrochloride 500 mg and 850 mg film-coated tablets.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
8
A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,
is listed below:
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
9
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
10
Discussion on the clinical aspects
The grant of Marketing Authorisations is recommended for these applications.
V User consultation
The package leaflet has been evaluated via a user consultation study, in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The language used for
the purpose of user testing the PIL was English.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
11
The results show that the package leaflet meets the criteria for readability, as set out in the guideline on
the readability of the label and package leaflet of medicinal products for human use.
VI Overall conclusion, benefit/risk assessment and recommendation
The quality of the products is acceptable, and no new non-clinical or clinical concerns have been
identified. The applicant’s product is identical to the reference product. Extensive clinical experience
with metformin hydrochloride is considered to have demonstrated the therapeutic value of the
compound. The benefit-risk assessment is, therefore, considered to be positive.
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
12
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient
Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are
available on the MHRA website.
The approved labelling for Metformin Hydrochloride 500 mg and 850 mg film-coated tablets is
presented below:
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
13
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
14
PAR Metformin Hydrochloride 500 and 850 mg film-coated tablets PL 42289/0003-4
15
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, commitmen
Date
submitted
Application
type
Scope Outcome
