public assessment report levodopa/carbidopa/entacapone · pdf fileukpar...

Public Assessment Report

Levodopa/Carbidopa/Entacapone 50 mg/12.5 mg/200

mg film-coated tablets



Levodopa/Carbidopa/Entacapone 100 mg/25 mg/200 mg

film-coated tablets





Levodopa/Carbidopa/Entacapone 200 mg/50 mg/200


(Levodopa, carbidopa and entacapone)

UK Licence No.: PL 36687/0161-0166

Torrent Pharma (UK) Ltd

UKPAR Levodopa/Carbidopa/Entacapone film-coated tablets PL 36687/0106-0166

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Lay Summary

Levodopa/Carbidopa/Entacapone 50 mg/12.5 mg/200 mg film-coated tablets


Levodopa/Carbidopa/Entacapone 100 mg/25 mg/200 mg film-coated tablets



Levodopa/Carbidopa/Entacapone 200 mg/50 mg/200 mg film-coated tablets

(levodopa, carbidopa and entacapone)

The products Levodopa/Carbidopa/Entacapone 50 mg/12.5 mg/200 mg, 75 mg/18.75

mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg /200 mg, 150 mg/37.5 mg/200

mg and 200 mg/50 mg/200 mg film-coated tablets may be referred to as

‘Levodopa/Carbidopa/Entacapone film-coated tablets’ in this lay summary.

This is a summary of the Public Assessment Report (PAR) for

Levodopa/Carbidopa/Entacapone film-coated tablets (PL 36687/0161-0166). It

explains how Levodopa/Carbidopa/Entacapone film-coated tablets were assessed and

their authorisation recommended, as well as the conditions of use. It is not intended to

provide practical advice on how to use these products.

For practical information about using Levodopa/Carbidopa/Entacapone film-coated

tablets, patients should read the package leaflet or contact their doctor or pharmacist.

What are Levodopa/Carbidopa/Entacapone film-coated tablets and what are

they used for?

These medicines are the same as Levodopa/Carbidopa/Entacapone Torrent Tablets

(PL 36687/0125-0130), authorised to the same Marketing Authorisation Holder

(Torrent Pharma (UK) Ltd).

Levodopa/Carbidopa/Entacapone film-coated tablets are used for the treatment of

Parkinson’s disease.

How do Levodopa/Carbidopa/Entacapone film-coated tablets work?

Parkinson’s disease is caused by low levels of a substance called dopamine in the

brain.

Levodopa/Carbidopa/Entacapone film-coated tablets contain three active substances

(levodopa, carbidopa and entacapone) in one film-coated tablet. Levodopa increases

the amount of dopamine and hence reduces the symptoms of Parkinson’s disease.

Carbidopa and entacapone improve the antiparkinson effects of levodopa.

How are Levodopa/Carbidopa/Entacapone film-coated tablets used?

Levodopa/Carbidopa/Entacapone film-coated tablets are taken by mouth.

Levodopa/Carbidopa/Entacapone film-coated tablets can only be obtained with a

prescription. The tablets should be taken exactly as told by the doctor or pharmacist.

The patient should check with the doctor or pharmacist if not sure.


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For adults and elderly:

The patient’s doctor will tell the patient exactly how many tablets of this medicine to

take each day.

The tablets are not intended to be split or broken into smaller pieces.

The patient should take only one tablet each time.

Depending on how the patient responds to treatment, the patient’s doctor may suggest

a higher or lower dose.

If the patient is taking Levodopa/Carbidopa/Entacapone 50 mg/12.5 mg/200 mg, 75

mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg or 150

mg/37.5 mg/200 mg tablets, no more than 10 tablets per day should be taken.

If a patient is taking Levodopa/Carbidopa/Entacapone 200 mg/50 mg/200 mg, they

should not take more than 7 tablets of this strength per day.

The patient should speak to the doctor or pharmacist if he/she thinks the effect of this

medicine is too strong or too weak, or if he/she experiences possible side effects.

For further information on how Levodopa/Carbidopa/Entacapone film-coated tablets

are used, please refer to the package leaflet and Summaries of Product Characteristics

available on the Medicines and Healthcare products Regulatory Agency (MHRA)

website.

What benefits of Levodopa/Carbidopa/Entacapone film-coated tablets have been

shown in studies? As Levodopa/Carbidopa/Entacapone film-coated tablets ((PL 36687/0161-0166) are

considered to be identical to Levodopa/Carbidopa/Entacapone Torrent Tablets (PL

36687/0125-0130), their benefits and risks are taken as being the same as those for

Levodopa/Carbidopa/Entacapone Torrent Tablets (PL 36687/0125-0130).

What are the possible side effects from Levodopa/Carbidopa/Entacapone film-

coated tablets?

Like all medicines, this medicine can cause side effects, although not everybody gets

them.

The most common side effect Levodopa/Carbidopa/Entacapone film-coated tablets

which may affect more than 1 in 10 people are:

- uncontrolled movements (dyskinesias)

- feeling sick (nausea)

- harmless reddish-brown discoloration of urine

- muscle pain

- diarrhoea.

The common side effects with Levodopa/Carbidopa/Entacapone film-coated tablets

which may affect up to 1 in 10 people are:


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- light-headedness or fainting due to low blood pressure, high blood pressure

- worsening of Parkinson`s symptoms, dizziness, drowsiness

- vomiting, abdominal pain and discomfort, heartburn, dry mouth, constipation

- inability to sleep, hallucinations, confusion, abnormal dreams (including

nightmares), tiredness

- mental changes – including problems with memory, anxiety and depression

(possibly with thoughts of suicide)

- heart or artery disease events (for example chest pain), irregular heart rate or rhythm

- more frequent falling

- shortness of breath

- increased sweating, rashes

- muscle cramps, swelling of legs

- blurred vision

- anaemia

- decreased appetite, decreased weight

- headache, joint pain

- urinary tract infection.

For the full list of all side effects reported with Levodopa/Carbidopa/Entacapone film-

coated tablets, see section 4 of the package leaflet.

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

Why are Levodopa/Carbidopa/Entacapone film-coated tablets approved?

These medicines are the same as the already approved

Levodopa/Carbidopa/Entacapone Torrent Tablets (PL 36687/0125-0130). No new or

unexpected safety concerns arose from these applications. It was, therefore,

considered that the benefits of Levodopa/Carbidopa/Entacapone film-coated 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

Levodopa/Carbidopa/Entacapone film-coated tablets?

A Risk Management Plan (RMP) has been developed to ensure that

Levodopa/Carbidopa/Entacapone film-coated 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

Levodopa/Carbidopa/Entacapone film-coated tablets, including the appropriate

precautions to be followed by healthcare professionals and patients.

Other information about Levodopa/Carbidopa/Entacapone film-coated tablets

Marketing Authorisations were granted in the UK on 21 July 2016.

For more information about taking Levodopa/Carbidopa/Entacapone film-coated

tablets, read the package leaflet, or contact your doctor or pharmacist.

The full PAR for Levodopa/Carbidopa/Entacapone film-coated tablets follows this

summary.

This summary was last updated in September 2016.


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Table of Contents

I Introduction Page 6

II Quality aspects Page 7

III Non-clinical aspects Page 8

IV Clinical aspects Page 9

V User consultation Page 10

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 10

Table of content of the PAR update

Page 24


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I Introduction The Medicines and Healthcare products Regulatory Agency (MHRA) granted Torrent

Pharma (UK) Ltd, Marketing Authorisations for the medicinal products

Levodopa/Carbidopa/Entacapone 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,

100 mg/25 mg/200 mg, 125 mg/31.25 mg /200 mg, 150 mg/37.5 mg/200 mg and 200

mg/50 mg/200 mg film-coated tablets (PL 36687/0161-0166) on 21 July 2016. These

products are prescription only medicines (POM) indicated for the treatment of adult

patients with Parkinson’s disease and end-of-dose motor fluctuations not stabilised on

levodopa/dopa decarboxylase (DDC) inhibitor treatment.

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

Levodopa/Carbidopa/Entacapone Torrent Tablets (PL 36687/0125-0130), which were

first authorised to Torrent Pharma (UK) Ltd on 12 September 2014.

The active ingredients in these products are levodopa, carbidopa and entacapone.

Levodopa mediates the antiparkinsonian effect whereas carbidopa and entacapone

inhibit the peripheral metabolism of levodopa.

Levodopa is a precursor of dopamine and is given as replacement therapy in

Parkinson's disease.

Carbidopa is a peripheral DOPA-decarboxylase inhibitor. It prevents metabolism of

levodopa to dopamine in the peripheral circulation, ensuring that a higher proportion

of the dose reaches the brain, where dopamine acts. A lower dose of levodopa can be

used, reducing the incidence and severity of side effects.

Entacapone is a reversible, specific and mainly peripherally acting catechol-O-

methyltransferase (COMT) inhibitor. Entacapone decreases the metabolic loss of

levodopa to 3-O-methyldopa (3-OMD) mainly in peripheral tissues. The amount of

levodopa available to the brain is increased, thus prolongs the clinical response to

levodopa.

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 these product types at all sites responsible for the

manufacture and assembly of these products.

A Risk Management Plan (RMP) and a summary of the pharmacovigilance system

have been provided with these applications, and these are satisfactory.


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II Quality aspects II.1 Introduction These are abridged simple, informed consent applications for



mg/50 mg/200 mg film-coated tablets (PL 36687/0161-0166), submitted under Article

10c of Directive 2001/83/EC, as amended. The applicant has cross-referred to

Levodopa/Carbidopa/Entacapone Torrent Tablets (PL 36687/0125-0130), which were

first authorised to Torrent Pharma (UK) Ltd on 12 September 2014. The current

applications are considered valid.

II.2. Drug Substance

Drug substance specifications

The proposed drug substance specifications are consistent with the details registered

for the cross-reference products.

II.3. Medicinal Product

Names

The proposed product names are Levodopa/Carbidopa/Entacapone 50 mg/12.5

mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg /200

mg, 150 mg/37.5 mg/200 mg and 200 mg/50 mg/200 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 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,

100 mg/25 mg/200 mg, 125 mg/31.25 mg /200 mg, 150 mg/37.5 mg/200 mg or 200

mg/50 mg/200 mg of Levodopa/Carbidopa/Entacapone respectively as active

ingredients. The route of administration is oral.

The products are packaged in either:

1. Oriented polyamide/aluminium/polyvinylchloride/aluminium

(OPA/Al/PVC/Al) blisters.

2. High-density polyethylene (HDPE) bottles, with continuous threaded closures

and induction sealing wads or HDPE bottles, neck finish with child-resistant

closures and induction sealing wads. Each HDPE bottle contains 1 silica gel

canister.

The products are available in pack sizes of 10, 30, 100, 130, 175, 250 and 500

(hospital pack, for use on more than one patient) film-coated tablets.

Not all pack sizes may be marketed.

The proposed shelf-life is 3 years with no special storage conditions. Once the bottle

is opened the product must be used within 6 months.

The proposed packaging and shelf-life are consistent with the details registered for the

cross-reference products.

Legal status

These products are prescription only medicines (POM).


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Marketing Authorisation Holder/Contact Persons/Company

Torrent Pharma (UK) Ltd, Unit 4, Charlwood Court, County Oak Way, Crawley,

West Sussex RH11 7XA, United Kingdom

The Qualified Person (QP) responsible for pharmacovigilance is stated and a

satisfactory Curriculum Vitae (CV) has been provided.

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.

Qualitative and quantitative compositions

The proposed compositions are consistent with the details registered for the

cross-reference products.

Manufacturing processes

The proposed manufacturing processes are consistent with the details registered for

the cross-reference products and the maximum batch size is stated.

Finished product/shelf-life specifications 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 is manufactured to the same formula utilising the same process

as the cross-reference products, Levodopa/Carbidopa/Entacapone Torrent Tablets (PL

36687/0125-0130).

Expert Report

The applicant cross-refers to the data for Levodopa/Carbidopa/Entacapone Torrent

Tablets (PL 36687/0125-0130), to which these applications are claimed to be

identical. This is acceptable. The applicant has included expert reports for 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

Levodopa/Carbidopa/Entacapone Torrent Tablets (PL 36687/0125-0130) and, as such,

have been judged to be satisfactory. The grant of Marketing Authorisations was

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.


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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.

The Marketing Authorisation Holder has provided details of a suitable

pharmacovigilance system that fulfils the requirements and provides adequate

evidence that they have the services of a qualified person responsible for

pharmacovigilance, and have the necessary means for the notification of any adverse

reaction suspected of occurring either in the Community or in a third country.

The grant of Marketing Authorisations is recommended.

Risk Management Plan (RMP)

The applicant has submitted an 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



mg/50 mg/200 mg film-coated tablets.

A summary of safety concerns and planned risk minimisation activities, as

approved in the RMP, is listed below:


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The applicant proposes only routine risk minimisation measures, which are detailed in

the SmPCs. These are considered sufficient. No additional risk minimisation measures

are considered necessary.

V User consultation The package leaflet is identical to the leaflet for the reference products.

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 products are identical to the reference products.

The benefit-risk assessment is, therefore, considered to be positive.


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Summary of Product Characteristics, Patient Information Leaflet &

Labels In accordance with Directive 2012/84/EU, the current approved UK versions of the

SmPCs and PIL for this product are available on the MHRA website.

The current approved label is listed below:


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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

public assessment report levodopa/carbidopa/entacapone · pdf fileukpar...

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