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MHRA-UKPAR – Paracetamol and Caffeine 500mg/65mg Tablets PL 00071/0659

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PARACETAMOL AND CAFFEINE 500MG/65MG TABLETS

PL 00071/0659

UKPAR

TABLE OF CONTENTS

Lay Summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 13

Steps taken after authorisation – summary Page 14

Summary of Product CharacteristicsPage 15

Patient Information Leaflet Page 20

Labelling Page 23

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PL 00071/0659

LAY SUMMARY

The Medicines Healthcare products Regulatory Agency granted SmithKline Beecham

(SWG) Limited, trading as GlaxoSmithKline Consumer Healthcare a Marketing

Authorisation (licence) for the medicinal product Paracetamol and Caffeine 500mg/65mg

Tablets (PL 00071/0659) 19th May 2010. This is a pharmacy-only medicine (P) used to for

the relief of headache, migraine, backache, rheumatic pain, toothpain and period pain. It

also relieves discomfort in colds, flu and sore throat and helps reduce temperature.

The tablets contain two active ingredients, paracetamol and caffeine, this combination has

been widely available for many years. Paracetamol is a painkiller and reduces yourtemperature when you have a fever. Caffeine acts to further help the effectiveness of

paracetamol.

This application is similar to the already granted and currently marketed medicine Panadol

Extra tablets (PL 00071/0306).

The proposed product contains an established combination of paracetamol and caffeine,

and this combination is widely available.

No new or unexpected safety concerns arose from this application and it was, therefore,

judged that the benefits of taking Paracetamol and Caffeine 500mg/65mg Tablets outweighthe risks; hence a Marketing Authorisation has been granted.

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PL 00071/0659

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction Page 4

Pharmaceutical assessment Page 5

Preclinical assessment Page 8

Clinical assessment Page 9

Overall conclusions and risk benefit assessment Page 12

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INTRODUCTION

The UK granted Marketing Authorisations for the medicinal products Paracetamol and

Caffeine 500mg/65mg Tablets (PL 00071/0659) to SmithKline Beecham (SWG) Limited,

trading as GlaxoSmithKline Consumer Healthcare on 19th May 2010. This product is a pharmacy-only medicine.

The product contains the active ingredients paracetamol and caffeine. The active

ingredients exert their effect by unrelated pharmacological mechanisms. Paracetamol is a

centrally acting analgesic (a pain killer that acts on pain centres on the brain), which is used

to relieve mild to moderate pain in the body and also acts as an antipyretic to help reduce

body temperature; caffeine is a mild stimulant.

This application was submitted as a national abridged application according to Article 8.3

of Directive 2001/83/EC. The aim of this application was to update the formulation of the

currently marketed Panadol Extra Tablets (PL 00071/0306) changing the tablet shape, film

coat and incorporating printing ink on the tablet.

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PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE (1)

Paracetamol

INN/ BAN Paracetamol

Chemical name: N-(4-hydroxyphenyl)acetamide

Structure

Molecular formula: C8H9 NO2

Molecular weight: 151.2

General Properties

Description: Paraectamol is a white, crystalline powder. It is sparingly

soluble in water, free soluble in alcohol and very slightly soluble in dichloromethane.

Manufacture

All aspects of the manufacture and control of the active substance paracetamol are covered

by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

DRUG SUBSTANCE (2)

Caffeine

INN/ BAN Caffeine

Chemical name: 1,3,7-trimethyl-1,3-dihydro-1H-purine-2,5-dione, or

1,3,7-trimethylxanthine.

Structure

Molecular formula: C8H10 N4O2

Molecular weight: 194.2

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General Properties

Caffeine is a white or almost white, crystalline powder. It is sparingly soluble in

water, freely soluble in boiling water, and slightly soluble in ethanol.

ManufactureAll aspects of the manufacture and control of the active substance paracetamol are covered

by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

DRUG PRODUCT

Other ingredients

Other ingredients consist of pharmaceutical excipients, namely starch pregelatinised, maize

starch, purified talc, croscarmellose sodium, stearic acid, povidone, potassium sorbate,

hypromellose and triacetin. All the ingredients within the tablet comply with relevant Ph.

Eur monographs.

The printing ink consists of: propylene glycol, shellac, brilliant blue FCF (E133), sodium

lactate and dimethylpolysiloxane. The composition of the printing ink is from non-

pharmacopoieal grade material; this is satisfactory considering that these ingredients are

used in such small quantities.

Appropriate justification for the inclusion of each excipient has been provided.

Satisfactory Certificates of Analysis have been provided for all the excipients.

None of the excipients used contains material of animal or human origin.

There were no novel excipients used and no overages.

Pharmaceutical Development

Suitable pharmaceutical development data have been provided for this application.

The pharmaceutical development was aimed at updating the current Panadol Extra Tablets

(PL 00071/0306) changing the debossing of the tablet to printing onto the tablet.

Manufacture

A description and flow-chart of the manufacturing method have been provided. In-process

controls are satisfactory based on process validation data and controls on the finished

product. Process validation has been carried out on batches of the product. The resultsappear satisfactory.

Finished product specification

The finished product specification is satisfactory. Test methods have been described and

adequately validated, as appropriate. Batch data have been provided and comply with the

release specification. Certificates of analysis have been provided for any working standards

used.

Container Closure System

The finished product is packed in a blister pack composed of polyvinylchloride/aluminium

(PVC/Al) and then packed with the patient information leaflet (PIL) into an outercardboard carton. Pack sizes are 4, 6, 8, 10, 12, 16, 20, 24, 30, 32 tablets.

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The marketing authorisation holder has stated that not all pack sizes may be marketed. The

Marketing Authorisation Holder (MAH) has committed to submitting mock-ups for all

packaging for assessment before those pack sizes are commercially marketed.

Specifications and Certificates of Analysis for all packaging materials have been provided.These are satisfactory. All primary product packaging complies with EU legislation

regarding contact with food.

Stability

Finished product stability studies have been conducted in accordance with current

guidelines and in the packaging proposed for marketing.

Based on the results, a shelf-life of 60 months has been set with the following storage

precaution “Do not store above 25oC”.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),Labels

The SPC, PIL and labelling are pharmaceutically acceptable.

MAA form

The MAA form is pharmaceutically satisfactory.

Expert Report

The pharmaceutical expert report has been written by an appropriately qualified person and is a

suitable summary of the pharmaceutical dossier.

ConclusionIt is recommended that a Marketing Authorisation is granted for this application.

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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. A preclinical expert report has been written by a suitably

qualified person and is satisfactory.

The marketing authorisation holder has provided adequate justification for not submitting

an Environmental Risk Assessment (ERA). These were applications for generic products

and there is no reason to conclude that marketing of these products will change the overall

use pattern of the existing market. The marketing authorisation holder has provided

adequate justification for not submitting a Risk Management Plan (RMP).

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CLINICAL ASSESSMENTINTRODUCTION

Clinical Background

Paracetamol has been widely available as an over-the-counter analgesic since the 1950s.

Paracetamol tablets (500 mg) were first marketed in the UK in 1956. The maximum

recommended adult dose is 1.0 g every 4-6 hr up to a maximum of 4 g in 24 hours.

The proposed product contains an established combination of paracetamol and caffeine,

and this combination is widely available.

Caffeine acts as an analgesic adjuvant which enhances the clinical efficacy of paracetamol.

GlaxoSmithKline data on file and published data support the efficacy and safety profile of

products containing this combination.

The Clinical Overview has adequately reviewed all the relevant clinical documentation

relevant to this application. In view of the widespread use of paracetamol and the nature of

the paracetamol and caffeine formulation, the data presented here are considered adequate

in support of this application.

IndicationsParacetamol and Caffeine 500 mg / 65 mg Tablets are a mild to moderate analgesic and

antipyretic. The tablets are recommended for the treatment of most painful and febrile

conditions, for example, headache, including migraine, backache, toothache, pain of

osteoarthritis, and dysmenorrhoea, and for relieving the fever, aches and pains of colds and

flu, and sore throat.

Dose and Dose Regimen

Each tablet contains 500 mg paracetamol and 65 mg caffeine. The maximum recommended

dose of paracetamol and caffeine is two tablets (500 mg paracetamol, 65 mg caffeine in

each tablet) every 4-6 hours, up to a maximum of 8 tablets in 24 hours.

Legal Status

The proposed legal Status is P – not subject to medical prescription; supply through

pharmacies only. This type of combination tablet formulation has been available in the EU

without prescription for many years.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Overview

A confirmatory pharmacokinetic study has demonstrated that paracetamol and caffeine is

bioequivalent to PANADOL (also known as PANODIL Tablets) for the paracetamolcomponent. Results from a supportive pharmacokinetic study are consistent with the

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confirmatory study. Data from the studies indicate that there is no pharmacokinetic

interaction between paracetamol and caffeine. Further details regarding this study are

contained in the Clinical overview.

The pharmacokinetics of both paracetamol and caffeine, alone and in combination, is well

established and has been adequately reviewed by the Clinical Expert.

It has been established that no pharmacokinetic interaction occurs between paracetamol and

caffeine.

Assessor’s overall conclusions on pharmacokinetics

The pharmacokinetics of this combination is well-established and adequately reviewed in

this dossier.

Bioequivalence

There are no important issues related to bioavailability that might affect efficacy or safety

of Paracetamol and Caffeine 500 mg / 65 mg Tablets. A confirmatory pharmacokineticstudy has demonstrated that paracetamol and caffeine is bioequivalent to PANADOL (also

known as PANODIL Tablets) for the paracetamol component. Results from a supportive

pharmacokinetic study are consistent with the confirmatory study. Data from the studies

indicate that there is no pharmacokinetic interaction between paracetamol and caffeine. No

new studies have been conducted with the proposed formulation and none are required for

this type of application.

Pharmacodynamics

Pharmacodynamics and mechanism of action

The primary pharmacodynamics of paracetamol and caffeine alone and in combination is

well described and has been adequately reviewed by the Clinical Expert.

CLINICAL EFFICACY

The superior analgesic efficacy of paracetamol 500 mg/caffeine 65 mg compared to the

single actives and placebo has previously been demonstrated in clinical studies. This has

been adequately reviewed in the Clinical Overview. Caffeine acts as an analgesic adjuvant

which enhances the efficacy of paracetamol.

ParacetamolThe antipyretic activity of paracetamol is thought to be mediated by central prostaglandin

synthetase inhibition. This may also play a role in the analgesic effect though the precise

mechanism remains unclear. Paracetamol does not have an anti-inflammatory effect and,

unlike NSAIDs, does not inhibit peripheral prostaglandin sysnthesis and serious gastro-

intestinal adverse events are not associated with this active.

Caffeine

Caffeine is a methylxanthine and has a mild stimulant effect. The specific mechanism by

which it acts as an analgesic adjuvant remains unclear, but may be mediated via adenosine

antagonism (adenosine being one of the kinins released in association with pain), inhibition

of COX-2 synthesis or by affecting the emotional response to pain.

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CLINICAL SAFETY

The overall safety profile of products containing paracetamol and caffeine is well-

established with extensive safety monitoring conducted on all currently marketed

formulations. The safety profile of this combination has been adequately reviewed in the

Clinical Overview. There are currently no safety concerns regarding this combination.

Pharmacovigilance & Risk Management Plans

An overview of GlaxoSmithKline's organisation and processes for conducting

pharmacovigilance activities has been provided and is consistent with regulatory

requirements. The MHRA agrees that a formal Risk-Management Plan is not required for

this product.

EXPERT REPORTS

The Clinical Expert Report has been written by a suitably qualified person.

PRODUCT LITERATURE

SmPC

This is satisfactory.

Patient Information Leaflet

This is satisfactory.

User Testing: A Bridging Report Summary is provided

According to The Medicines (Marketing Authorisations and Miscellaneous Amendments)

Regulations 2004 [SI 2004/3224] this report considers the legibility, clarity and ease of use

of the Patient Information provided with Paracetamol and Caffeine 500 mg / 65 mg

Tablets. By referring to the Patient Information provided with similar products which have

been successfully user tested, it is appropriate to consider that the Patient Information

provided with Paracetamol and Caffeine 500 mg / 65 mg Tablets is legible, clear and easy

to use by consumers.

Assessor's comment: this approach is considered to be satisfactory, and no further user

testing is required.

LabelThis is considered to be satisfactory.

Application Form

Satisfactory

CONCLUSION

From a Clinical perspective and the Benefit-Risk evaluation is considered to be favourable,

and MA is recommended.

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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY

The important quality characteristics of Paracetamol and Caffeine 500mg/65mg Tablets are

well-defined and controlled. The specifications and batch analytical results indicate

consistency from batch to batch. There are no outstanding quality issues that would have a

negative impact on the benefit/risk balance.

PRECLINICAL

No new preclinical data were submitted and none are required for an application of this

type.

EFFICACY

The superior analgesic efficacy of paracetamol 500mg/caffeine 65mg compared to the

single actives and placebo has previously been demonstrated in clinical studies. The use of

this combination has been widely available for many years.

No new or unexpected safety concerns arise from this application.

The SPC, PIL and labelling are satisfactory and consistent with those for the innovator

product.

RISK BENEFIT ASSESSMENT

The quality of the product is acceptable and no new preclinical or clinical safety concerns

have been identified. Extensive clinical experience with paracetamol and caffeine is

considered to have demonstrated the therapeutic value of the compound. The risk benefit is,

therefore, considered to be positive.

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PL 00071/0659

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 20th May 2009.

2 Following standard checks and communication with the applicant the MHRAconsidered the application valid on 9th June 2009.

3 Following assessment of the applications the MHRA requested further

information relating to the quality dossiers on 24th August 2009 and 17th

February 2010.

4 The applicant responded to the MHRA’s requests, providing further information

on the quality dossier on 20th October 2009 and 26th April 2010.

5 The application was determined on 19th May 2010.

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PL 00071/0659

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCTParacetamol and Caffeine 500 mg / 65 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach tablet contains 500mg paracetamol and 65mg caffeine.

For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet.

White capsule-shaped, film-coated tablets printed on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indicationsParacetamol and Caffeine 500 mg / 65 mg Tablets are a mild to moderate analgesic and antipyretic.The tablets are recommended for the treatment of most painful and febrile conditions, for example,

headache, including migraine, backache, toothache, pain of osteoarthritis, and dysmenorrhoea, andfor relieving the fever, aches and pains of colds and flu, and sore throat.

4.2 Posology and method of administration

Adults:Two tablets up to four times daily. The dose should not be repeated more frequently than every 4

hours. Do not exceed 8 tablets in 24 hours.

Elderly:

As for adults.

Children: Not recommended for children under 12 years.

For oral administration only.

4.3 Contraindications

Hypersensitivity to paracetamol, caffeine and/or any of the other constituents.

4.4 Special warnings and precautions for use

Medical consultation is advised in the administration of paracetamol to patients with renal or hepaticimpairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Excessive intake of caffeine containing drinks should be avoided while taking this product.

Do not exceed the stated dose.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients should be advised not to take other paracetamol-containing products concurrently.

If symptoms persist consult your doctor.

Keep out of the reach and sight of children.

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4.5 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone andabsorption reduced by colestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding;

occasional doses have no significant effect.

4.6 Pregnancy and lactation

Paracetamol-caffeine is not recommended for use during pregnancy due to the possible increasedrisk of spontaneous abortion associated with caffeine consumption.

Caffeine in breast milk may potentially have a stimulating effect in breast fed infants but significanttoxicity has not been observed.

4.7 Effects on ability to drive and use machines

None.

4.8 Undesirable effects

Paracetamol

Body System Undesirable effect Frequency

Blood and Lymphaticsystem disorders

Thrombocytopenia Very rare (

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c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation,cachexia.

SymptomsSymptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and

abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalitiesof glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal

failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, maydevelop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have beenreported.

ManagementImmediate treatment is essential in the management of paracetamol overdose. Despite a lack of

significant early symptoms, patients should be referred to hospital urgently for immediate medicalattention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of

overdose or the risk of organ damage. Management should be in accordance with establishedtreatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1

hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion(earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hoursafter ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. Ifvomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside

hospital. Management of patients who present with serious hepatic dysfunction beyond 24h fromingestion should be discussed with the National Poisons Information Service (NPIS) or a liver unit.

Caffeine

Symptoms Overdose of caffeine may result in epigastric pain, vomiting, diuresis, tachycardia or cardiac

arrhythmia, or CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremorsand convulsions).

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Management

Patients should receive general supportive care (e.g. hydration and maintenance of vital signs). Theadministration of activated charcoal may be beneficial when performed within one hour of theoverdose, but can be considered for up to four hours after the overdose. The CNS effects of overdosemay be treated with intravenous sedatives.

Summary

Treatment of overdose requires assessment of plasma paracetamol levels for antidote treatment, withsigns and symptoms of caffeine toxicity being managed symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides ATC code: N02B E01

The combination of paracetamol and caffeine is a well established analgesic combination.

Paracetamol is an antipyretic and analgesic. Its mechanism of action is believed to include inhibition

of prostaglandin synthesis, primarily within the central nervous system. The lack of peripheral prostaglandin inhibition confers important pharmacological properties such as the maintenance ofthe protective prostaglandins within the gastrointestinal tract. Paracetamol is, therefore, particularly

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suitable for patients with a history of disease or on concomitant medication where peripheral prostaglandin inhibition would be undesirable (such as, for example, those with a history of GI bleeding or the elderly).

Clinical data has demonstrated that the combination of paracetamol and caffeine gives betterefficacy than paracetamol alone.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal tract. It isrelatively uniformly distributed throughout most body fluids and exhibits variable protein binding.Excretion is almost exclusively renal, in the form of conjugated metabolites.

Caffeine is rapidly absorbed from the gastrointestinal tract and is widely distributed throughout the body. It is almost completely metabolized in the liver by oxidation and demethylation to variousxanthine derivatives, which are excreted in the urine. The mean plasma half life is about 4.9 hours

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already

included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Starch pregelatinisedMaize starchPurified TalcCroscarmellose sodium

Stearic acidPovidone

Potassium sorbateHypromelloseTriacetin

Printing Ink:Propylene glycol

ShellacBrilliant Blue FCF (E133)Sodium LactateDimethylpolysiloxane

6.2 Incompatibilities

None.

6.3 Shelf life

60 months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC 250 or 300µm / aluminium foil 20µm blister packs in an outer cardboard carton, containing 4,6, 8, 10, 12, 16, 20, 24, 30, 32 tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

None.

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7 MARKETING AUTHORISATION HOLDERSmithKline Beecham (SWG) Limited980 Great West Road

BrentfordMiddlesexTW8 9GS

United Kingdom

Trading as GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8 MARKETING AUTHORISATION NUMBER(S)PL 00071/0659

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/05/2010

10 DATE OF REVISION OF THE TEXT19/05/2010

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PATIENT INFORMATION LEAFLET

PARACETAMOL AND CAFFEINE 500MG/65MG TABLETS-TEXT

PL 00071/0659

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