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Public Assessment Report

Decentralised Procedure

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets

(paracetamol, ibuprofen)

Procedure No: UK/H/6034-6035/001/DC

UK Licence No: PL 20692/0132, PL 20692/0133

Vale Pharmaceuticals Limited

PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC

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Lay Summary

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets

(paracetamol and ibuprofen)

This is a summary of the public assessment report (PAR) for Paracetamol/Ibuprofen 500

mg/150 mg film-coated tablets (PL 20692/0132 and PL 20692/0133; UK/H/6034-

6035/001/DC). It explains how Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets

were assessed and their authorisation recommended, as well as their conditions of use. It is

not intended to provide practical advice on how to use Paracetamol/Ibuprofen 500 mg/150

mg film-coated tablets.

For practical information about using Paracetamol/Ibuprofen 500 mg/150 mg film-coated

tablets, patients should read the Patient Information Leaflet (PIL) or contact their doctor or

pharmacist.

What are Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets and what are they

used for?

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets contain two active ingredients,

paracetamol and ibuprofen, in each single tablet.

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets are used for short-term

symptomatic treatment of mild to moderate pain.

How do Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets work?

Paracetamol works to stop the pain messages from getting through to the brain.

Ibuprofen belongs to a group of medicines called non-steroidal anti-inflammatory drugs (or

NSAIDs). It relieves pain and reduces inflammation (swelling, redness or soreness).

How are Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets used?

The pharmaceutical form of Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets is a

film-coated tablet and the route of administration is oral.

The patient should always take this medicine exactly as his/her doctor has advised. The

patient should check with his/her doctor or pharmacist if unsure. Do not take

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets for more than 3 days.

Recommended dose:

Adults: The usual dosage is one (500 mg paracetamol and 150 mg ibuprofen) to two (1000

mg paracetamol and 300 mg ibuprofen) tablets taken every six hours, as required up to a

maximum of six tablets in 24 hours. The lowest effective dose should be used for the shortest

time necessary to relieve symptoms. The patient should consult their doctor if the symptoms

persist or worsen or if the product is required for more than 3 days.

Do not take more than 6 tablets in a period of 24 hours.

If the patient’s doctor has prescribed a different dose, directions given by the doctor should

be followed.

Take Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets with a full glass of water.

The score line is only to facilitate breaking for ease of swallowing and not to divide into


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equal doses.

Use in children under 18 years

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets should not be taken by children

under 18 years.

Please read Section 3 of the PIL for detailed information on dosing recommendations, the

route of administration, and the duration of treatment.

The medicine can be obtained without a prescription.

What benefits of Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets have been

shown in studies?

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets are a fixed combination product

of two known active substances. A study was undertaken to show that the combination

product produced the same levels of active substances in the body, when compared to

products that contained the active substances individually. This showed that combining these

actives in a single product does not affect how they work individually. Furthermore, data on

efficacy and safety studies of Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets was

provided, which showed that these products are effective in the temporary relief of pain

associated with: headache, migraine, backache, period pain, dental pain, muscular pain, cold

and flu symptoms, sore throat and fever.

What are the possible side effects from Paracetamol/Ibuprofen 500 mg/150 mg film-

coated tablets?

Like all medicines, these medicines can cause side effects although not everybody gets them.

For the full list of all side effects reported with Paracetamol/Ibuprofen 500 mg/150 mg film-

coated tablets, see Section 4 of the package leaflet available on the MHRA website.

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

Why are Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets approved?

The view was that the benefits of Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets

outweigh the identified risks and it was recommended that these products be approved for

use.

What measures are being taken to ensure the safe and effective use of

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets?

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

500 mg/150 mg film-coated tablets are used as safely as possible. Based on this plan, safety

information has been included in the Summary of Product Characteristics (SmPC) and the

PIL for these products, 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 and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets

Austria, Germany, Croatia, Ireland and the UK agreed to grant a marketing authorisation for

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets on 07 August 2017

(UK/H/6034/001/DC). The marketing authorisation in the UK was granted on 27 October


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2017.

Belgium, France, Luxembourg, the Netherlands and the UK agreed to grant a marketing

authorisation for Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets on 29 September

2017 (UK/H/6035/001/DC). The marketing authorisation in the UK was granted on 27

October 2017.

This product is a duplicate of Combogesic 500 mg/150 mg film-coated tablets and Tachicold

500 mg/150 mg film-coated tablets (PL 20692/0040-0041; UK/H/2383-2384/001/DC).

The full PAR for Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets follows this

summary.

For more information about treatment with Paracetamol/Ibuprofen 500 mg/150 mg film-

coated tablets, read the PIL or contact your doctor or pharmacist.

This summary was last updated in December 2017.


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TABLE OF CONTENTS

I Introduction Page 6

II Quality aspects Page 8

III Non-clinical aspects Page 10

IV Clinical aspects Page 13

V User consultation Page 19

VI Overall conclusion, benefit/risk assessment

and recommendation

Page 19

Table of content of the PAR update for

MRP and DCP

Page 27


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I Introduction Based on the review of the data on quality, safety and efficacy the Austria, Belgium, Croatia,

France, Germany, Ireland, Luxembourg, the Netherlands and the UK considered that the

applications for Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets (PL 20692/0132

and PL 20692/0133; UK/H/6034-6035/001/DC) could be approved.

These applications were submitted using the Decentralised Procedure (DCP) made under

Article 10b of Directive 2001/83/EC, as amended, applicable for fixed combination products

of known active substances.

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets are a pharmacy (P) medicines,

indicated for the short-term symptomatic treatment of mild to moderate pain.

Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets contain the active ingredients

paracetamol and ibuprofen.

Paracetamol is an analgesic and antipyretic agent. The mechanism by which paracetamol

reduces fever and pain is still not fully understood. Paracetamol reduces the production of

prostaglandins, although it has little anti-inflammatory activity. It appears to act via at least

two pathways, possibly involving the inhibition of the enzyme cyclooxygenase (COX),

modulation of the endogenous cannabinoid system, and acting centrally to reduce

temperature.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic, and

anti-inflammatory activities. It inhibits cyclooxygenase (COX), thus inhibiting prostaglandin

synthesis.

The RMS 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 products.

For manufacturing sites within the Community, the RMS has accepted copies of current

manufacturer authorisations issued by inspection services of the competent authorities as

certification that acceptable standards of GMP are in place at those sites. For manufacturing

sites outside the Community, the RMS has accepted copies of current GMP Certificates of

satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’

issued by the inspection services of the competent authorities (or those countries with which

the EEA has a Mutual Recognition Agreement for their own territories) as certification that

acceptable standards of GMP are in place at those non-Community sites.

A single-dose and a 7-day repeated oral dose study were undertaken by the applicant to

compare the effects of a combination of ibuprofen and paracetamol, in the ratio used in the

product, to the effects of either drug alone. These two non-clinical studies were carried out in

accordance with Good Laboratory Practice (GLP). In addition, published literature on the

single and repeated dose toxicity of both ibuprofen and paracetamol was reviewed by the

applicant. The remainder of the non-clinical dossier is based upon published literature and the

GLP status of the cited studies is not known.

The applicant has submitted a bioavailability study to show bioequivalence between the

separate actives and the combination of these actives in the fasted and fed state. Four clinical

trial studies were undertaken to support these applications: two pivotal studies, one


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exploratory study and a dose-response study. Owing to the size of the exploratory study and

the assumptions made this was of limited use in supporting these licence applications. The

dose-response study is considered acceptable and is further supported by the efficacy seen in

the clinical trials. The pivotal studies were well conducted and showed that the combination

was better than the single actives (statistically in one and numerically in another) and better

than placebo. The applicant has stated that all studies were performed according to GCP

protocols.

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

provided with these applications and are satisfactory.

Published information on the environmental effects of ibuprofen and paracetamol has been

reviewed and together with the fact that both substances are well known and widely used, and

that use of these combination products is unlikely to increase environmental exposure to

either paracetamol or ibuprofen, the ERA is considered acceptable.

At the end of the decentralised procedure, these applications were referred to the Co-

ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)

by some of the Concerned Member States (CMS) due to the following issues:

• The rationale of the Fixed Dose Combination (FDC) was not considered justified.

• Additional benefit for the new FDC compared to the mono-components has not been

demonstrated.

• Adequate safety profile of the new FDC has not been shown.

As an agreement could not be reached by Day 60 of the CMDh procedure, the procedure was,

therefore, referred under Article 29(4) of Directive 2001/83/EC as amended, on 21 October

2016 to the Committee for Medicinal Products for Human Use (CHMP).

In February 2017, the CHMP concluded that the objections raised by some member states

should not prevent the grant of marketing authorisations for these products. However, a

further list of outstanding issues for clarification was adopted. The applicant responded with

an acceptable response in April 2017. Based on the CHMP opinion, the RMS and CMS

countries considered that the applications could be approved on 29 September 2017. After a

subsequent national phase, Marketing Authorisations were granted in the UK on 27 October

2017.


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II Quality aspects II.1 Introduction Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets are white coloured, capsule

shaped 19 mm in length film-coated tablets with break-line on one side and plain on the other

side. The score line is only to facilitate breaking for easy of swallowing and not to divide into

equal doses. Each tablet contains 500 mg paracetamol and 150 mg ibuprofen.

The excipients present in the tablet core are: maize starch, pregelatinised maize starch

microcrystalline cellulose, croscarmellose sodium, magnesium stearate, talc and for the tablet

coat: Opadry white (containing hypromellose (E464), lactose monohydrate, titanium dioxide

(E171), macrogol/PEG 4000 and sodium citrate (E331), and talc.

The tablets are presented in polyvinyl chloride (PVC) film / aluminium foil blisters, which

are further packed in cartons in pack sizes of 8, 10, 16, 20, 24, 30 and 32 film-coated tablets.

Not all pack sizes may be marketed, however, the marketing authorisation holder has agreed

to provide mock-ups of any pack size to the relevant regulatory authorities before marketing.

II.2 Drug Substance Paracetamol

INN: Paracetamol

Chemical Name: N-(4-hydroxyphenyl)acetamide.

Structure:

Molecular formula: C8H9NO2

Molecular weight: 151.2

Appearance: White crystalline powder.

Solubility: Sparingly soluble in water, freely soluble in alcohol, very slightly

soluble in methylene chloride.

Paracetamol is the subject of a European Pharmacopoeia monograph.

The manufacture and control of the active substance, paracetamol, are covered by European

Directorate for the Quality of Medicines and Healthcare (EDQM) certificates of suitability.

Satisfactory information has been provided on the stability of the active substance and on the

packaging materials.

Ibuprofen

INN: Ibuprofen

Chemical Name: (2RS)-2-[4-(2-methylpropyl)phenyl]propanoic acid.

Structure:

Molecular formula: C13H18O2

Molecular weight: 206.3


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Appearance: White or almost white, crystalline powder or colourless crystals.

Solubility: Practically insoluble in water, freely soluble in acetone, in methanol

and methylene chloride. It dissolves in dilute solutions of alkali

hydroxides and carbonates.

Ibuprofen is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, ibuprofen, are covered by

European Directorate for the Quality of Medicines and Healthcare (EDQM) certificates of

suitability.

II.3 Medicinal Product Pharmaceutical development

The objective of the pharmaceutical development programme was to produce a white film-

coated, capsule-shaped, easy-to-swallow, fixed-dose combination of paracetamol and

ibuprofen in a tablet form that would quickly, and fully, release the incorporated drug

substances.

All the excipients used in the manufacture of the proposed formulation comply with their

respective European Pharmacopoeial monographs, with the exception of Opadry White OY-

LS-58900, which complies with an in-house specification.

A statement from the manufacturer/supplier of Opadry White OY-LS-58900 has confirmed

that the composition and that the relevant ingredients comply with the requirements of

Directive 95/45/EC, concerning colorants in foodstuff.

Satisfactory certificates of analysis have been provided for all excipients showing compliance

with their proposed specifications.

The magnesium stearate used in this product is of plant origin.

The supplier of Opadry White OY-LS-58900 has certified that the lactose monohydrate is

obtained from healthy animals in the same condition as those used to collect milk for

consumption and was prepared without the use of ruminant material other than calf rennet.

The other excipients, according to their suppliers, are produced without animal or human

origin materials.

No genetically modified organisms (GMO) have been used in the preparation of these

excipients.


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Manufacture of the product

Satisfactory batch formulae have been provided for manufacture of the finished products,

together with an appropriate account of the manufacturing process. The manufacturing

process has been validated for manufacture of pilot-scale and production-scale batches and is

satisfactory.

Finished Product Specification

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

have been adequately validated, as appropriate. Batch data have been provided from three

production-scale batches that comply with the release specification. Certificates of analysis

have been provided for all working standards used.

Stability of the product

Stability studies were performed in accordance with current guidelines on batches of the

finished product, packed in the packaging proposed for marketing. The data from these

studies support a shelf life of 3 years with the storage condition of “Store in the original

blister package in order to protect from light”.

Suitable post approval stability commitments have been provided.

II.4 Discussion on chemical, pharmaceutical and biological aspects

The grant of a marketing authorisations is recommended for these applications.

III Non-clinical aspects

III.1 Introduction

Ibuprofen and paracetamol are both well-established active substances and the extensive

literature on their pharmacology, pharmacokinetics and toxicology have been reviewed.

Additional studies have been undertaken to support these applications.

The non-clinical overview has been written by an appropriately qualified person and is a

suitable summary of the non-clinical aspects of the dossier.

III.2 Pharmacology

Ibuprofen and paracetamol are both well-established active substances and the extensive

literature on their primary pharmacodynamics have been reviewed.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic, and

anti-inflammatory activities. It inhibits cyclooxygenase (COX), thus inhibiting prostaglandin

synthesis.

Paracetamol is an analgesic and antipyretic agent. The mechanism by which paracetamol

reduces fever and pain is still not fully understood. Paracetamol reduces the production of

prostaglandins, although it has little of the anti-inflammatory activity. It appears to act via (at

least) two pathways, possibly involving the inhibition of COX, modulation of the endogenous

cannabinoid system and acting centrally to reduce temperature.

The applicant states that there is clinical experience of use of the combination (or

paracetamol and an NSAID) that shows more severe pain may be managed whilst minimising

side effects, although evidence for this is not presented in the non-clinical dossier.


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The primary adverse effects on the function of key organ systems associated with ibuprofen

involve the GI tract (irritation and bleeding), kidney (interstitial nephritis, renal papillary

necrosis), and cardiovascular system (hypertension, myocardial infarction, stroke,

thrombosis) and that those associated with paracetamol involve the liver (hepatocellular

necrosis).

The non-clinical overview critically discusses effects on the kidney and on the GI tract using

both published literature and the results of a 7-day oral toxicity study in rats that was

conducted to evaluate and compare the GI and renal effects of ibuprofen and paracetamol

alone and in combination at a ratio matching that in the product and at a dose above the

maximum recommended dose of the product (six tablets/day). The results of this study

showed that there was not an increased risk of renal or gastrointestinal toxicity from use of

the combination at this ratio and dosage.

III.3 Pharmacokinetics

Pharmacokinetic studies have not been conducted by the applicant; literature has been

reviewed.

Both paracetamol and ibuprofen are rapidly and completely absorbed following oral

administration and both have a short half-life of about 2 to 3 hours, therefore multiple doses

during throughout the day are required.

Ibuprofen is highly protein bound (>99% in humans), whereas paracetamol does not bind

extensively to plasma proteins. Paracetamol is widely distributed and crosses the blood:brain

barrier readily.

Ibuprofen is extensively metabolised in the liver, mainly by CYP2C9 to hydroxylated and

carboxylated compounds, with subsequent formation of their glucuronides.

The major pathways for paracetamol metabolism are Phase II conjugation to glucuronide and

sulphate metabolites. Paracetamol metabolites include a minor hydroxylated intermediate,

NAPQI, which is hepatotoxic but is detoxified by conjugation with glutathione at therapeutic

doses.

Both ibuprofen and paracetamol are predominantly excreted from the body as metabolites in

urine.

III.4 Toxicology

Published literature on the single and repeated dose toxicity of both ibuprofen and

paracetamol was reviewed.

The primary toxicities associated with ibuprofen involve the gastrointestinal (GI) tract

(irritation and bleeding), kidney (interstitial nephritis, renal papillary necrosis), and

cardiovascular system (hypertension, myocardial infarction, stroke, thrombosis). The primary

toxicity associated with paracetamol involves the liver (hepatocellular necrosis).

In addition to the literature review, two studies were sponsored by the applicant, a single-

dose and a 7-day repeated oral dose study to compare the effects of a combination of

ibuprofen and paracetamol in the ratio used in the product to the effects of either drug alone.


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In the single-dose study, the combination of paracetamol and ibuprofen at the approximate

ratio used in the proposed product and at a dose >10 times the maximum dose, had no greater

toxicity that did either drug alone when administered at the same (or similar) dose.

In the repeated-dose study, changes in haematology parameters with the combination were

similar to the sum of the effects of ibuprofen and paracetamol alone (increased monocyte

counts, lymphocyte counts and large unstained cell counts) or to the effect of paracetamol

alone (greater basophil counts and reticulocyte counts), although each of the parameters was

stated to remain within the normal variation for female rats. Although the study provides

some reassurance that there is no novel toxicity with the combination, the effects that were

noted appeared to be additive. The ratio chosen for the product does not appear to have been

adequately justified; however, it is considered that additional non-clinical studies will not be

required given that the maximum daily dose of both active substances was used. If there is

any alteration to the ratio of the drugs this would likely be intended to decrease the quantity

of one or both compounds with a view to improving the safety profile, in fact the proposed

product is intended to have a maximum dose regimen of one to two tablets taken four times

daily up to a maximum six tablets/day, which is lower than that represented in the completed

study.

In response to questions on the choice of combination study, the Applicant has highlighted

that the purpose of the completed non-clinical studies was to establish whether there was an

increase in gastrointestinal and renal toxicity using the combination product. It has been

further emphasised that the purpose of establishing pain efficacy and pharmacodynamics, at

least from a preclinical perspective, can be based upon literature and clinical use data. The

need to demonstrate efficacy in an animal model is not necessary for compounds such as

paracetamol and ibuprofen, in which a vast amount of data is available already.

The Applicant presented some additional rationale for the doses selected for these toxicity

studies in rats. The prime objective of the studies was to establish a basis of additive toxicity

between paracetamol and ibuprofen. Dose selection was to allow that known toxicity

associated with ibuprofen on its own wouldn’t drive the findings of adding paracetamol to

administration. It is acknowledged that this may have been a driver in dose selection for the

applicant’s studies and it is important that there was no evidence of increased gastric toxicity

associated with treatment of the combination in the rats. An updated literature search has

been conducted and supplied in an updated non-clinical overview.

Overall although limitations in the conducted toxicity studies have been identified it is

considered that additive adverse effects between paracetamol and ibuprofen have not been

identified. Given the wide clinical use of these two drugs, both individually and in

combination the need for further non-clinical examination is not considered relevant. The

applicant has highlighted that there are no clinical signs of gastrointestinal or renal adverse

effects from the completed clinical dosing of the proposed paracetamol 500 mg + 150 mg

ibuprofen fixed dose combination product and overall determination of the effectiveness of

the combination product will have to be determined from the clinical assessment.

Neither ibuprofen nor paracetamol are considered to possess genotoxic or carcinogenic

potential at therapeutic doses.

Limited information is reportedly available regarding the potential effects of ibuprofen and

paracetamol on reproduction and development, the proposed section 4.6 of the SmPC

includes information on both active substances and the general warnings for NSAIDs and is

in accordance with the QRD template and is now aligned to the wording agreed from CMDh

and the Pharmacovigilance Working Party (PhVWP) for paracetamol and ibuprofen.


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No concerns are raised in respect to impurities or use of excipients in the final proposed drug

product.

III.5 Ecotoxicity/environmental risk assessment (ERA)

Published information on the environmental effects of ibuprofen and paracetamol has been

reviewed. Together with the fact that both substances are well-known and widely used, and

that use of these combination products is unlikely to increase environmental exposure to

either paracetamol or ibuprofen, the ERA is considered acceptable.

III.6 Discussion on the non-clinical aspects

No unexpected toxicity was observed in the combination product and no interactions between

the two active substances, paracetamol and ibuprofen, were evident. No safety concerns are

raised on the combination of paracetamol and ibuprofen in the proposed product formulation.

There are no objections to approval of Paracetamol/Ibuprofen 500 mg/150 mg film-coated

tablets from a non-clinical point of view.

IV Clinical aspects IV.1 Introduction

The applicant’s clinical overview on the clinical pharmacology, efficacy and safety of the

product has been written by an appropriately qualified person and is adequate.

IV.2 Pharmacokinetics

The applicant has provided an adequately conducted bioavailability study. The study shows

bioequivalence between the separate actives and the combination in the fasted state.

• Treatment A: 2 tablets of Paracetamol 500 mg (total dose 1000 mg), in the fasted state

• Treatment B: 2 tablets of Ibuprofen 150 mg (total dose 300 mg), in the fasted stated

• Treatment C: 2 tablets of Maxigesic® (total dose Paracetamol 1000 mg + Ibuprofen

300 mg), in the fasted state

• Treatment D: 2 tablets of Maxigesic® (total dose Paracetamol 1000 mg + Ibuprofen

300 mg), in the fed state

Table 1 Bioequivalence Confidence Intervals and Intrasubject CV% of paracetamol for the

Treatments A and C

Table 2 Bioequivalence Confidence Intervals and Intrasubject CV% of ibuprofen for the

Treatments B and C

Tables 1 and 3 show a significant food effect seen with paracetamol, but not with ibuprofen.


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It is noted that the point estimates for fasted/fed states are generally less than 100%.

Table 3 Bioequivalence Confidence Intervals and Intrasubject CV% of paracetamol for the

Treatments D and C

Table 4 Bioequivalence Confidence Intervals and Intrasubject CV% of ibuprofen for the

Treatments D and C

The applicant has therefore fulfilled the request for the study and bioequivalence has been

shown in the fasted state. As the fed state leads to a slight underexposure there is no need to

amend the SmPC in this case. The applicant has discussed the pharmacokinetics (PK) in

special populations and potential interactions adequately.

IV.3 Pharmacodynamics

The pharmacodynamics of the constituent actives are well known. The applicant has

discussed the action and synergistic effect of dosing paracetamol and ibuprofen together.

This is further backed up by the data seen in the efficacy trials, where the combination is

better than the single actives.

IV.4 Clinical efficacy

Study AFT-MX-3 was a dose response study and a double-blind, placebo-controlled,

randomised, parallel group comparison of the effects of different paracetamol and ibuprofen

combination doses and placebo in participants with pain from removal of 2-4 third molars. Its

objective was to compare time-adjusted SPIDs (Summed Pain Intensity Differences from

baseline) of the VAS pain intensity scores up to 24 hours after the first dose of study

medication among the four treatment groups to determine the form of the dose-response

relationship. The results showed that the means of time-adjusted SPIDs in placebo group

(mean=6.63, SD=19.79) is significantly lower than either the one of Combination ¼ dose

group (mean=19.25, SD=19.99), the Combination ½ dose group (mean=20.44, SD=20.78) or

the Combination full dose group (mean=20.12, SD=18.01). The overall fixed effect of

treatment was tested on this endpoint in the general linear model and the difference has

reached the statistical significance (p=0.002). Following this, the pair-wise comparison

between placebo group and each active treatment group was conducted and the difference has

reached statistical significance (Placebo vs. Combination full dose P=0.004; Placebo vs.

Combination ½ Dose P=0.002; Placebo vs. Combination ¼ Dose P=0.002). In the study the

actives have all been shown to be statistically superior to placebo. They all seem numerically

similar to each other; however, no formal comparison between the actives has been

performed.


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Study AFT-MX-1 was a phase III, pivotal study with a prospective, parallel group, double-

blind comparison of the analgesic effect of a combination of paracetamol and ibuprofen,

paracetamol alone, or ibuprofen alone in patients with postoperative pain. Its objective was to

compare the analgesic effects and safety of paracetamol and ibuprofen combined

(Combination) versus paracetamol alone or ibuprofen alone in adults with postoperative pain.

The results showed that the mean time-adjusted AUCs calculated from the VAS pain scores

in the Combination treatment group at rest (mean=22.3, SE=3.2) and on activity (mean=28.4,

SE=3.4) were significantly lower than the means in the paracetamol alone treatment group (at

rest: mean=33.0 [SE=3.1]; on activity: mean=40.4 [SE=3.3]). These comparisons were

statistically significant (p=0.007 on rest; p=0.006 on activity). The combination of

paracetamol and ibuprofen had greater analgesic efficacy than the same dose of paracetamol

alone. The mean of time-adjusted AUCs calculated from the VAS pain scores in the

Combination treatment group at rest (mean=22.3, SE=3.2) and on activity (mean=28.4,

SE=3.4) were significantly lower than the means in the ibuprofen alone treatment group (at

rest: mean=34.8 [SE=3.2]; on activity; mean=40.2 [SE=3.4]). These comparisons were

statistically significant (p=0.003 on rest; p=0.007 on activity). The combination of

paracetamol and ibuprofen had greater analgesic efficacy than the same dose of ibuprofen

alone. The primary objective shows that the combination was statistically superior to the

actives on their own. The secondary analyses show either no difference or in favour of the

combination. The study was well conducted and showed that the combination is statistically

superior to the actives on their own.

Study AFT-MX-4 was a phase II exploratory study with a double-blind, randomized, parallel

group comparison of the effects of paracetamol and ibuprofen combined (Combination) with

paracetamol, low and high dose ibuprofen on patients with pain from osteoarthritis of the

knee, and a 12 month open label extension. Its objective was to compare the analgesic

efficacy and clinical safety of Combination (paracetamol 500mg and ibuprofen 150 mg) with

the other 3 treatment groups (paracetamol 500 mg; low dose ibuprofen 150 mg; high dose

ibuprofen 300mg) in patients who have painful osteoarthritis of the knee. The results showed

a mean improvement in the WOMAC VAS pain score from baseline to week 4 in the

Combination treatment group (mean=25.1, SE=2.1) is greater than the mean improvement in

the paracetamol alone group (mean=22.1, SE=2.3, p=0.168) and in the ibuprofen low dose

group (mean=20.9, SE=2.2, p=0.085). The mean improvement in the WOMAC VAS pain

score from baseline to week 4 in the ibuprofen high dose treatment group (mean=26.4,

SE=2.2) is greater than the mean improvement in the Combination group (mean=25.1,

SE=2.1, p=0.638). The study has shown that in osteoarthritis pain, the combination is

effective. However, as a phase II exploratory study it cannot be used to support arthritis in the

SmPC.

The second pivotal study (AFT-MX-6E) in another acute pain model (arthroscopy) was

completed in April 2014. This study is an acute pain study for mild-moderate pain since

arthroscopy is a minor surgical procedure which results in little ongoing pain and in fact as

discussed below pain dissipates rapidly. This Phase 3 study was designed as a prospective,

parallel-group, double-blind, placebo comparison of the clinical efficacy and safety of

Maxigesic (2 tablets, each tablet containing 500 mg paracetamol and 150 mg ibuprofen)

versus its individual components (either 1000 mg paracetamol or 300 mg ibuprofen) and

versus placebo in 300 patients suffering of moderate to severe pain due to post-arthroscopy

surgery of the knee. The results of the pairwise treatment comparisons performed for the

primary endpoint (SPID 0-24 hours) are presented in tables 3 and 4 below. The per-protocol

population excluded 9 subjects. The sensitivity of the results were compared by conducting

the analysis using two different approaches – [1] SPID 0-24hr values for patients not


16

requiring rescue and [2] SPID 0-24hr values for all patients with the pre-rescue values carried

forward for the observation period i.e. LOCF [Last Observation Carried Forward].

As seen from both Tables 3 and 4, Maxigesic® provides more effective pain relief than

placebo with a high level of statistical significance (p < 0.01). It should be noted though that

comparison of either paracetamol 1000 mg or ibuprofen 300 mg every six hours did not

result in a SPID 0-24hr statistically significantly superior to placebo [p > 0.05]. There was

still a trend towards the SPID 0-24hr values for both paracetamol [49-71% greater] and

ibuprofen [22-49% greater] being improved versus placebo. However, these improvements

were much less than those observed for Maxigesic® [77-107%]. The comparison between

paracetamol and ibuprofen with Maxigesic® did not reach the significance level [p > 0.05].

The reason for this was that the pain scores observed in the study were low over the 0-24

hour time period. The surgical procedure which utilised key hole surgery caused minimal

damage from the surgery and the pain scores decreased very rapidly. These sort of pain

studies require a significant level of pain in order to demonstrate significant differences

between analgesic treatments.


17

Overall, the applicant has shown efficacy versus the single actives and placebo. The applicant

has now updated the posology to 1-2 tablets every 6 hours up to 6 tablets in 24 hours and this

is acceptable in what is a pro re nata over the counter medicine (PRN OTC) medicine.

The dose ranging study is considered acceptable and is further supported by the efficacy seen

in the clinical trials.

Conclusion on clinical efficacy

The pivotal studies were well conducted and showed that the combination was better than the

single actives (statistically in one and numerically in another) and better than placebo.

IV.5 Clinical safety

The safety for this combination and its posology is supported within the application. The

posology is acceptable as it has a maximum of four times daily dosing with a maximum of 6

tablets in a 24-hour period, as per the available UK combination product.

As can be seen from the adverse event rates, no untoward patterns were seen across the

studies. Rates of gastro-intestinal adverse events were comparable to the actives and placebo.

However, the applicant will have to comment on the GI adverse event rates seen in the open

label extension study, as well as comment on why the NSAID like adverse events have not

been attributed to the combination. The long-term safety data is also in a small data set and

with the novel posology is not considered large enough to support long-term use. No death or

SAE events attributable to the actives were seen in these trials.

The laboratory results from study AFT-MX-6E are considered acceptable and do not raise

any untoward concerns.

The post marketing experience for the product outside of the UK is supportive of its safety.

IV.6 Risk Management Plan (RMP)

The marketing authorisation holder 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 Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets.

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

RMP, are listed below:


18

Summary table of safety concerns

i) ibuprofen


19

ii) paracetamol

V.7 Discussion on the clinical aspects

The grant of marketing authorisations is recommended for the applications.

V User consultation A user consultation with target patient groups on the package information leaflet (PIL) has

been performed on the basis of a bridging report making reference to Combogesic 500

mg/150 mg film-coated tablets and Tachicold 500 mg/150 mg film-coated tablets,

UK/H/2383-2384/001/DC. The bridging report submitted by the applicant is acceptable.

VI Overall conclusion, benefit/risk assessment and

recommendation The quality of the product is acceptable, and no new non-clinical or clinical safety concerns

have been identified with the combination product. The posology is equivalent to the

available combination in the UK. The benefit/risk assessment is, therefore, considered to be

positive.

The SmPC, PIL and labelling are satisfactory and in line with current guidelines. In

accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs and

PILs for these products are available on the MHRA website.

The currently approved labels are listed below:


20

PL 20692/0132


21


22


23

PL 20692/0133


24


25


26


27

Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

(Type II variations, PSURs, commitments)

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

public assessment report - mhra.gov.uk · pdf fileparacetamol is an analgesic and antipyretic...

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