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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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.
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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:
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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Summary table of safety concerns
i) ibuprofen
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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:
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PL 20692/0132
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
21
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PL 20692/0133
PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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PAR Paracetamol/Ibuprofen 500 mg/150 mg film-coated tablets UK/H/6034-6035/001/DC
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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)