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Lemsip Max/Nurofen All Day/Night Cold and Flu Tablets/Flu Relief Tablets/Flu Relief
PL 00063/0541 and 0556
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LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
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LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
UKPAR
TABLE OF CONTENTS
Lay Summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 10
Steps taken after authorisation – summary
Page 11
Summary of Product Characteristics
Page 12
Product Information Leaflet
Page 27
Labelling
Page 29
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LEMSIP MAX ALL DAY COLD AND FLU TABLETS
LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
LEMSIP MAX ALL NIGHT COLD AND FLU TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
LAY SUMMARY
The MHRA granted Reckitt Benckiser Healthcare (UK) Limited Marketing Authorisations
(licences) for the medicinal products Lemsip Max All Day Cold and Flu Tablets, Lemsip
Max All Day Flu Relief Tablets, Lemsip Max All Day Flu Relief, Nurofen All Day Cold
and Flu Tablets, Nurofen All Day Flu Relief Tablets and Nurofen All Day Flu Relief,
Lemsip Max All Night Cold and Flu Tablets, Lemsip Max All Night Flu Relief Tablets,
Lemsip Max All Night Flu Relief, Nurofen All Night Cold and Flu Tablets, Nurofen All
Night Flu Relief Tablets and Nurofen All Night Flu Relief on 17th November 2008. These
products are indicated for relieving the symptoms associated with colds and flu, including
relief of aches and pains, sore throats, headache, nasal congestion (blocked nose) and
lowering of temperature.
These products, to be available on general-sales licences (GSL), contain ibuprofen and
phenylephrine hydrochloride. Ibuprofen belongs to a group of medicines known as nonsteroidal anti-inflammatory drugs (NSAIDs) and is effective against aches and pains
(including headaches), swelling and can also reduce a fever. Phenylephrine hydrochloride
reduces swelling in the passages of the nose, relieving nasal congestion and reducing the
pressure which may cause a headache (nasal decongestant).
No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Lemsip Max All Day Cold and Flu Tablets, Lemsip Max
All Day Flu Relief Tablets, Lemsip Max All Day Flu Relief, Nurofen All Day Cold and Flu
Tablets, Nurofen All Day Flu Relief Tablets and Nurofen All Day Flu Relief, Lemsip Max
All Night Cold and Flu Tablets, Lemsip Max All Night Flu Relief Tablets, Lemsip Max All
Night Flu Relief, Nurofen All Night Cold and Flu Tablets, Nurofen All Night Flu Relief
Tablets and Nurofen All Night Flu Relief outweigh the risks, hence Marketing
Authorisations has been granted.
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LEMSIP MAX ALL DAY COLD AND FLU TABLETS
LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
LEMSIP MAX ALL NIGHT COLD AND FLU TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
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 10
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INTRODUCTION
The UK granted Reckitt Benckiser Healthcare (UK) Limited marketing authorisations for
the medicinal products Lemsip Max All Day Cold and Flu Tablets, Lemsip Max All Day
Flu Relief Tablets, Lemsip Max All Day Flu Relief, Nurofen All Day Cold and Flu Tablets,
Nurofen All Day Flu Relief Tablets and Nurofen All Day Flu Relief, Lemsip Max All
Night Cold and Flu Tablets, Lemsip Max All Night Flu Relief Tablets, Lemsip Max All
Night Flu Relief, Nurofen All Night Cold and Flu Tablets, Nurofen All Night Flu Relief
Tablets and Nurofen All Night Flu Relief (PL 00063/0541 and 0556) on 17th November
2008. The products are available on a General-Sales Licence (GSL) and contain the active
substances ibuprofen and phenylephrine hydrochloride.
The applications were submitted as abridged applications, according to Article 10a of
Directive 2001/83/EC, well-established use applications. The products contain 200mg
ibuprofen and 5mg phenylephrine.
No new data were submitted nor were they necessary for these applications, as both active
substances are well-known pharmaceutical ingredients that have been used for many years
in other products. All data used in support of these applications were obtained from
bibliographic references.
Ibuprofen is an analgesic/antipyretic for aches and pains, and lowering of temperature that
acts via inhibition of prostaglandin synthesis. Phenylephrine is a sympathomimetic agent
(alpha-1- adrenergic agonist) which acts by vasoconstriction as a nasal decongestant.
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PHARMACEUTICAL ASSESSMENT
DRUG SUBSTANCE
Ibuprofen
Chemical name:
N-(4-hydroxyphenyl)acetamide
Structure:
Description:
White crystalline powder
Molecular formula:
C13H18O2
MW:
206.3
Ibuprofen is the subject of a European Pharmacopoeia monograph.
Ibuprofen is supplied by three active substance manufacturers. The manufacture and
control of ibuprofen from all manufacturers are covered by Certificates of Suitability.
Batch analysis data are provided from all manufacturers and comply with the proposed
specifications.
Specifications have been provided for all packaging used. All primary packaging complies
with current European Directives concerning contact with food (2002/72/EC).
Based on stability data submitted, suitable retest periods have been set for active ibuprofen
from all manufacturers. Suitable post approval stability commitments have been given to
provide additional stability data as and when it becomes available.
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DRUG SUBSTANCE
Phenylephrine hydrochloride
Chemical name:
(1R)-1-(3-hydroxyphenyl)-2-(methylamino)ethanol hydrochloride
Structure:
Description:
White or almost white crystalline powder
Molecular formula:
C9H14ClNO2
RMS:
203.7
Phenylephrine is the subject of a European Pharmacopoeia monograph.
The manufacture and control of phenylephrine is covered by a Certificate of Suitability.
Batch analysis data are provided and comply with the proposed specifications.
Specifications have been provided for all packaging used. All primary packaging complies
with current European Directives concerning contact with food (2002/72/EC).
Based on stability data submitted, a suitable retest period has been set for active
phenylephrine hydrochloride. Suitable post approval stability commitments have been
given to provide additional stability data as and when it becomes available.
DRUG PRODUCT
Description and Composition of the Drug Product
The product is a yellow, round biconvex, film-coated tablet with an identifying logo in
black on one face.
Other ingredients consist of pharmaceutical excipients, namely microcrystalline cellulose,
sodium starch glycolate Type A, hypromellose, magnesium stearate, talc, purified water,
industrial methylated spirits, mastercote yellow FA 0156 (containing hypromellose,
quinoline yellow aluminium lake, sunset yellow aluminium lake and titanium dioxide) and
black printing ink (containing shellac, iron oxide black and propylene glycol).
All excipients used comply with their respective European Pharmacopoeia monograph,
with the exception of the mastercote yellow FA 0156 and black printing ink (which are
tested to a suitable in-house specification), and industrial methylated spirits (which is tested
to a British Pharmacopoeia monograph). The printing ink and mastercote yellow FA 0156
conform to EU Directives 95/45/EC.
Suitable certificates of analysis have been provided for all excipients used. None of the
excipients used contain materials of animal or human origin.
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Product Development
The objective of the product development was to produce an immediate release,
film-coated tablet, containing ibuprofen 200 mg and phenylephrine HCl 5 mg.
Manufacture
A description and flow-chart of the manufacturing method has 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 finished product.
The results appear satisfactory.
Finished Product Specification
The finished product specifications are satisfactory. Test methods have been described and
have been adequately validated, as appropriate. Batch data have been provided and comply
with the release specifications. Certificate of analysis have been provided for all working
standards used.
Container Closure System
All finished product is packaged in a strip pack consisting of a blister tray of white
pigmented 250μm PVC/40gsm PVDC laminate, heat-sealed to lacquered 20μm aluminium
foil containing 2, 4 or 8 tablets. One or two trays are packed in cardboard cartons, in pack
sizes of. 4, 6, 8, 10, 12, 14 or 16 tablets.
The marketing authorisation holder has stated that not all proposed pack sizes are intended
for marketing and has committed to submitting mock-ups to the MHRA for approval before
marketing any strengths of finished product.
Specifications and Certificates of Analysis for all packaging have been provided. These are
satisfactory. All primary packaging has been shown to comply with EU Directive
2002/72/EC regarding the contact of materials with food.
Stability
Stability studies have been conducted on batches of the finished product supplied by the
finished product manufacturer, in the packaging proposed for marketing, in accordance
with current guidelines. Based on the results, a shelf-life of 2 years has been set, with the
storage instructions “Store in a dry place”, “Store in the original package”, “Store below
25°C” and “Keep out of reach and sight of children.”.
The applicant has provided suitable post approval stability commitments to follow-up the
current batches on stability.
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ADMINISTRATIVE
Expert Report
A pharmaceutical expert report has been written by a suitably qualified person and is
satisfactory.
Summary of Product Characteristics (SPC)
These are pharmaceutically satisfactory.
Labelling
These are pharmaceutically satisfactory.
Patient Information Leaflet
These are consistent with the SPC and are satisfactory. A package leaflet has been
submitted to the MHRA along with results of consultations with target patient groups
("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The
results indicate that the package leaflet is well-structured and organised, easy to understand
and written in a comprehensive manner. The tests show that the patients/users are able to
act upon the information that it contains.
MAA Form
These are satisfactory.
Conclusion
It is recommended that Marketing Authorisations are granted for these applications.
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PRECLINICAL ASSESSMENT
INTRODUCTION
No new preclinical data have been supplied with this application and none are required for
applications of this type.
PHARMACOLOGY/PHARMACOKINETICS/TOXICOLOGY
The analgesic, antipyretic and anti-inflammatory properties of ibruprofen are attributed to
COX-1- and COX-2-mediated inhibition of prostaglandin synthesis.
Phenylephrine hydrochloride is a selective α1-adrenergic agonist acting at the post synaptic
level, causing vasoconstriction within the nasal mucosa to reduce nasal congestion.
The pharmacodynamics, pharmacokinetics and toxicology of ibuprofen and phenylephrine
hydrochloride are well-established and will not be reviewed further. The individual active
ingredients have been in use for many years and there is a wealth of clinical data available.
No new preclinical studies have been performed in support of this application and the
applicant has provided a literature review.
The non-clinical overview was written by an appropriately qualified person and is a
thorough review of the pharmacology and toxicology of ibuprofen and phenylephrine
hydrochloride.
The non-clinical overview focuses on the published pharmacological and toxicological data
for the proposed active substances separately with only a brief discussion on the proposed
concomitant use. It is noted that, at the time of national grant, this is the first combination
of ibuprofen and phenylephrine hydrochloride and that bridging studies addressing
pharmacodynamic, pharmacokinetic and toxicological interactions would usually be
expected in-line with the Guideline on the Non-clinical Development of Fixed
Combinations of Medicinal Products. However, a suitable justification has been provided
for the absence of these studies, by arguing that no interactions are anticipated based on
differing pharmacological targets, pharmacological actions and metabolic pathways of the
active substances. Additionally, neither active has demonstrated any secondary
pharmacological effects at the intended dose levels.
A clinical point for clarification was raised, requesting any available information on the
concomitant use of ibuprofen and phenylephrine. This point has subsequently been
resolved on the basis that phenylephrine is similar pharmacologically to pseudoephedrine,
which has historically been combined with ibuprofen.
EXCIPIENTS
The applicant has discussed the safety profiles of the individual excipients in the
non-clinical overview. The proposed excipients are well-known and have been in use in
pharmaceutical food or preparations for many years.
IMPURITIES
The non-clinical overview provides a thorough discussion of potential impurities arising
from manufacture or degradation of the drug product. The impurity profiles are reported to
be within the limits set out in the European Phamacopoeia and do not require toxicological
qualification.
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SUMMARY OF PRODUCT CHARACTERISTICS (SPC)
The preclinical sections of the SPC are similar to those for already licensed products
containing these active substances and are generally acceptable from a non-clinical point of
view.
ECOTOXICITY/ENVIRONMENTAL RISK ASSESSMENT
The applicant has not submitted an environmental risk assessment in-line with the
guideline on the environmental risk assessment of medicinal products for human use
(EMEA/CHMP/SWP/447/00). Instead, the applicant argues that both active substances are
well-established, with many years of sales worldwide and that marketing of this additional
presentation will not significantly increase the exposure levels of these active substances to
the environment. The justification for the absence of an environmental risk assessment is
acceptable.
ASSESSOR’S OVERALL CONCLUSIONS
The preclinical overview has adequately reviewed relevant published non-clinical data, and
discussed the impurity profiles and proposed excipients. In addition, the applicant has
justified the lack of bridging studies and an environmental risk assessment. As such, no
non-clinical concerns are raised either by the use of ibuprofen and phenylephrine in
combination or the proposed formulation.
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CLINICAL ASSESSMENT
CLINICAL PHARMACOLOGY
Pharmacokinetics
Ibuprofen
In human plasma, ibuprofen is 99% protein-bound onto a single primary site on albumin.
Plasma protein binding of ibuprofen may be non-linear. This high degree of binding results
in a relatively low volume of distribution. Although ibuprofen is extensively bound to
albumin, this does not appear to be a clinically important issue regarding drug interactions.
For example, ibuprofen does not significantly displace warfarin from albumin binding sites.
Ibuprofen is metabolised by oxidation of the isobutyl group and glucuronidation of the
carboxyl moiety. The isobutyl group is hydroxylated both on the tertiary centre, giving
2-(4-(2hydroxy-2-methylpropyl)phenyl)-propionic acid, and also on one of the methyl
groups, giving 2-(4-(2-hydroxymethy1-propyl)phenyl)-propionic acid, which is then further
oxidized to 2-(4-(carboxypropyl)phenyl)-propionic acid. Both of these metabolites are
conjugated with glucuronic acid and all the excretion products, free and conjugates, are
pharmacologically inactive. A further route of metabolism involves the formation of the
acyl CoA thioester, the essential intermediate in the metabolic chiral inversion from (-)-Rto (+)-S-ibuprofen.
The elimination half-life of ibuprofen is relatively short, ranging from 0.9 to 2.5 hours
(with a mean of 1.9 hours). Excretion of the metabolites in the urine is usually complete
within 24 hours of taking the last dose. Total urinary excretion of ibuprofen and its
metabolites is a linear function of dosage. Ibuprofen has a very short half life and,
therefore, it is unlikely to influence renal function, except in conditions where renal
function is already compromised. Furthermore, accumulation of ibuprofen does not seem to
occur during prolonged therapeutic dosing.
Phenylephrine
Despite its widespread use as a systemically acting decongestant, the pharmacokinetics of
phenylephrine is relatively poorly documented. Pre-systemic metabolism (i.e. in the gut)
occurs primarily by monoamine oxidase. Absorption is then fairly rapid, with a Tmax of 1-2
hours in aqueous solution. Once within the blood stream, phenylephrine is further
metabolised by the liver and its oral bioavailability is estimated to be ~38%. The variability
in exposure after oral dosage of aqueous solutions, as indicated by the area under the
plasma–drug concentration–time curve (AUC), was about 1.2 fold in a study of four
subjects. In another study of 20 subjects, the standard deviation on the AUC was about
20%.
Data on the protein binding characteristics of this drug is lacking. Penetration into the
central nervous system appears to be minimal and it does not seem to be excreted into
breast milk to any significant degree. The volume of distribution of phenylephrine at steady
state has been estimated as 184–543 L.
Most of an oral dose of phenylephrine is metabolised, with only 2.6% appearing unchanged
in the urine after 48 hours. The metabolites of phenylephrine do not contribute to its
pharmacological activity. The elimination half-life of phenylephrine is 2-3 hours and the
average total clearance has been estimated to be 125.7 litres per hour. A later study
reported a number of pharmacokinetic parameters for an orally administered solution of
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20mg phenylephrine hydrochloride in combination with 4mg of carbinoxamine. Cmax of
phenylephrine in the combination was 432ng/ml, Tmax was 1.0 hour and the elimination
half-life was 2.5 hours, agreeing with the earlier study. Despite this relatively low oral
availability, clinically the drug is effective as a decongestant via the oral route.
The combination of ibuprofen and PE
The maximum recommended OTC daily dose of ibuprofen as a single product is 1200mg
and the maximum OTC daily dose of phenylephrine hydrochloride is 60mg. The proposed
combination tablet containing 200mg ibuprofen and 5mg phenylephrine hydrochloride at
an initial dose of 2-tablets every 4 hours with a maximum of 6-tablets in 24 hours, will
provide a maximum daily dose of 1200 mg ibuprofen and 30 mg phenylephrine
hydrochloride.
Assessor’s overall conclusions on pharmaokinetics
The metabolic pathways for the two actives are different. Therefore, no pharmacokinetic
interactions are anticipated. The applicant has conducted a bioequivalence study (see
below) that shows the inclusion of phenylephrine to the formulation does not affect the
absorption of ibuprofen.
Bioequivalence
The following bioequivalence study has been submitted with this application:
“A randomised, single-dose, crossover, open-label bioavailability study comparing the rate
and extent of absorption of ibuprofen from a fixed combination formulation of 200mg
ibuprofen and 5mg phenylephrine hydrochloride (Test product) with the rate and extent of
absorption of ibuprofen from standard Nurofen® tablets (Reference product) in normal
healthy volunteers”.
Subjects received study treatment after a 10-hour overnight fast. Blood samples were taken
pre- and up to 720 minutes post dose. The washout period was 3-7 days. The results from
the study are presented below:
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Assessor’s comment on bioequivalence
The study was appropriately designed to establish bioequivalence between the two
products. The 90% confidence intervals for Cmax and AUC0-inf were within 80-125%. The
rate and extent of absorption of ibuprofen from ibuprofen 200mg plus phenylephrine
hydrochloride 5mg fixed combination tablets is equivalent to ibuprofen from ibuprofen
200mg tablets. Therefore the inclusion of phenylephrine in a tablet formulation with
ibuprofen does not adversely affect the absorption of ibuprofen.
Pharmacodynamics
Introduction
The active ingredients exert their effects by unrelated pharmacological mechanisms.
Ibuprofen is an analgesic and antipyretic at doses indicated for colds and influenza. The
analgesic effect is exerted through the inhibition of prostaglandin biosynthesis peripherally,
while the antipyretic effect results from central inhibition of prostaglandin biosynthesis.
Phenylephrine is an alpha-1-adrenoreceptor agonist, which has a nasal decongestant effect.
No pharmacodynamic interactions are expected with these actives and this is based on their
different mechanisms of action and intended indications.
Assessor’s comment on pharmacodynamics
The pharmacodynamic effects of ibuprofen and phenylephrine are well-recognised. Due to
their different mechanisms of action, no pharmacodynamic interactions are expected
CLINICAL EFFICACY
Introduction
The common cold and influenza are associated with a number of symptoms. Phenylephrine
is used as a nasal decongestant, whereas ibuprofen is used to relieve headache/bodyaches
and fever. Hence, the combination is useful in the treatment of different symptoms of cold
and flu. This combination of a decongestant and antipyretic/analgesic is a well-established
combination therapy.
Although no clinical trials have been conducted using the proposed product,
bioequivalence studies have demonstrated bioequivalence between Ibuprofen 200 mg
tablets and Nurofen 200 mg tablets, and now Nurofen 200 mg and the present combination
(i.e. ibuprofen and phenylephrine).
The proposed indications for ibuprofen 200mg and phenylephrine hydrochloride 5mg are
the same as for those for Nurofen Cold & Flu (ibuprofen and pseudoephedrine). They
include the symptomatic relief of mild to moderate pain (such as soft tissue injuries and
muscular pain, backache, migraine, neuralgia, headache, sore throat, dental pain and
dysmenorrhoea), the symptomatic relief of fever, and the pain and fever of colds/influenza.
Ibuprofen
Ibuprofen at a dose of 400mg is regularly recommended for the treatment of symptoms of
the common cold and influenza. This is exemplified in a study by Winther et al. who
reported on the effects of 400 mg ibuprofen or placebo taken three times per day in 80
patients with common cold. The active treatment resulted in a significant reduction in
headache (p<0.008), earache (p<0.01), muscle/joint pain (p<0.045) and reduced body
temperature (p<0.02). Interestingly there was also a 40% reduction in sneezing (p<0.02)
and a 33% reduction in the symptom score for sneezing (p<0.04).
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Phenylephrine hydrochloride
This is a powerful post synaptic α-receptor agonist. It has a very low cardioselective betareceptor affinity and central stimulant activity is minimal. It is a recognised decongestant,
which acts by vasoconstriction to reduce oedema and swelling of the nasal mucosa. By this
means, nasal discharge may be reduced, and obstruction associated with colds and
influenza may be relieved.
The decongestant of choice is pseudoephedrine and this relates to its bioavailability and
number of recent trials demonstrating its efficacy for alleviating nasal congestion
associated with the common cold. However, due to misuse of pseudoephedrine and the
consequent control measures that are now required for this drug, suitable therapeutic
alternatives are necessary. There is evidence to suggest that phenylephrine is effective as an
oral nasal decongestant.
Recently, however, the efficacy of phenylephrine as a nasal decongestant has been called
into question and the topic of two reviews with conflicting outcomes.
Hatton et al. analysed eight unpublished studies using a random effects model. The primary
analysis was focused on administration of a single 10mg dose of phenylephrine
hydrochloride. The primary outcome measure was defined as the maximum reduction in
nasal airway resistance (NAR) over 120 minutes, expressed as the percent decrease from
baseline. This was measured by determining the mean change from baseline for both
phenylephrine hydrochloride and placebo. The main finding was that 10mg of
phenylephrine hydrochloride did not affect NAR as it was no different from placebo.
Indeed, the mean maximal difference between phenylephrine hydrochloride and placebo
was 10.1% (95% CI from ~0.8 to 23.9%). However, at a dose of 25mg, Hatton et al. did
report a significant reduction of maximal NAR (-27.6%; 95% CI from 17.5 to 37.7%).
This was followed by another review by Kollar et al. They reviewed the same population
of studies and incorporated both a random effects (like Hatton et al.) and fixed-effects
statistical model. In contrast, however, statistical significance was determined at 30 and 60
minutes after dosing (these were defined as the primary time-points) and, like Hatton et al.,
a change in NAR from baseline was the efficacy variable. Results showed that 10 mg of
phenylephrine hydrochloride was significantly (P<0.05) more effective than placebo at the
primary time-points (both 30 minutes and 60 minutes) and even at 90 minutes in both
fixed- and random-effects models.
Furthermore, using the fixed-effects model, 10mg of phenylephrine hydrochloride was also
significantly more effective than placebo at 120 and 180 minutes after dosing (P<0.05).
When compared with placebo, NAR was decreased by 6% after 30 and 45 minutes; -16.6%
after 60 minutes; and, less than -20% after 60 and 180 minutes. Thus, Kollar et al.
concluded that single oral doses of 10 mg of phenylephrine hydrochloride were effective
against the acute nasal congestion associated with common colds in adults.
The combination of ibuprofen and phenylephrine hydrochloride
The above sections indicate that ibuprofen targets the pain associated with a common cold
and that phenylephrine hydrochloride targets nasal congestion. Hence, both actives work in
synergy to alleviate the symptoms of a common cold and flu.
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The dose of phenylephrine hydrochloride used to relieve nasal congestion ranges between 5
and 20mg, with the frequency ranging between three and four times daily. The efficacious
dose in adults (based on the findings of Kollar et al.) is 10mg of phenylephrine
hydrochloride. In Nurofen for Cold & Flu, each tablet provides 5mg of phenylephrine
hydrochloride, so two tablets are required to reach the efficacious level of 10mg of
phenylephrine hydrochloride. These two tablets are then taken every 4 hours in order to
alleviate nasal congestion. This equates to a maximum daily dose of 30.0mg and this is
within the accepted dosage range for phenylephrine hydrochloride stipulated for a
pharmacy product (i.e. 40mg) and by the FDA (60mg).
Although no ibuprofen/phenylephrine hydrochloride combination product was available at
the time of assessment, both have been in widespread use as non-prescription ingredients
for many years. However, unlike ibuprofen, there are not many phenylephrine
hydrochloride products on the market. Countries such as the UK, Australia and the US are
adopting a modified approach to the registration of products containing phenylephrine
hydrochloride in place of pseudoephedrine hydrochloride. This approach is justified by the
pharmacological similarity between pseudoephedrine hydrochloride and phenylephrine
hydrochloride.
In view of the above, the marketing authorisation holder has provided data from studies
performed comparing ibuprofen/pseudoephedrine combination versus other products,
including ibuprofen and pseudoephedrine on their own. A summary of these studies is
provided below:
Assessor’s comment on clinical efficacy
Ibuprofen and phenylephrine hydrochloride have been in clinical use for many years. The
efficacy of ibuprofen in the proposed indications is well-recognised. The efficacy of
phenylephrine is more controversial. Despite the fact that there appears to be evidence from
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published literature on the anti-congestant effect of phenylephrine, this is not undisputable.
In spite of this, the pharmacological similarity between pseudoephedrine and phenylephrine
means that a substitution of pseudoephedrine for phenylephrine is accepted as reasonable.
This is further supported by the clinical trial data provided by the marketing authorisation
holder, comparing ibuprofen/pseudoephedrine combinations with these products
administered individually.
CLINICAL SAFETY
No new safety data have been provided. The clinical expert provides an overview of the
safety profile of the two active ingredients. The adverse events associated with use of
NSAIDS and phenylephrine are well-recognised.
Safety in special populations
Of special interest is use during pregnancy. Ibuprofen, in the last trimester of pregnancy,
can inhibit uterine contractions and cause the premature closure of the ductus arteriosus;
pulmonary hypertension in the neonate; increased bleeding tendency of mother and infant;
and increase in the incidence of oedema in the mother. Thus, the SPC indicates that the use
of Nurofen during the first 6 months of pregnancy should be avoided and it should not be
used during the last trimester of pregnancy as the onset of labour may be reduced and the
duration of labour extended.
Assessor’s comment on clinical safety
The safety profile of ibuprofen and phenylephrine is well-recognised. No new safety
concerns are anticipated with use of the two actives in a combination product.
EXPERT REPORTS
A Clinical Expert Report has been written by an appropriately qualified physician. It is an
adequate summary of the clinical aspects of the dossier.
PRODUCT LITERATURE
Summary of Product Characteristics (SPC)
The SPCs are clinically satisfactory.
Patient Information Leaflet (PIL)
The PILs are clinically satisfactory.
Labelling
The labelling is clinically satisfactory.
OVERALL CONCLUSION
At the time of assessing these applications, the combination of ibuprofen and
phenylephrine hydrochloride had never been marketed before. The marketing authorisation
holder has adequately presented information for phenylephrine and, where applicable, for
pseudoephedrine, such that grant of marketing authorisations are recommended for these
products.
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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Lemsip Max All Day Cold and Flu Tablets, Lemsip
Max All Day Flu Relief Tablets, Lemsip Max All Day Flu Relief, Nurofen All Day Cold
and Flu Tablets, Nurofen All Day Flu Relief Tablets and Nurofen All Day Flu Relief,
Lemsip Max All Night Cold and Flu Tablets, Lemsip Max All Night Flu Relief Tablets,
Lemsip Max All Night Flu Relief, Nurofen All Night Cold and Flu Tablets, Nurofen All
Night Flu Relief Tablets and Nurofen All Night Flu Relief 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 applications of this type.
EFFICACY
No new efficacy data were submitted and none are required for applications of this type.
No new or unexpected safety concerns arise from these applications.
The SPC, PIL and labelling are satisfactory and consistent with those for similar products.
RISK BENEFIT ASSESSMENT
The quality of the products is acceptable and no new preclinical or clinical safety concerns
have been identified. Extensive clinical experience with both ibuprofen and
phenylephrine/pseudoephedrine is considered to have demonstrated the therapeutic value of
the compound. The risk benefit is, therefore, considered to be positive.
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LEMSIP MAX ALL DAY COLD AND FLU TABLETS
LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
LEMSIP MAX ALL NIGHT COLD AND FLU TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
STEPS TAKEN FOR ASSESMENT
1
The MHRA received the marketing authorisation applications on 19/03/2008.
2
Following standard checks and communication with the applicant the MHRA
considered the application valid on 27/03/2008.
3
Following assessment of the application the MHRA requested further
information relating to the pharmaceutical dossier on 25/06/2008, relating to the
preclinical dossier on 25/09/2008, and further information relating to the clinical
dossier on 16/07/2008.
4
The applicant responded to the MHRA’s requests, providing further information
relating to the pharmaceutical and clinical dossiers on 09/09/2008, and relating
to the preclinical dossier on 29/10/2008.
5
The applications were determined on 17/11/2008
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LEMSIP MAX ALL DAY COLD AND FLU TABLETS
LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
LEMSIP MAX ALL NIGHT COLD AND FLU TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
STEPS TAKEN AFTER ASSESSMENT
Date
submitted
Application Scope
type
Outcome
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LEMSIP MAX ALL DAY COLD AND FLU TABLETS
LEMSIP MAX ALL DAY FLU RELIEF TABLETS
LEMSIP MAX ALL DAY FLU RELIEF
NUROFEN ALL DAY COLD AND FLU TABLETS
NUROFEN ALL DAY FLU RELIEF TABLETS
NUROFEN ALL DAY FLU RELIEF
LEMSIP MAX ALL NIGHT COLD AND FLU TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF TABLETS
LEMSIP MAX ALL NIGHT FLU RELIEF
NUROFEN ALL NIGHT COLD AND FLU TABLETS
NUROFEN ALL NIGHT FLU RELIEF TABLETS
NUROFEN ALL NIGHT FLU RELIEF
SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Lemsip Max All Day Cold & Flu Tablets, or
Lemsip Max All Day Flu Relief Tablets, or
Lemsip Max All Day Flu Relief, or
Nurofen All Day Cold & Flu Tablets or
Nurofen All Day Flu Relief Tablets, or
Nurofen All Day Flu Relief.
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredients
Quantity
Ibuprofen BP
200.0mg
Phenylephrine hydrochloride
5.0mg
For full list of excipients, see Section 6.1.
3
PHARMACEUTICAL FORM
Yellow film coated tablet, printed with an identifying motif (IPE) in black ink.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
For the relief of symptoms of cold and 'flu with associated congestion, including aches and pains,
headache, fever, sore throat, blocked nose and sinuses.
4.2
Posology and method of administration
For oral administration and short-term use only.
Adults, the elderly and children over 12 years:
The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.
The patient should consult a doctor if symptoms persist or worsen, or if the product is required for
more than 10 days.
Two tablets every 8 hours. Leave at least 4 hours between doses and do not exceed six tablets in any
24 hour period.
Not to be given to children under 12 years.
4.3
Contraindications
Hypersensitivity to ibuprofen, phenylephrine or any of the excipients in the product. Hypertension
and severe coronary heart disease.
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Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or
urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes or proven
ulceration or bleeding).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Severe heart failure, renal failure or hepatic failure (see Section 4.4).
Last trimester of pregnancy.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see Section 4.5).
4.4
Special warnings and precautions for use
Ibuprofen
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms (see gastrointestinal and cardiovascular risks below).
The elderly are at increased risk of consequence of adverse reactions to NSAIDs, especially
gastrointestinal bleeding and perforation which may be fatal.
Respiratory: Bronchospasm may be precipitated in patients suffering from or with a previous
history of bronchial asthma or allergic disease.
Other NSAIDs: The use of this product with concomitant NSAIDs, including cyclo-oxygenase-2
selective inhibitors, should be avoided (see Section 4.5).
SLE and mixed connective tissue disease: Systemic lupus erythematosus and mixed connective
tissue disease - increased risk of aseptic meningitis (see Section 4.8).
Renal: Renal impairment as renal function may further deteriorate (see Sections 4.3 and 4.8).
Hepatic: Hepatic dysfunction (see Sections 4.3 and 4.8).
Cardiovascular and cerebrovascular effects: Caution (discussion with doctor or pharmacist) is
required prior to starting treatment in patients with a history of hypertension and/or heart failure as
fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400
mg daily) and in long-term treatment, may be associated with a small increased risk of arterial
thrombotic events (for example, myocardial infarction or stroke). Overall, epidemiological studies
do not suggest that low dose ibuprofen (≤1200 mg daily) is associated with an increased risk of
myocardial infarction.
Impaired female fertility: There is limited evidence that drugs which inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on
ovulation. This is reversible on withdrawal of treatment.
Gastrointestinal: NSAIDs should be given with care to patients with a history of gastrointestinal
disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8).
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any
time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients
with a history of ulcer, particularly if complicated with haemorrhage or perforation (see Section 4.3),
and in the elderly. These patients should commence treatment on the lowest dose available.
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Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal
symptoms (especially GI bleeding), particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the
risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective
serotonin-reuptake inhibitors or anti-platelets agents such as aspirin (see Section 4.5).
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be
withdrawn.
Dermatological: Serious skin reactions, some of them fatal, including exfoliating dermatitis,
Stevens-Johnson Syndrome, and toxic epidermal necrolysis, have been reported very rarely in
association with the use of NSAIDs (see Section 4.8). Patients appear to be at highest risk of these
reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases
within the first month of treatment. This product should be discontinued at the first appearance of
skin rash, mucosal lesions or any other sign of hypersensitivity.
The label will include:
Read the enclosed leaflet before taking this product.
Do not take if you:
• Have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding.
• Are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers.
• Are taking other NSAID painkillers, or aspirin with a daily dose above 75 mg.
Speak to a pharmacist or your doctor before taking if you:
• Have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver,
kidney or bowel problems.
• Are a smoker.
• Are pregnant.
If symptoms persist or worsen, consult your doctor.
Phenylephrine
Phenylephrine should be used with care in patients with hyperthyroidism, cardiovascular disease,
diabetes mellitus, closed angle glaucoma, prostatic enlargement and hypertension.
4.5
Interaction with other medicinal products and other forms of interaction
Ibuprofen
Ibuprofen should not be used in combination with:
Aspirin: Unless low-dose aspirin (not above 75 mg daily) has been advised by a doctor, as this may
increase the risk of adverse reactions (see Section 4.4).
Other NSAIDs including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or
more NSAIDs as this may increase the risk of adverse reactions (see Section 4.4).
Ibuprofen should be used with caution in combination with:
Anti-coagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see Section
4.4).
Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can
increase the risk of nephrotoxicity.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4).
Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): Increased risk of
gastrointestinal bleeding (see Section 4.4).
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Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma
glycoside levels.
Lithium: There is evidence for potential increase in plasma levels of lithium.
Methotrexate: There is potential for an increase in plasma methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as
NSAIDs can reduce the effect of mifepristone.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine.
There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs
receiving concurrent treatment with zidovudine and ibuprofen.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions
associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an
increased risk of developing convulsions.
Phenylephrine
Phenylephrine may adversely interact with other sympathomimetics, vasodilators and beta-blockers.
Phenylephrine is not recommended for patients currently receiving or within two weeks of stopping
therapy with monoamine oxidase inhibitors (MAOIs).
4.6
Pregnancy and lactation
Ibuprofen
Whilst no teratogenic effects have been demonstrated to in animal experiments, the use of this
product should, if possible, be avoided during the first six months of pregnancy.
During the third trimester, ibuprofen is contraindicated as there is a risk of premature closure of the
fetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be
delayed and the duration increased with an increased bleeding tendency in both mother and child
(see Section 4.3).
In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to
affect the breast-fed infant adversely.
See Section 4.4 regarding female fertility.
Phenylephrine
Due to the vasoconstrictive properties of phenylephrine, the product should be used in caution in
patients with a history of pre-eclampsia.
Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if
the benefits outweigh this risk.
There is no information on use of phenylephrine in lactation.
4.7
Effects on ability to drive and use machines
No adverse effects known.
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4.8
Undesirable effects
Ibuprofen
Hypersensitivity reactions have been reported following treatment with ibuprofen and these may
consist of:
(a) Non-specific allergic reaction and anaphylaxis.
(b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm or dyspnoea.
(c) Various skin reactions, e.g. pruritis, urticaria, angioedema and, more rarely, exfoliative and
bullous dermatoses (including epidermal necrolysis and erythema multiforme).
The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for
short-term use. In the treatment of chronic conditions, under long-term treatment, additional effects
may occur.
Hypersensitivity reactions
Uncommon: Hypersensitivity reactions with urticaria and pruritus.
Very rare: Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal
swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).
Exacerbation of asthma and bronchospasm.
Gastrointestinal
The most commonly-observed adverse events are gastrointestinal in nature.
Uncommon: Abdominal pain, nausea and dyspepsia.
Rare: Diarrhoea, flatulence, constipation and vomiting.
Very rare: Peptic ulcer, perforation and gastrointestinal haemorrhage, melaena, haematemesis,
sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis and mouth ulceration.
Exacerbation of colitis and Crohn's disease (see Section 4.4).
Nervous System
Uncommon: Headache, dizziness and tinnitus.
Very rare: Aseptic meningitis - single cases have been reported very rarely.
Renal
Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with
increased serum urea and oedema.
Hepatic
Very rare: Liver disorders.
Haematological
Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia,
agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms,
severe exhaustion, unexplained bleeding and bruising.
Dermatological
Uncommon: Various skin rashes.
Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson
Syndrome, erythema multiforme and toxic epidermal necrolysis, can occur.
Immune System
In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed
connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic
meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation, have been
observed (see Section 4.4).
Cardiovascular and Cerebrovascular
Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
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Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400
mg daily) and in long-term treatment, may be associated with a small increased risk of arterial
thrombotic events (for example, myocardial infarction or stroke) (see Section 4.4).
Phenylephrine
High blood pressure with headache, vomiting and rarely, palpitations.
Also, rare reports of allergic reactions.
4.9
Overdose
Ibuprofen
In children, ingestion of more than 400 mg/kg may cause symptoms. In adults, the dose response
rate effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Symptoms
Patients who have ingested clinically important amounts of NSAIDs will develop no more than
nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal
bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system,
manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients
develop convulsions. In serious poisoning metabolic acidosis may occur and prothrombin time/INR
may be prolonged, probably due to interference with the actions of circulating clotting factors.
Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management
Management should be symptomatic and supportive and include the maintenance of a clear airway
and monitoring of cardiac and vital signs until stable. Consider oral administration of activated
charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent
or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give
bronchodilators for asthma.
Phenylephrine
Features of severe overdosage of phenylephrine include haemodynamic changes and cardiovascular
collapse with respiratory depression.
Treatment includes early gastric lavage and symptomatic and supportive measures.
Hypertensive effects may be treated with an intravenous alpha-receptor blocking agent.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
M01AE51 - Ibuprofen, combinations.
Ibuprofen
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of
prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever.
Furthermore, ibuprofen reversibly inhibits platelet aggregation.
The therapeutic effect of ibuprofen in symptoms relating to the common cold and influenza has a
duration of up to 8 hours.
Phenylephrine
Phenylephrine is a post-synaptic alpha-receptor agonist with low cardioselective beta-receptor
affinity and minimal central stimulant activity. It is a recognised decongestant and acts by
vasoconstriction to reduce oedema and nasal swelling.
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5.2
Pharmacokinetic properties
Ibuprofen
Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the
whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty
stomach. When taken with food, peak levels are observed after 1-2 hours. These times may vary
with different dosage forms.
The half-life of ibuprofen is about 2 hours.
In limited studies, ibuprofen appears in the breast milk in very low concentr-ations.
Phenylephrine
Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral
route due to first-pass metabolism.
It retains activity as a nasal decongestant when given orally, the drug distributing through the
systemic circulation to the vascular bed of the nasal mucosa.
When taken by mouth as a nasal decongestant, phenylephrine is usually given at intervals of 4-6
hours.
Ibuprofen and Phenylephrine Combination
The ibuprofen component of this fixed combination (ibuprofen 200 mg plus phenylephrine
hydrochloride 5 mg) is absorbed faster than standard ibuprofen 200 mg tablets, with therapeutic
levels being reached in 26.4 minutes (from the fixed combination) as opposed to 55.2 minutes (for
standard ibuprofen).
5.3
Preclinical safety data
There are no findings of relevance to the prescriber other than those already mentioned elsewhere in
the SPC.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Microcrystalline cellulose
Sodium starch glycolate Type A
Hypromellose
Magnesium stearate
Talc
Water, purified
Industrial methylated spirits
Mastercote yellow FA 0156
Black printing ink
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
Two years.
6.4
Special precautions for storage
Store in a dry place.
Store in the original package.
Store below 25°C.
Keep out of reach and sight of children.
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6.5
Nature and contents of container
A strip pack consisting of a blister tray of white pigmented 250 μm PVC/40 gsm PVDC laminate
heat-sealed to lacquered 20 μm aluminium foil containing 2, 4 or 8 tablets. One or two trays packed
in a cardboard carton (i.e. 4, 6, 8, 10, 12, 14 or 16 tablets).
6.6
Special precautions for disposal
Not applicable.
7
MARKETING AUTHORISATION HOLDER
Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, United Kingdom.
8
MARKETING AUTHORISATION NUMBER(S)
PL 00063/0541
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/11/2008
10
DATE OF REVISION OF THE TEXT
17/11/2008
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1
NAME OF THE MEDICINAL PRODUCT
Lemsip Max All Night Cold & Flu Tablets, or
Lemsip Max All Night Flu Relief Tablets, or
Lemsip Max All Night Flu Relief, or
Nurofen All Night Cold & Flu Tablets or
Nurofen All Night Flu Relief Tablets, or
Nurofen All Night Flu Relief.
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredients
Quantity
Ibuprofen BP
200.0mg
Phenylephrine hydrochloride
5.0mg
For full list of excipients, see Section 6.1.
3
PHARMACEUTICAL FORM
Yellow film coated tablet, printed with an identifying motif (IPE) in black ink.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
For the relief of symptoms of cold and 'flu with associated congestion, including aches and pains,
headache, fever, sore throat, blocked nose and sinuses.
4.2
Posology and method of administration
For oral administration and short-term use only.
Adults, the elderly and children over 12 years:
The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.
The patient should consult a doctor if symptoms persist or worsen, or if the product is required for
more than 10 days.
Two tablets to be taken before the patient goes to bed. Leave at least 4 hours between doses and do
not exceed six tablets in any 24 hour period.
Not to be given to children under 12 years.
4.3
Contraindications
Hypersensitivity to ibuprofen, phenylephrine or any of the excipients in the product. Hypertension
and severe coronary heart disease.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or
urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes or proven
ulceration or bleeding).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Severe heart failure, renal failure or hepatic failure (see Section 4.4).
Last trimester of pregnancy.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see Section 4.5).
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4.4
Special warnings and precautions for use
Ibuprofen
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms (see gastrointestinal and cardiovascular risks below).
The elderly are at increased risk of consequence of adverse reactions to NSAIDs, especially
gastrointestinal bleeding and perforation which may be fatal.
Respiratory: Bronchospasm may be precipitated in patients suffering from or with a previous
history of bronchial asthma or allergic disease.
Other NSAIDs: The use of this product with concomitant NSAIDs, including cyclo-oxygenase-2
selective inhibitors, should be avoided (see Section 4.5).
SLE and mixed connective tissue disease: Systemic lupus erythematosus and mixed connective
tissue disease - increased risk of aseptic meningitis (see Section 4.8).
Renal: Renal impairment as renal function may further deteriorate (see Sections 4.3 and 4.8).
Hepatic: Hepatic dysfunction (see Sections 4.3 and 4.8).
Cardiovascular and cerebrovascular effects: Caution (discussion with doctor or pharmacist) is
required prior to starting treatment in patients with a history of hypertension and/or heart failure as
fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400
mg daily) and in long-term treatment, may be associated with a small increased risk of arterial
thrombotic events (for example, myocardial infarction or stroke). Overall, epidemiological studies
do not suggest that low dose ibuprofen (≤1200 mg daily) is associated with an increased risk of
myocardial infarction.
Impaired female fertility: There is limited evidence that drugs which inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on
ovulation. This is reversible on withdrawal of treatment.
Gastrointestinal: NSAIDs should be given with care to patients with a history of gastrointestinal
disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8).
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any
time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients
with a history of ulcer, particularly if complicated with haemorrhage or perforation (see Section 4.3),
and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal
symptoms (especially GI bleeding), particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the
risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective
serotonin-reuptake inhibitors or anti-platelets agents such as aspirin (see Section 4.5).
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be
withdrawn.
Dermatological: Serious skin reactions, some of them fatal, including exfoliating dermatitis,
Stevens-Johnson Syndrome, and toxic epidermal necrolysis, have been reported very rarely in
association with the use of NSAIDs (see Section 4.8). Patients appear to be at highest risk of these
reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases
within the first month of treatment. This product should be discontinued at the first appearance of
skin rash, mucosal lesions or any other sign of hypersensitivity.
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The label will include:
Read the enclosed leaflet before taking this product.
Do not take if you:
• Have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding.
• Are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers.
• Are taking other NSAID painkillers, or aspirin with a daily dose above 75 mg.
Speak to a pharmacist or your doctor before taking if you:
• Have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver,
kidney or bowel problems.
• Are a smoker.
• Are pregnant.
If symptoms persist or worsen, consult your doctor.
Phenylephrine
Phenylephrine should be used with care in patients with hyperthyroidism, cardiovascular disease,
diabetes mellitus, closed angle glaucoma, prostatic enlargement and hypertension.
4.5
Interaction with other medicinal products and other forms of interaction
Ibuprofen
Ibuprofen should not be used in combination with:
Aspirin: Unless low-dose aspirin (not above 75 mg daily) has been advised by a doctor, as this may
increase the risk of adverse reactions (see Section 4.4).
Other NSAIDs including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or
more NSAIDs as this may increase the risk of adverse reactions (see Section 4.4).
Ibuprofen should be used with caution in combination with:
Anti-coagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see Section
4.4).
Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can
increase the risk of nephrotoxicity.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4).
Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): Increased risk of
gastrointestinal bleeding (see Section 4.4).
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma
glycoside levels.
Lithium: There is evidence for potential increase in plasma levels of lithium.
Methotrexate: There is potential for an increase in plasma methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as
NSAIDs can reduce the effect of mifepristone.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine.
There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs
receiving concurrent treatment with zidovudine and ibuprofen.
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Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions
associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an
increased risk of developing convulsions.
Phenylephrine
Phenylephrine may adversely interact with other sympathomimetics, vasodilators and beta-blockers.
Phenylephrine is not recommended for patients currently receiving or within two weeks of stopping
therapy with monoamine oxidase inhibitors (MAOIs).
4.7
Pregnancy and lactation
Ibuprofen
Whilst no teratogenic effects have been demonstrated to in animal experiments, the use of this
product should, if possible, be avoided during the first six months of pregnancy.
During the third trimester, ibuprofen is contraindicated as there is a risk of premature closure of the
fetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be
delayed and the duration increased with an increased bleeding tendency in both mother and child
(see Section 4.3).
In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to
affect the breast-fed infant adversely.
See Section 4.4 regarding female fertility.
Phenylephrine
Due to the vasoconstrictive properties of phenylephrine, the product should be used in caution in
patients with a history of pre-eclampsia.
Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if
the benefits outweigh this risk.
There is no information on use of phenylephrine in lactation.
4.7
Effects on ability to drive and use machines
No adverse effects known.
4.8
Undesirable effects
Ibuprofen
Hypersensitivity reactions have been reported following treatment with ibuprofen and these may
consist of:
(a) Non-specific allergic reaction and anaphylaxis.
(b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm or dyspnoea.
(c) Various skin reactions, e.g. pruritis, urticaria, angioedema and, more rarely, exfoliative and
bullous dermatoses (including epidermal necrolysis and erythema multiforme).
The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for
short-term use. In the treatment of chronic conditions, under long-term treatment, additional effects
may occur.
Hypersensitivity reactions
Uncommon: Hypersensitivity reactions with urticaria and pruritus.
Very rare: Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal
swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).
Exacerbation of asthma and bronchospasm.
Gastrointestinal
The most commonly-observed adverse events are gastrointestinal in nature.
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Uncommon: Abdominal pain, nausea and dyspepsia.
Rare: Diarrhoea, flatulence, constipation and vomiting.
Very rare: Peptic ulcer, perforation and gastrointestinal haemorrhage, melaena, haematemesis,
sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis and mouth ulceration.
Exacerbation of colitis and Crohn's disease (see Section 4.4).
Nervous System
Uncommon: Headache, dizziness and tinnitus.
Very rare: Aseptic meningitis - single cases have been reported very rarely.
Renal
Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with
increased serum urea and oedema.
Hepatic
Very rare: Liver disorders.
Haematological
Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia,
agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms,
severe exhaustion, unexplained bleeding and bruising.
Dermatological
Uncommon: Various skin rashes.
Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson
Syndrome, erythema multiforme and toxic epidermal necrolysis, can occur.
Immune System
In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed
connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic
meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation, have been
observed (see Section 4.4).
Cardiovascular and Cerebrovascular
Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400
mg daily) and in long-term treatment, may be associated with a small increased risk of arterial
thrombotic events (for example, myocardial infarction or stroke) (see Section 4.4).
Phenylephrine
High blood pressure with headache, vomiting and rarely, palpitations.
Also, rare reports of allergic reactions.
4.9
Overdose
Ibuprofen
In children, ingestion of more than 400 mg/kg may cause symptoms. In adults, the dose response
rate effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Symptoms
Patients who have ingested clinically important amounts of NSAIDs will develop no more than
nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal
bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system,
manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients
develop convulsions. In serious poisoning metabolic acidosis may occur and prothrombin time/INR
may be prolonged, probably due to interference with the actions of circulating clotting factors.
Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
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Management
Management should be symptomatic and supportive and include the maintenance of a clear airway
and monitoring of cardiac and vital signs until stable. Consider oral administration of activated
charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent
or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give
bronchodilators for asthma.
Phenylephrine
Features of severe overdosage of phenylephrine include haemodynamic changes and cardiovascular
collapse with respiratory depression.
Treatment includes early gastric lavage and symptomatic and supportive measures.
Hypertensive effects may be treated with an intravenous alpha-receptor blocking agent.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
M01AE51 - Ibuprofen, combinations.
Ibuprofen
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of
prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever.
Furthermore, ibuprofen reversibly inhibits platelet aggregation.
The therapeutic effect of ibuprofen in symptoms relating to the common cold and influenza has a
duration of up to 8 hours.
Phenylephrine
Phenylephrine is a post-synaptic alpha-receptor agonist with low cardioselective beta-receptor
affinity and minimal central stimulant activity. It is a recognised decongestant and acts by
vasoconstriction to reduce oedema and nasal swelling.
5.2
Pharmacokinetic properties
Ibuprofen
Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the
whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty
stomach. When taken with food, peak levels are observed after 1-2 hours. These times may vary
with different dosage forms.
The half-life of ibuprofen is about 2 hours.
In limited studies, ibuprofen appears in the breast milk in very low concentr-ations.
Phenylephrine
Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral
route due to first-pass metabolism.
It retains activity as a nasal decongestant when given orally, the drug distributing through the
systemic circulation to the vascular bed of the nasal mucosa.
When taken by mouth as a nasal decongestant, phenylephrine is usually given at intervals of 4-6
hours.
Ibuprofen and Phenylephrine Combination
The ibuprofen component of this fixed combination (ibuprofen 200 mg plus phenylephrine
hydrochloride 5 mg) is absorbed faster than standard ibuprofen 200 mg tablets, with therapeutic
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levels being reached in 26.4 minutes (from the fixed combination) as opposed to 55.2 minutes (for
standard ibuprofen).
5.3
Preclinical safety data
There are no findings of relevance to the prescriber other than those already mentioned elsewhere in
the SPC.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Microcrystalline cellulose
Sodium starch glycolate Type A
Hypromellose
Magnesium stearate
Talc
Water, purified
Industrial methylated spirits
Mastercote yellow FA 0156
Black printing ink
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
Two years.
6.4
Special precautions for storage
Store in a dry place.
Store in the original package.
Store below 25°C.
Keep out of reach and sight of children.
6.5
Nature and contents of container
A strip pack consisting of a blister tray of white pigmented 250 μm PVC/40 gsm PVDC laminate
heat-sealed to lacquered 20 μm aluminium foil containing 2, 4 or 8 tablets. One or two trays packed
in a cardboard carton (i.e. 4, 6, 8, 10, 12, 14 or 16 tablets).
6.6
Special precautions for disposal
Not applicable.
7
MARKETING AUTHORISATION HOLDER
Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, United Kingdom.
8
MARKETING AUTHORISATION NUMBER(S)
PL 00063/0556
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/11/2008
10
DATE OF REVISION OF THE TEXT
17/11/2008
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