NUROFEN PLUS

Active substance: IBUPROFEN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Nurofen Plus

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Active constituents:
Ibuprofen Ph Eur
Codeine phosphate Ph Eur

3

200.0 mg
12.8 mg

PHARMACEUTICAL FORM
Tablet

4.1

Therapeutic indications

Nurofen Plus (which contains codeine) is indicated in patients older than 12
years of age for the short term treatment of acute, moderate pain (such as
rheumatic and muscular pain, backache, migraine, headache, neuralgia, period
pain and dental pain) which is not considered to be relieved by other
analgesics such as paracetamol, ibuprofen or aspirin alone.

4.2

Posology and method of administration
For oral administration and short-term use only.
Recommended dosage:
Adults:
One or two tablets every four to six hours.

Children aged 12-18 years:
One or two tablets every four to six hours.
Children under 12 years:
Nurofen plus (which contains Codeine) should not be used in children below the age
of 12 years because of the risk of opioid toxicity due to the variable and

unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).
Elderly:
No special dosage modifications are required for elderly patients, unless renal
or hepatic function is impaired, in which case dosage should be assessed
individually.

Do not take more than 6 tablets in 24 hours.
Leave at least four hours between doses and do not take more than 1200mg in
any 24 hour period.
The duration of treatment should be limited to 3 days and if no effective pain
relief is achieved the patients/carers should be advised to seek the views of a
physician.
Codeine should be used at the lowest effective dose for the shortest period of
time necessary to relieve symptoms. The patient should consult a doctor if
symptoms persist or worsen, or if the product is required for more than 3 days.

4.3

Contraindications
Hypersensitivity to ibuprofen or any of the constituents in the product.
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.
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct
episodes of proven ulceration or bleeding).
History of upper gastrointestinal bleeding or perforation, related to previous
NSAIDs therapy.
Severe hepatic failure, renal failure or heart failure (See section 4.4, Special
warnings and precautions for use).
Last trimester of pregnancy (See section 4.6 Pregnancy and lactation).
In women during breastfeeding (see section 4.6)
Hypersensitivity to codeine, respiratory depression, chronic constipation.
Severe heart failure.
In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or
adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk
of developing serious and lifethreatening adverse reactions (see section 4.4)

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers

4.4

Special warnings and precautions for use
Undesirable effects may be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see GI and
cardiovascular risks below).
The elderly are at increased frequency 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 Nurofen Plus with concomitant NSAIDS including
cyclooxygenase-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 Undesirable effects).
Renal:
Renal impairment as renal function may further deteriorate (See section 4.3
and Section 4.8).
Hepatic:
Hepatic dysfunction (See section 4.3 and Section 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 (e.g. ≤ 1200 mg daily) is associated with
an increased risk of myocardial infarction.
Nurofen Plus tablets should be used with caution in those with hypotension
and/ or hypothyroidism. The tablets should be used with caution in patients
with raised intracranial pressure or head injury.
Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/
prostaglandin synthesis may cause impairment of female fertility by an effect
on ovulation. This is reversible upon 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 Undesirable effects).
GI bleeding, ulceration or perforation, which can be fatal, has been reported
with all NSAIDs at anytime 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 when 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 gastrotoxicity or bleeding, such as
corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such
as aspirin (see section 4.5 Interactions).
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the
treatment should be withdrawn.
Dermatological:
Serious skin reactions, some of them fatal, including exfoliative 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. Nurofen PLUS should be discontinued at the first
appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
CYP2D6 metabolism
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active
metabolite. If a patient has a deficiency or is completely lacking this enzyme
an adequate analgesic effect will not be obtained.
Estimates indicate that up to 7% of the Caucasian population may have this
deficiency. However, if the patient is an extensive or ultra-rapid metaboliser
there is an increased risk of developing side effects of opioid toxicity even at
commonly prescribed doses. These patients convert codeine into morphine
rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow
breathing, small pupils, nausea, vomiting, constipation and lack of appetite . In
severe cases this may include symptoms of circulatory and respiratory
depression which may be life-threatening and very rarely fatal. Estimates of
prevalence of ultra-rapid metabolisers in different populations are summarised
below:
Population
African/Ethiopian

Prevalence %
29%

African American

3.4% to 6.5%

Asian

1.2% to 2%

Caucasian

3.6% to 6.5%

Greek

6.0%

Hungarian

1.9%

Northern European

1%-2%

Post-operative use in children
There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for
obstructive sleep apnoea, led to rare, but life-threatening adverse events
including death (see also section 4.3). All children received doses of codeine
that were within the appropriate dose range; however there was evidence that
these children were either ultrarapid or extensive metabolisers in their ability
to metabolise codeine to morphine.
Children with compromised respiratory function
Codeine is not recommended for use in children in whom respiratory function
might be compromised including neuromuscular disorders, severe cardiac or
respiratory conditions, upper respiratory or lung infections, multiple trauma or
extensive surgical procedures. These factors may worsen symptoms of
morphine toxicity.

The label will include:
Front of pack:


Can cause addiction



For three days use only

Back of pack:


List of indications as agreed in 4.1 of the SmPC



If you need to take this medicine continuously for more than three days
you should see your doctor or pharmacist



This medicine contains codeine which can cause addiction if you take
it continuously for more than three days. If you take this medicine for
headaches for more than three days it can make them worse

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
75mg
• are breastfeeding
Speak to a pharmacist or your doctor before taking this product if you
• have or have had asthma , diabetes, high cholesterol, high blood pressure,
a stroke, liver, heart, kidney or bowel problems
• are a smoker
• are pregnant
If symptoms persist or worsen, consult your doctor.
The leaflet will include:


Headlines section (to be prominently displayed at the start of the PIL)
• This medicine can only be used for …….(indications)
• You should only take this product for a maximum of three days at a
time. If you need to take it for longer than three days you should see
your doctor or pharmacist for advice
• This medicine contains codeine which can cause addiction if you take
it continuously for more than three days. This can give you withdrawal
symptoms from the medicine when you stop taking it
• If you take this medicine for headaches for more than three days it can
make them worse



Section 2 : Before taking – Do not take
• This medicine contains codeine which can cause addiction if you take
it continuously for more than three days. This can give you withdrawal
symptoms from the medicine when you stop taking it
• If you take a painkiller for headaches for more than three days it can
make them worse



Section 3: Dosage
• (In the dosage warning section): This medicine should not be taken for
more than 3 days. If the pain does not improve after 3 days, talk to
your doctor for advice.





Section 4: Side effects
• Some people may have side-effects when taking this medicine. If you
have any unwanted side-effects you should seek advice from your
doctor, pharmacist or other healthcare professional. Also you can help
to make sure that medicines remain as safe as possible by reporting any
unwanted side-effects via the internet at www.yellowcard.gov.uk;
alternatively you can call Freephone 0808 100 3352 (available between
10am-2pm Monday – Friday) or fill in a paper form available from
your local pharmacy.


4.5

This medicine contains codeine and can cause addiction if you take it
continuously for more than three days. When you stop taking it you
may get withdrawal symptoms. You should talk to your doctor or
pharmacist if you think you are suffering from withdrawal symptoms.

How do I know if I am addicted?
If you take the medicine according to the instructions on the pack it is
unlikely that you will become addicted to the medicine. However, if
the following apply to you it is important that you talk to your doctor:
o You need to take the medicine for longer periods of time
o You need to take more than the recommended dose
o When you stop taking the medicine you feel very unwell but
you feel better if you start taking the medicine again

Interaction with other medicinal products and other forms of interaction
Ibuprofen should not be used in combination with:
Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by
a doctor, as this may increase the risk of adverse reactions (See section 4.4).
Experimental data suggest that ibuprofen may inhibit the effect of low dose
aspirin on platelet aggregation when they are dosed concomitantly. However,
the limitations of these data and the uncertainties regarding extrapolation of ex
vivo data to the clinical situation imply that no firm conclusions can be made
for regular ibuprofen use, and no clinically relevant effect is considered to be
likely for occasional ibuprofen use (see section 5.1).
Other NSAIDS including cyclooxygenase-2 selective inhibitors: Avoid
concomitant use of two or more NSAIDs as this may increase the risk of
adverse effects (see section 4.4).
Codeine – interacts with monoamine oxidase inhibitors.
Ibuprofen should be used with caution in combination with:
Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, 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 of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (See
section 4.4 Special warnings).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):
increased risk of gastrointestinal bleeding (see section 4.4).
Cardiac glycosides: NSAIDS may exacerabate cardiac failure, reduce GFR
and increase plasma glycoside levels.
Lithium: There is evidence for potential increases in plasma levels of lithium.
Methotrexate: There is a 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 hematological 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.

4.6

Pregnancy and lactation
Whilst no teratogenic effects have been demonstrated in animal experiments,
the use of Nurofen Plus should, if possible, be avoided during the first 6
months of pregnancy.
During the 3rd trimester, ibuprofen is contraindicated as there is there is a risk
of premature closure of the foetal 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 Contraindications).
Codeine should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses codeine and its active metabolite may be present
in breast milk at very low doses and is unlikely to affect the breast fed infant.
However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels
of the active metabolite, morphine, may be present in breast milk and on very
rare occasions may result in symptoms of opioid toxicity in the infant, which
may be fatal.

If symptoms of opioid toxicity develop in either the mother or the infant, then
all codeine containing medicines should be stopped and alternative non-opioid
analgesics prescribed. In severe cases consideration should be given to
prescribing naloxone to reverse these effects.
See section 4.4 regarding female fertility.

4.7

Effects on ability to drive and use machines
Patient may become dizzy or sedated with NUROFEN PLUS tablets.
affected, patients should not drive or operate machinery.

If

This medicine can impair cognitive function and can affect a patient’s ability
to drive safely. This class of medicine is in the list of drugs included in
regulations under 5a of the Road Traffic Act 1988. When taking this medicine,
patients should be told:





The medicine is likely to affect your ability to drive
Do not drive until you know how the medicine affects you
It is an offence to drive while under the influence of this medicine
However, you would not be committing an offence (called ‘statutory
defence’) if:
-

4.8

The medicine has been taken to treat a medical or dental problem and
You have taken it according to the information provided with the
medicine and
It was not affecting your ability to drive safely

Undesirable effects
Hypersensitivity reactions have been reported and these may consist of:
(a) Non-specific allergic reactions and anaphylaxis.
(b) Respiratory tract reactivity,
bronchospasm, dyspnoea.

e.g.

asthma,

aggravated

asthma,

(c) Various skin reactions, e.g. pruritus, 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 adverse 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 or gastrointestinal haemorrhage, melaena,
haematemesis, sometimes fatal, particularly in the elderly. Ulcerative
stomatitis, gastritis.
Exacerbation of ulcerative colitis and Crohn’s disease (See section 4.4).
Nervous System:
Uncommon: Headache
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-Johnsons 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 2400mg 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).
Side effects to codeine include constipation, respiratory depression, cough
suppression, nausea and drowsiness.
Regular prolonged use of codeine is known to lead to addiction and symptoms
of restlessness and irritability may result when treatment is then stopped.
Prolonged use of a painkiller for headache can make them worse.

4.9

Overdose
Overuse of this product, defined as consumption of quantities in excess of the
recommended dose, or consumption for a prolonged period, may lead to
physical or psychological dependency. Symptoms of restlessness and
irritability may result when treatment is stopped.
Symptoms of overdose with ibuprofen include;
In children ingestion of more than 400 mg/kg may cause symptoms. In adults
the dose response effect is less clear cut. The half-life in overdose is 1.5-3
hours.
Symptoms
Most 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 the 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.
Symptoms of overdose with codeine include;
Nausea and vomiting are prominent features. Respiratory depression,
excitability, convulsions, hypotension and loss of consciousness may occur
with large codeine overdose.

The stomach should be emptied. If severe CNS depression has occurred,
artificial respiration, oxygen and parenteral naloxone may be needed.
Imbalance in electrolyte levels should be considered.

5.1

Pharmacodynamic properties
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its
efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces
inflammatory pain, swelling and fever. Furthermore, ibuprofen reversibly
inhibits platelet aggregation.
Codeine is a centrally acting weak narcotic analgesic. Codeine exerts its
effects through µ opioid receptors, and its analgesic effect is due to its
conversion to morphine. The combination of a well tolerated peripheral
analgesic with a centrally acting analgesic provides optimum pain relief with a
lower potential for producing side effects. Codeine, particularly in
combination with other analgesics such as paracetamol, has been shown to be
effective in acute nociceptive pain.

Experimental data suggest that ibuprofen may inhibit the effect of low dose
aspirin on platelet aggregation when they are dosed concomitantly. In one
study, when a single dose of ibuprofen 400mg was taken within 8 h before or
within 30 min after immediate release aspirin dosing (81mg), a decreased
effect of ASA on the formation of thromboxane or platelet aggregation
occurred. However, the limitations of these data and the uncertainties
regarding extrapolation of ex vivo data to the clinical situation imply that no
firm conclusions can be made for regular ibuprofen use, and no clinically
relevant effect is considered to be likely for occasional ibuprofen use.

5.2

Pharmacokinetic properties
The elimination half-life of both ibuprofen and codeine is approximately three
hours, and both drugs are given three to fours times daily. The combination of
the two drugs is therefore appropriate from a pharmacokinetic viewpoint; the
tablet exhibits normal release characteristics for both active substances.

5.3

Preclinical safety data
Not applicable.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Microcrystalline cellulose, Sodium starch glycollate, Starch pregelatinised,
Hypromellose
Film coating:
Hypromellose Ph Eur
Opaspray White M-1-17111B
Talc Ph Eur

6.2

Incompatibilities
None known.

6.3

Shelf life
36 months.

6.4

Special precautions for storage
Store in a dry place below 25ºC.

6.5

Nature and contents of container
Blister packs containing 6, 8, 12, 16, 18, 24 or 32 tablets.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Reckitt Benckiser Healthcare (UK) Ltd
Slough
SL1 4AQ

8

MARKETING AUTHORISATION NUMBER(S)
PL 00063/0376

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16 May 1994 / 19 September 2008

10

DATE OF REVISION OF THE TEXT
15/09/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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