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IBUPROFEN AND PARACETAMOL 200MG/500MG TABLETS

Active substance(s): IBUPROFEN / PARACETAMOL

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Ibuprofen and Paracetamol 200mg/500mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains ibuprofen 200 mg and paracetamol 500 mg.
For a full list of excipients see section 6.1

3

PHARMACEUTICAL FORM
Film-coated tablets (Tablets)
White to off-white, oval shaped, pearlescent tablets de-bossed with an
identifying helix.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
For the temporary relief of mild to moderate pain associated with migraine,
headache, backache, period pain, dental pain, rheumatic and muscular pain,
pain of non-serious arthritis, cold and flu symptoms, sore throat and fever.
This product is especially suitable for pain which requires stronger analgesia
than ibuprofen or paracetamol alone.
Ibuprofen and Paracetamol 200mg/500mg tablets is indicated in adults aged 18 years.

4.2

Posology and method of administration
For oral administration and short term-use only.
Undesirable effects may be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see section 4.4). The
patient should consult a doctor if the symptoms persist or worsen or if the
product is required for more than 3 days.
Adults: One tablet to be taken up to three times per day with water. Leave at
least six hours between doses.

If the one tablet dose does not control symptoms, a maximum of two tablets
may be taken up to three times a day. Leave at least six hours between doses.
Do not take more than six tablets (3000mg Paracetamol, 1200mg Ibuprofen) in
any 24 hours period.
To minimise side effects, it is recommended that patients take Nuromol with
food.
Elderly: No special dosage modifications are required (see section 4.4).
The elderly are at increased risk of the serious consequences of adverse
reactions. If an NSAID is considered necessary, the lowest effective dose
should be used for the shortest possible duration. The patient should be
monitored regularly for gastrointestinal bleeding during NSAID therapy.
Not for use by children under 18 years.

4.3

Contraindications
This product is contraindicated:


In patients with a known hypersensitivity to ibuprofen, paracetamol or any
other excipients, see section 6.1.



In patients with a history of hypersensitivity reactions (e.g. bronchospasm,
angioedema, asthma, rhinitis, or urticaria) associated with acetylsalicylic
acid or other non-steroidal anti-inflammatory drugs (NSAIDs).



In patients with a history of, or an existing gastrointestinal
ulceration/perforation or bleeding, including that associated with NSAIDs
(see Section 4.4).



Patients with defects in coagulation.



In patients with severe hepatic failure, severe renal failure or severe heart
failure (NYHA Class IV) (see Section 4.4).



In concomitant use with other NSAID containing products, including
cyclo-oxygenase-2 (COX-2) specific inhibitors and doses of acetylsalicylic
acid above 75 mg daily – increased risk of adverse reactions (see Section
4.5).



In concomitant use with other paracetamol-containing products – increased
risk of serious adverse effects (see Section 4.5).



During the last trimester of pregnancy due to risk of premature closure of
the foetal ductus arteriosus with possible pulmonary hypertension (see
Section 4.6)

4.4

Special warnings and precautions for use
The hazard of paracetamol overdose is greater in patients with non-cirrhotic
alcoholic liver disease. Immediate medical advice should be sought in the
event of an overdose, even if the patient feels well, because of the risk of
delayed, serious liver damage.
Undesirable effects may be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see Section 4.2, and
gastrointestinal and cardiovascular risks below) and by patients taking the
dose with food (see Section 4.2).
Elderly:
The elderly have an increased frequency of adverse reactions to NSAIDs
especially gastrointestinal bleeding and perforation which may be fatal (see
Section 4.2).
Caution is required in patients with certain conditions:


Respiratory disorders:

In patients suffering from, or with a history of, bronchial asthma or allergic
disease NSAIDs have been reported to precipitate bronchospasm.


Cardiovascular, renal and hepatic impairment:

The administration of NSAIDs may cause a dose dependent reduction in
prostaglandin formation and precipitate renal failure. Patients at greatest
risk of this reaction are those with impaired renal function, cardiac
impairment, liver dysfunction, those taking diuretics and the elderly. Renal
function should be monitored in these patients (see Section 4.3).


Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of
hypertension and/or mild to moderate congestive heart failure as fluid
retention and oedema have been reported in association with NSAID therapy.
Clinical trial data suggest that use of ibuprofen, particularly at high doses
(2400 mg daily) with a small increased risk of arterial thrombotic events (e.g.
myocardial infarction or stroke). Overall, epidemiological studies do not
suggest that low dose ibuprofen (e.g. ≤1200mg daily) is associated with an
increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA IIIII), established ischaemic heart disease, peripheral arterial disease, and/or
cerebrovascular disease should only be treated with ibuprofen after careful
consideration and high doses (2400 mg/day) should be avoided. Careful
consideration should be exercised before initiating long-term treatment for
patients with risk factors for cardiovascular events (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking) particularly if high doses of
ibuprofen (2400 mg/day) are required.


Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal (GI) bleeding, ulceration and 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.
Combination therapy with protective agents (e.g. misoprostol or proton pump
inhibitors) should be considered for these patients, and also for patients
requiring concomitant low dose acetylsalicylic acid, or other drugs likely to
increase gastrointestinal risk (see below and 4.5).
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 antiplatelet agents such as acetylsalicylic acid (see Section 4.5).
When GI bleeding or ulceration occurs in patients receiving ibuprofen
containing products, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of GI disease
(ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated
(see Section 4.8).


SLE and mixed connective tissue disease:

In patient with systemic lupus erythematosus (SLE) and mixed connective
tissue disease disorders there may be an increased risk of aseptic
meningitis (see Section 4.8).


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. Use of this product should be discontinued at the first
appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.


Impaired female fertility:

The use of the product may impair female fertility and is not recommended in
women attempting to conceive. In women who have difficulties conceiving or
who are undergoing investigation of infertility, withdrawal of the product
should be considered.

4.5

Interaction with other medicinal products and other forms of interaction
This product (like any other paracetamol containing products) is
contraindicated in combination with other paracetamol containing products –
increased risk of serious adverse effects (see Section 4.3).
This product (like any other ibuprofen containing products and NSAIDs) is
contraindicated in combination with:
Acetylsalicylic acid
Concomitant administration of ibuprofen and acetylsalicylic acid is not
generally recommended because of the potential of increased adverse effects.


Other NSAIDs including cyclo-oxygenase-2 selective inhibitors as these
may increase the risk of adverse effects (see Section 4.3).

This product (like any other paracetamol containing products) should be used
with caution in combination with:



Chloramphenicol: Increased plasma concentration of chloramphenicol.
Cholestyramine: The speed of absorption of paracetamol is reduced by
cholestyramine. Therefore, cholestyramine should not be taken within one
hour if maximal analgesia is required.
• Metoclopramide and Domperidone: The absorption of paracetamol is
increased by metoclopramide and domperidone. However, concurrent use
need not be avoided.
• Warfarin: The anticoagulant effect of warfarin and other coumarins may
be enhanced by prolonged regular use of paracetamol with increased risk
of bleeding; occasional doses have no significant effect.
This product (like any other ibuprofen containing products and NSAIDs)
should be used with caution in combination with:






Anticoagulants: NSAIDs may enhance the effects of anticoagulants, i.e.
warfarin.
Antihypertensives: (ACE inhibitors and Angiotensin II Antagonists) and
diuretics: NSAIDs may reduce the effects of these drugs. In some patients
with compromised renal function (e.g dehydrated patients or elderly
patients with compromised renal function) the co-administration of an
ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including
possible acute renal failure, which is usually reversible. These interactions
should be considered in patients taking a coxib concomitantly with ACE
inhibitors or angiotensin II antagonists. Therefore, the combination should
be administered with caution, especially in the elderly. Patients should be
adequately hydrated and consideration should be given to monitoring of
renal function after initiation of concomitant therapy and periodically
therafter. Diuretics may increase the risk of nephrotoxicity of NSAIDS.
Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs):
Increased risk of gastrointestinal bleeding (see Section 4.4).
Acetylsalicylic acid: Experimental data suggest that ibuprofen may
competitively inhibit the effect of low dose acetylsalicylic acid on platelet

aggregation when they are dosed concomitantly. Although there are uncertainties
regarding extrapolation of these data to the clinical situation, the possibility that
regular, long-term use of ibuprofen may reduce the cardioprotective effect of
low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is
considered to be likely for occasional ibuprofen use (see section 5.1).












4.6

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR
and increase plasma glycoside levels.
Ciclosporin: Increased risk of nephrotoxicity.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding
(see Section 4.4).
Diuretics: Reduced diuretic effect. Diuretics may increase the risk of
nephrotoxicity of NSAIDs.
Lithium: Decreased elimination of lithium.
Methotrexate: Decreased elimination of methotrexate.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone
administration as NSAIDs can reduce the effect of mifepristone.
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.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are
given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity with 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.

Pregnancy and lactation
Pregnancy:
There is no experience of use of this product in humans during pregnancy.
Paracetamol
Epidemiological studies in human pregnancy have shown no ill effects due to
paracetamol use at the recommended dosage.
Ibuprofen
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the
embryo/foetal development. Data from epidemiological studies suggest an increased
risk of miscarriage and of cardiac malformation and gastroschisis after use of a
prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for
cardiovascular malformation was increased from less than 1%, up to approximately
1.5%. The risk is believed to increase with dose and duration of therapy. In animals,
administration of a prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post-implantation loss and embryo-foetal lethality. In addition,
increased incidences of various malformations, including cardiovascular, have been
reported in animals given a prostaglandin synthesis inhibitor during the organogenetic
period.

During the first and second trimester of pregnancy, Ibuprofen should not be given
unless clearly necessary. If Ibuprofen is used by a woman attempting to conceive, or
during the first and second trimester of pregnancy, the dose should be kept as low and
duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may
expose the foetus to:
-

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and
pulmonary hypertension);

-

renal dysfunction, which may progress to renal failure with oligohydroamniosis;

the mother and the neonate, at the end of the pregnancy, to:
-

possible prolongation of bleeding time, an anti-aggregating effect which may
occur even at very low doses;

-

inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, Ibuprofen is contraindicated during the 3rd trimester of pregnancy (see
section 4.3).

Therefore if possible, the use of this product should be avoided in the first six
months of pregnancy and contraindicated in the last three months of
pregnancy (see Section 4.3).
Lactation:
Ibuprofen and its metabolites can pass in very small amounts (0.0008% of the
maternal dose) into the breast milk. No harmful effects to infants are known.
Paracetamol is excreted in breast milk but not in a clinically significant
amount. Available published data do not contraindicate breastfeeding.
Therefore it is not necessary to interrupt breastfeeding for short-term
treatment with the recommended dose of this product.
See Section 4.4 regarding female fertility.

4.7

Effects on ability to drive and use machines
Undesirable effects such as dizziness, drowsiness, fatigue and visual
disturbances are possible after taking NSAIDs. If affected patients should not
drive or operate machinery.

4.8

Undesirable effects
Clinical trials with this product have not indicated any other undesirable
effects other than those for ibuprofen or paracetamol alone.

The following table lists adverse effects from pharmacovigilance data
experienced by patients taking ibuprofen alone or paracetamol alone in shortterm and long-term use.
Blood and
lymphatic
system
disorders

Very rare
(≤1/10,000)

Haematopoietic disorders (agranulocytosis,
anaemia, aplastic anaemia, haemolytic
anaemia leucopenia, neutropenia,
pancytopenia and thrombocytopenia).
First signs are: fever, sore throat,
superficial mouth ulcers, flu-like symptoms,
severe exhaustion, unexplained bleeding and
bruising and nose bleeding.

Immune system
disorders

Very rare
(≤1/10,000)

Hypersensitivity reactions1 have been
reported. These may consist of non-specific
allergic reactions and anaphylaxis.
Severe hypersensitivity reactions.
Symptoms can include: facial, tongue and
larynx swelling, dyspnoea, tachycardia,
hypotension, (anaphylaxis, angioedema or
severe shock).

Psychiatric
disorders

Very rare
(≤1/10,000)

Confusion, depression and hallucinations.

Nervous system
disorders

Uncommon
(≥1/1,000 to ≤1/100):

Headache and dizziness.

Very rare
(≤1/10,000)

Paraesthesia, optic neuritis and somnolence.
Single cases of aseptic meningitis in patients
with existing autoimmune disorders (such as
systemic lupus erythematosus and mixed
connective tissue disease) during treatment
with ibuprofen, with symptoms such as:
stiff neck, headache, nausea, vomiting, fever
or disorientation have been observed (see
Section 4.4).

Eye disorders

Very rare
(≤1/10,000)

Visual disturbance.

Ear and
labyrinth
disorders

Very rare
(≤1/10,000)

Tinnitus and vertigo.

Cardiac
disorders

Very rare
(≤1/10,000)

Oedema, hypertension and cardiac failure
have been reported in association with
NSAID treatment.
Clinical studies suggest that use of
ibuprofen, particularly at a high dose (2400
mg/day) may be associated with a small
increased risk of arterial thrombotic events
(for example myocardial infarction or

stroke) (see section 4.4).
Respiratory
and thoracic
and mediastinal
disorders

Very rare
(≤1/10,000)

Respiratory reactivity including: asthma,
exacerbation of asthma, bronchospasm and
dyspnoea.

Gastrointestinal
Disorders

Common
(≥1/100 to ≤1/10)

Abdominal pain, diarrhoea, dyspepsia,
nausea, stomach discomfort and vomiting

Uncommon
(≥1/1,000 to
≤1/100):

Flatulence and constipation

Uncommon
(≥1/1,000 to
≤1/100):

Peptic ulcer, perforation or
gastrointestinal haemorrhage, with
symptoms of melaena haematemesis
sometimes fatal, particularly in the
elderly (see section 4.4).
Ulcerative stomatitis and exacerbation
of ulcerative colitis and Crohn’s
disease following administration (see
section 4.4). Less frequently gastritis
has been observed and pancreatitis
reported.

Hepatobiliary
disorders

Very rare
(≤1/10,000)

Abnormal liver function, hepatitis and
jaundice.
In overdose paracetamol can cause acute
hepatic failure, hepatic failure, hepatic
necrosis and liver injury (see Section 4.9).

Skin and
subcutaneous
tissue disorders

Uncommon
(≥1/1,000 to ≤1/100)

Rashes of various types including pruritis
and urticaria.
Angioedema and swelling face.

Very rare
(≤1/10,000)

Hyperhiddrosis, purpura and
photosensitivity.
Exfoliative dermatoses. Bullous reactions
including erythema multiforme, Stevens
Johnson Syndrome and Toxic Epidermal
Necrolysis.

Renal and
urinary
disorders

Very rare
(≤1/10,000)

Nephrotoxicity in various forms, including
interstitial nephritis, nephrotic syndrome,
and acute and chronic renal failure.

General
disorders and
administration
site conditions

Very rare
(≤1/10,000)

Fatigue and malaise.

Investigations

Common
(≥1/100 to ≤1/10)

Alanine aminotransferase increased, gammaglutamyltransferase increased and liver
function tests abnormal with paracetamol.

Blood creatinine increased and blood urea
increased.
Uncommon
(≥1/1,000 to ≤1/100)

Aspartate aminotransferase increased, blood
alkaline phosphatase increased, blood
creatine phosphokinease increased, blood
creatinine increased, haemoglobin decreased
and platelet count increased.

1

Hypersensitivity reactions have been reported. These may consist of (a) non-specific
allergic reactions and anaphylaxis, (b) respiratory tract activity, e.g. asthma,
aggravated asthma, bronchospasm or dyspnoea, or (c) various skin reactions e.g,
pruritus, urticaria, angioedema and, more rarely, exfoliative and bullous dermatoses
(including epidermal necrolysis, and erythema multiforme).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk
balance of the medicinal product. Healthcare professionals are asked to report
any suspected adverse reactions via the national reporting system.

4.9

Overdose
Paracetamol

Liver damage is possible in adults who have taken 10 g (equivalent to 20
tablets) or more of paracetamol. Ingestion of 5 g (equivalent to 10 tablets) or
more of paracetamol may lead to liver damage if the patient has one or more
of the risk factors below:
a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin,
primidone, rifampicin, St John's Wort or other drugs that induce liver
enzymes.
b) Regularly consumes alcohol in excess of recommended amounts.
c) Is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis,
HIV infection, starvation, cachexia
Symptoms
Symptoms of paracetamol overdose in the first 24 hours include pallor, nausea,
vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48
hours after ingestion as liver function tests become abnormal. Abnormalities of
glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic
failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral
oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested
by loin pain, haematuria and proteinuria, may develop even in the absence of severe
liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management
Immediate treatment is essential in the management of paracetamol overdose.
Despite a lack of significant early symptoms, patients should be referred to
hospital urgently for immediate medical attention. Symptoms may be limited
to nausea or vomiting and may not reflect the severity of overdose or the risk
of organ damage. Management should be in accordance with established
treatment guidelines.
Treatment with activated charcoal should be considered if the overdose has
been taken within 1 hour. Plasma paracetamol concentration should be
measured at 4 hours or later after ingestion (earlier concentrations are
unreliable).
Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of
paracetamol however; the maximum protective effect is obtained up to 8 hours
post ingestion. The effectiveness of the antidote declines sharply after this
time.
If required the patient should be given intravenous-N-acetylcysteine, in line
with the established dosage schedule. If vomiting is not a problem, oral
methionine may be a suitable alternative for remote areas, outside hospital.
Patients who present with serious hepatic dysfunction beyond 24 hours from
ingestion should be managed in accordance with established guidelines.
Ibuprofen
In children ingestion of more than 400 mg/kg of Ibuprofen 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 if there is a co-incident of
dehydration. 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

ATC Code: M01AE51 – Musculoskeletal system, anti-inflammatory and antirheumatic
products, non-steroids, propionic acid derivatives. Ibuprofen combinations.
The pharmacological actions of ibuprofen and paracetamol differ in their site and mode of
action. These complementary modes of action are synergistic which results in greater
antinociception and antipyresis than the single actives alone.
Ibuprofen is an NSAID that has demonstrated its efficacy in the common animal experimental
inflammation models by inhibition of prostaglandin synthesis. Prostaglandins sensitise
nociceptive afferent nerve terminals to mediators such as bradykinin. Ibuprofen therefore
elicits an analgesic effect through peripheral inhibition of the cycloxygenase-2 (COX-2)
isoenzyme with a subsequent reduction in sensitisation of nociceptive nerve terminals.
Ibuprofen has also been shown to inhibit induced-leucocyte migration into inflamed areas.
Ibuprofen has a pronounced action within the spinal cord due, in part, to the inhibition of
COX. Ibuprofen's antipyretic effects are produced by the central inhibition of prostaglandins
in the hypothalamus. Ibuprofen reversibly inhibits platelet aggregation. In humans, ibuprofen
reduces inflammatory pain, swellings and fever.
Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic
acid on platelets 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 acetylsalicylic acid (81mg), a decreased effect of acetylsalicylic acid 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.
Paracetamol's exact mechanism of action is still not completely defined; however there is
considerable evidence to support the hypothesis of a central antinociceptive effect. Various
biochemical studies point to inhibition of central COX 2 activity. Paracetamol may also
stimulate the activity of descending 5-hydroxytryptamine (serotonin) pathways that inhibit
nociceptive signal transmission in the spinal cord. Evidence has shown that paracetamol is a
very weak inhibitor of peripheral COX-1 and 2 isoenzymes.
This product is especially suitable for pain which requires stronger pain relief than ibuprofen
400 mg or paracetamol 1000 mg alone, and faster pain relief than ibuprofen.
Randomised, double-blind placebo-controlled studies were conducted with the combination
using the acute pain model of post-operative dental pain. The studies show that:
• This product provides more effective pain relief than paracetamol 1000 mg (p<0.0001).
• Duration of analgesia was significantly longer for this product (8.4 hours) compared to
paracetamol 500 mg (4 hours, p<0.0001) or 1000 mg (5.2 hours, p<0.0001).
• The global evaluation of the study medication by the subjects showed high levels of
satisfaction with 88.0% rating the product as 'good', 'very good' or 'excellent' in achieving

pain relief. The fixed combination product performed significantly better than ibuprofen
200mg, paracetamol 500mg and 1000 mg (p<0.001 in all cases).
A one tablet dose of this product provides more effective pain relief than a combination of
paracetamol 1000 mg / codeine phosphate 30 mg (p=0.0001) and was shown to be noninferior to a combination of ibuprofen 400 mg / codeine phosphate 25.6 mg.
This product has a fast onset of action with 'confirmed perceptible pain relief' achieved in a
median of 15.6 minutes (1tablet dose) or 18.3 minutes (2 tablets dose), which is faster than
for ibuprofen 200 mg (30.1 minutes, p<0.001), ibuprofen 400 mg (23.8 minutes, p=0.0001)
and paracetamol 500 mg (23.7 minutes, p=0.0001). 'Meaningful pain relief' for this product
was achieved in a median of 39.3 minutes (1 tablet dose) or 44.6 minutes ( 2 tablets dose),
which was significantly faster than for ibuprofen 200 mg (80.0 minutes, p<0.0001), ibuprofen
400 mg (70.5 minutes, p=0.0001), paracetamol 500 mg (50.4 minutes, p=0.001) and
paracetamol 1000 mg (45.6 minutes, p<0.05)
Other randomised, double-blind placebo-controlled studies were conducted with the
combination using the acute pain model of post-operative dental pain. The studies show that:
• This product provides more effective pain relief than paracetamol 1000 mg (p<0.0001) and
ibuprofen 400 mg (p< 0.05).
• Duration of analgesia was significantly longer for this product (9.1 hours) compared to
paracetamol 500 mg (4 hours) or 1000 mg (5.2 hours).
• The global evaluation of the study medication by the subjects showed high levels of
satisfaction with 93.2% rating the product as 'good', 'very good' or 'excellent' in achieving
pain relief. The fixed combination product performed significantly better than paracetamol
1000 mg (p<0.0001).
Another randomised, double-blind controlled clinical study was conducted with the product in
the treatment of chronic knee pain. The study showed that:
• The product provides more effective pain relief than paracetamol 1000 mg in short term
treatment (p<0.01) and long term treatment (p<0.01).
• The global evaluation of the product by the subjects showed high levels of satisfaction with
60.2% rating the product as 'good' or 'excellent' as a long term treatment for a painful knee.
The product performed significantly better than paracetamol 1000 mg (p<0.001).
This product provides more effective pain relief than a combination of paracetamol 1000 mg /
codeine phosphate 30 mg (p<0.0001), and a combination of ibuprofen 400 mg / codeine
phosphate 25.6 mg (p=0.0001).

5.2

Pharmacokinetic properties
Ibuprofen is well absorbed from the gastrointestinal tract and is extensively
bound to plasma proteins. Ibuprofen diffuses into the synovial fluid. Plasma
levels of ibuprofen from this product are detected from 5 minutes with peak

plasma concentrations achieved within 1-2 hours after ingestion on an empty
stomach. When this product was taken with food peak ibuprofen plasma levels
were lower and delayed by a median of 25 minutes, but overall extent of
absorption was equivalent.
Ibuprofen is metabolised in the liver to two major metabolites with primary
excretion via the kidneys, either as such or as major conjugates, together with
a negligible amount of unchanged ibuprofen. Excretion by the kidney is both
rapid and complete. The elimination half-life is approximately 2 hours.
In limited studies, ibuprofen appears in the breast milk in very low
concentrations.
No significant differences in ibuprofen pharmacokinetic profile are observed
in the elderly.
Paracetamol is readily absorbed from the gastrointestinal tract. Plasma protein
binding is negligible at usual therapeutic concentrations, although this is
dose-dependent. Plasma levels of paracetamol from this product are detected
from 5 minutes with peak plasma concentrations occurring at 0.5-0.67 hours
after ingestion on an empty stomach. When this product was taken with food
peak paracetamol plasma levels were lower and delayed by a median of 55
minutes, but overall extent of absorption was equivalent.
Paracetamol is metabolised in the liver and excreted in the urine mainly as the
glucuronide and sulphate conjugates, with about 10% as glutathione
conjugates. Less than 5% is excreted as unchanged paracetamol. The
elimination half-life is approximately 3 hours.
A minor hydroxylated metabolite, which is usually produced in very small
amounts by mixed function oxidases in the liver and detoxified by conjugation
with liver glutathione, may accumulate following paracetamol overdose and
cause liver damage.
No significant differences in the paracetamol pharmacokinetic profile are
observed in the elderly.
The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol
taken as this product are not altered when taken in combination as a single or
repeat dose.
This product is formulated using a technology which releases both Ibuprofen
and Paracetamol simultaneously, so that the active ingredients deliver a
combination effect.

5.3

Preclinical safety data
The toxicological safety profile of ibuprofen and paracetamol has been
established in animal experiments and in humans from extensive clinical
experience. There are no new preclinical data of relevance to the prescriber

which are additional to the data already presented in this Summary of Product
Characteristics.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Croscarmellose sodium
Microcrystalline cellulose
Colloidal anhydrous silica
Magnesium stearate
Stearic acid
Film Coat
Polyvinyl alcohol
Titanium Dioxide
Talc
Macrogol
Potassium aluminium silicate (E555)
Polysorbate

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions

6.5

Nature and contents of container
Opaque, white PVC with PVdC (polyvinylidene chloride), heat-sealed to
aluminium foil, blister pack containing:
4, 6, 8, 10, 12, 16, 20, 24, 32 film-coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Reckitt Benckiser Healthcare (UK) Ltd
Slough, Berkshire
SL1 3UH
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00063/0579

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/10/2013

10

DATE OF REVISION OF THE TEXT
31/10/2013

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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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