Brufen 400 mg bruisgranulaat
|ATC||M01AE01 - Ibuprofen|
|Registratiedatum||20 december 2012|
2132 JD HOOFDDORP
|Hulpstof(fen)||APPELZUUR, (DL)(+-)(E 296)|
CARMELLOSE (E 466)
NATRIUMCARBONAAT 0-WATER (E 500 (I))
NATRIUMLAURILSULFAAT (E 487)
NATRIUMWATERSTOFCARBONAAT (E 500 (II))
POVIDON K 30 (E 1201)
SACCHAROIDE NATRIUM 0-WATER (E 954)
SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT
Brufen 400 mg bruisgranulaat 2
QUALITATIVE AND QUANTITATIVE COMPOSITION
One sachet contains 400 mg ibuprofen.
Excipients with known effect
One sachet also contains 666.7 mg sucrose and 100 mg sodium.
For a full list of excipients, see section 6.1. 3
White granules, with orange flavour. 4
Mild to moderate pain.
Rheumatic conditions such as arthritic diseases e.g. rheumatoid arthritis, degenerative arthritic
conditions (e.g. osteoarthritis), non-articular rheumatic conditions, other muscular and joint
disorders, and soft tissue injuries. 4.2
Posology and method of administration
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms (see section 4.4).
The ibuprofen dose depends on the patient’s age and body weight. The maximum single daily dose
for adults should not exceed 800 mg of ibuprofen.
Method of administration
In order to achieve a faster onset of action, the dose may be taken on an empty stomach.
The effervescent granules should be mixed with water to make an orange flavoured, fizzy drink.
Empty the contents of the sachet into a glass of water, stir and drink immediately. A transient
sensation of burning in the mouth or throat may occur with Brufen ; ensure that the granules are
dissolved in plenty of water. Mild to moderate pain and fever
Adults and adolescents older than 12 years (≥40 kg):
400 mg given as a single dose or up to 3 times a day with an interval of 4 to 6 hours.
The maximum daily dose should not exceed 1200 mg.
Adults and adolescents over 12 years of age (≥40 kg):
400 mg 1‑3 times a day, with an interval of 4‑6 hours, as needed. The maximum daily dose should
not exceed 1200 mg.
The usual dose is 400 mg 3 times a day. Maintenance doses of 1200 mg daily may be effective in
some patients. In acute and severe conditions the dose may be increased to a maximum of 2400 mg
in divided doses. Adolescents over 12 years of age (≥40 kg)
The recommended dose is 20 mg/kg to a maximum of 40 mg/kg body weight daily in 3 to 4 divided
doses. The maximum daily dose should not exceed 2400 mg.
Brufen is not suitable for use in children under 12 years. Other more appropriate Ibuprofen
formulations are available for this population.
NSAIDs should be used with particular caution in elderly patients who are more prone to adverse
events (see section 4.4 and 4.8). If treatment is considered necessary, the lowest dose for the shortest
duration necessary to control symptoms should be used. Treatment should be reviewed at regular
intervals and discontinued if no benefit is seen or intolerance occurs.
Impaired renal function
In patients with mild or moderate reduction of renal function, the dose should be kept as low as
possible for the shortest duration necessary to control symptoms and renal function monitored. (For
patients with severe renal failure see section 4.3). Impaired liver function
In patients with mild or moderate reduction of liver function, the dose should be kept as low as
possible for the shortest duration necessary (For patients with severe liver failure see section 4.3). 4.3
Brufen is contraindicated in patients with:
- hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- previous hypersensitivity reactions (e.g. asthma, rhinitis, urticaria or angioedema) in response to
acetylsalicylic acid or other NSAIDs
- history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy
- active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven
ulceration or bleeding)
- severe hepatic or severe renal insufficiency
- severe heart failure or coronary heart disease
- last trimester of pregnancy (see section 4.6)
- significant dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)
- cerebrovascular or other active bleeding
- dishaematopoiesis of unknown origin
- children younger than 12 years of age. 4.4
Special warnings and precautions for use
The use of Brufen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors,
should be avoided.
Asthmatic patients are to seek their doctor’s advice before using ibuprofen (see below).
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below). Patients
treated with NSAIDs long term should undergo regular medical supervision to monitor for adverse
Brufen should only be administered under strict consideration of the benefit-risk ratio in the
Systemic Lupus Erythematosus (SLE) or other autoimmune diseases.
Congenital disturbance of porphyrin metabolism (e.g. acute intermittent porphyria)
The first and second trimester of pregnancy
Special care has to be taken in the following cases:
Gastrointestinal diseases including chronic inflammatory intestinal disease (ulcerative
colitis, Crohn’s disease)
Cardiac insufficiency and hypertension
Reduced renal function
Blood coagulation defects
Allergies, hay fever, chronic swelling of nasal mucosa, adenoids, chronic obstructive
airway disease or bronchial asthma
Immediately after major surgical interventions
Gastrointestinal bleeding, ulceration and perforation
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
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 medicinal products likely to increase gastrointestinal risk. (See below
and section 4.5).
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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin or
heparin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid
(see section 4.5).
When GI bleeding or ulceration occurs in patients receiving Brufen, the treatment should be
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative
colitis, Crohn’s disease) as their condition may be exacerbated. (See section 4.8). 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).
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, 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
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart
disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with
ibuprofen after careful consideration. Similar consideration should be made before initiating longer-
term treatment of patients with risk factors for cardiovascular events (e.g. hypertension,
hyperlipidaemia, diabetes mellitus and smoking). Skin reactions
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. Brufen must be discontinued at the first appearance of skin rash, mucosal lesions, or
any other sign of hypersensitivity.
Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious
complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot
be ruled out. Thus, it is advisable to avoid use of Brufen in case of varicella.
Ibuprofen may cause the retention of sodium, potassium and fluid in patients who have not
previously suffered from renal disorders because of its effect on renal perfusion. This may cause
oedema or even lead to cardiac insufficiency or hypertension in predisposed patients.
As with other NSAIDs, the prolonged administration of ibuprofen to animals has resulted in renal
papillary necrosis and other pathological renal changes. In humans, there have been reports of acute
interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome. Cases of
renal toxicity have also been observed in patients in whom prostaglandins play a compensatory role
in the maintenance of renal perfusion. In these patients, administration of NSAIDs may cause a
dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which
may precipitate overt renal decompensation. Patients at greatest risk of suffering this reaction are
those with renal dysfunction, heart failure, hepatic dysfunction, those taking diuretics and ACE
inhibitors and the elderly. Discontinuation of NSAID treatment is generally followed by recovery to
the pre-treatment state. Other precautions
Bronchospasm, urticaria or angioedema may be precipitated in patients suffering from or with a
previous history of bronchial asthma, chronic rhinitis, sinusitis, nasal polyps, adenoids or allergic
Ibuprofen may mask the signs or symptoms of an infection (fever, pain and swelling).
Prolonged use of any type of painkiller for headaches can make them worse. If this situation is
experienced or suspected, medical advice should be obtained and treatment should be discontinued.
The diagnosis of medication overuse headache (MOH) should be suspected in patients who have
frequent or daily headaches despite (or because of) the regular use of headache medications.
In general terms, the habitual intake of painkillers particularly on combination of several pain-
relieving active substances, may lead to permanent renal damage with the risk of renal failure. This
risk may be increased under physical strain associated with loss of salt and dehydration. Therefore it
should be avoided.
During treatment with ibuprofen, some cases with symptoms of aseptic meningitis, such as stiff
neck, headache, nausea, vomiting, fever or disorientation have been observed in patients with
existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue
Ibuprofen may temporarily inhibit platelet aggregation and prolong the bleeding time. Therefore,
patients with coagulation defects or on anticoagulant therapy should be observed carefully.
In case of long-term treatment with ibuprofen, a periodical monitoring of hepatic and renal function
as well as the blood count is necessary, especially in high risk patients.
Consumption of alcohol should be avoided since it may intensify side effects of NSAIDs, especially
if affecting the gastrointestinal tract or the central nervous system.
Patients on ibuprofen should report to their doctor signs or symptoms of gastro-intestinal ulceration
or bleeding, blurred vision or other eye symptoms, skin rash, weight gain or oedema.
There is some evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may
cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of
treatment (see section 4.6).
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or
sucrase-isomaltase insufficiency should not take this medicine.
This medicinal product contains 100 mg sodium per dose. To be taken into consideration by patients
on a controlled sodium diet.
Interactions with other medicinal products and other forms of interaction
Concomitant use of
Other NSAIDs including
As a result of synergistic effects, the concurrent use of several
NSAIDs can increase the risk of gastrointestinal ulcers and
haemorrhage. Co-administration of ibuprofen with other NSAIDs
should therefore be avoided (see section 4.4).
Cardiac glycosides (Digoxin)
NSAIDs may exacerbate cardiac failure, reduce GFR and increase
plasma levels of cardiac glycosides. Monitoring of serum digoxin is
Increased risk of gastrointestinal ulceration or bleeding (see section
NSAIDs may enhance the effects of anticoagulants, such as warfarin
or heparin (see section 4.4). In case of simultaneous treatment,
monitoring of the coagulation state is recommended.
Increased risk of gastrointestinal bleeding (see section 4.4).
(e.g. clopidogrel and
Ibuprofen should be avoided in combination with acetylsalicylic
acid unless low dose acetylsalicylic acid has been advised by a
doctor, as this may increase the risk of adverse reactions.
Experimental data suggest that ibuprofen may inhibit the effect of
low dose acetylsalicylic acid 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)
Increased risk of gastrointestinal bleeding (see section 4.4).
Co-administration of ibuprofen with lithium preparations can
increase the serum level of these medicinal products. Checking the
serum lithium level is necessary.
NSAIDs should not be combined with ticlopidine due to a risk of an
additive effect in the inhibition of the platelet function.
Potassium sparing diuretics
concomitant use may cause hyperkaliaemia (check of serum
potassium is recommended)
Experimental studies indicate that ibuprofen counteracts the effect
of captopril of increased sodium excretion.
Diuretics and ACE-inhibitors can increase the nephrotoxicity of
NSAIDs. NSAIDs can reduce the effect of diuretics and
(Diuretics, ACE inhibitors,
antihypertensives, including ACE-inhibitors and beta-blockers. In
patients with reduced kidney function (e.g. dehydrated patients or
elderly patients with reduced kidney function), the concomitant use
of an ACE inhibitor and angiotension II antagonist with a
cyclooxygenase-inhibiting medicinal product can lead to further
impairment of kidney function and through to acute renal failure.
This is usually reversible. Such combinations should therefore only
be used with caution, especially in elderly patients. The patients
have to be instructed to drink sufficient liquid and periodic
monitoring of the kidney values should be considered for the time
immediately after the start of the combination therapy.
The concomitant administration of ibuprofen and potassium-sparing
diuretics or ACE-inhibitors can result in hyperkalaemia. Careful
monitoring of potassium levels is necessary.
NSAID inhibits the tubular secretion of methotrexate and certain
metabolic interactions can occur resulting in decreased clearance of
methotrexate. The administration of ibuprofen within 24 hours
before or after the administration of methotrexate can lead to an
elevated concentration of methotrexate and an increase in its toxic
effects. Therefore, concomitant use of NSAIDs and high doses of
methotrexate should be avoided. Also, the potential risk of
interactions in low dose treatment with methotrexate should be
considered, especially in patients with impaired renal function. In
combined treatment, renal function should be monitored.
The risk of kidney damage by ciclosporine is increased by the
concomitant administration of certain NSAIDs. This effect can not
be ruled out for the combination of ciclosporine and ibuprofen,
Elevated risk of nephrotoxicity.
There is evidence of an increased risk of haemarthrosis and
haematoma in HIV positive haemophilia patients receiving
concurrent treatment with zidovudine and ibuprofen. There may be
an increased risk of haematotoxicity during concomitant use of
zidovudine and NSAIDs. Blood counts 1-2 weeks after starting use
together are recommended.
Animal data indicate that NSAID’s can increase the risk of
convulsions associated with quinolone antibiotics. Patients taking
NSAID’s and quinolones may have an increased risk of developing
Concomitant administration of ibuprofen with CYP2C9 inhibitors
may increase the exposure to ibuprofen (CYP2C9 substrate). In a
(e.g. voriconazole or
study with voriconazole and fluconazole (CYP2C9 inhibitors), an
increased S(+)-ibuprofen exposure by approximately 80 to 100%
has been shown. Reduction of the ibuprofen dose should be
considered when potent CYP2C9 inhibitors are administered
concomitantly, particularly when high-dose ibuprofen is
administered with either voriconazole or fluconazole.
NSAIDs can increase the hypoglycemic effect of sulphonylureas. In
the case of simultaneous treatment, monitoring of blood glucose
levels is recommended.
Concomitant treatment with cholestyramine and ibuprofen results in
prolonged and reduced (25%) absorption of ibuprofen. The
medicinal products should be administered with at least two hours
NSAIDs can slow down the elimination of aminoglycosides and
increase their toxicity.
Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.
The use of ibuprofen in individuals with chronic alcohol
consumption (14-20 drinks/week or more) should be avoided due to
increased risk of significant GI adverse effects, including bleeding.
If NSAIDs are used within 8-12 days after mifepristone
administration, they can reduce the effect of mifepristone.
Fertility, pregnancy and lactation
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 the 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 losses 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 trimesters of
pregnancy, Brufen should not be given unless clearly necessary. If Brufen is used by a woman
attempting to conceive or during the first and second trimester, the dose should be kept as low as
possible 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
Renal dysfunction, which may progress to renal failure with oligohydramnios.
The mother and the neonate, at the end of pregnancy, to:
Possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very
Inhibition of uterine contractions, resulting in delayed or prolonged labour.
Consequently, Brufen is contraindicated during the last trimester of pregnancy. Breastfeeding
Ibuprofen is excreted in breast milk, but with therapeutic doses during short term treatment, the risk
for influence on the infant seems unlikely. If, however, longer treatment is prescribed, early weaning
should be considered. Fertility
The use of ibuprofen may impair fertility and is not recommended in women attempting to conceive.
In women who have difficulties conceiving or who are undergoing an investigation of infertility,
withdrawal of ibuprofen should be considered. 4.7
Effects on the ability to drive and use machines
Ibuprofen generally has no adverse effects on the ability to drive and use machinery. However since
at high dosage side effects such as fatigue, somnolence, vertigo (reported as common) and visual
disturbances (reported as uncommon) may be experienced, the ability to drive a car or operate
machinery may be impaired in individual cases. This effect is potentiated by simultaneous
consumption of alcohol.
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers,
perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4).
Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena,
heamatemesis, ulcerative stomatits, exacerbation of colitis and Crohn’s disease (see section 4.4)
have been reported following administration. Less frequently, gastritis has been observed.
Undesirable effects are mostly dose-dependent. Especially the risk for the occurrence of
gastrointestinal bleedings depends on the dosage range and duration of the treatment. Other known
risk factors, see section 4.4.
Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high dose
(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).
Oedema, hypertension, and cardiac failure, have been reported in association with NSAID
Adverse events at least possibly related to ibuprofen are displayed by MedDRA frequency
convention and system organ class. The following frequency groupings are used: Very common
(1/10), Common (1/100 to <1/10), Uncommon (1/1,000 to <1/100), Rare (1/10,000 to
<1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data).
System Organ Class
Blood and lymphatic
haematopoietic disorders (anaemia, leucopoenia,
thrombocytopenia, pancytopenia, agranulocytosis). The first
symptoms or signs may include: fever, sore throat, surface
mouth ulcers, flu-like symptoms, severe fatigue, nasal and skin
hypersensitivity reactions such as urticaria, pruritus, purpura
and exanthema as well as asthma attacks (sometimes with
lupus erythematosus syndrome
severe hypersensitivity reactions. The symptoms may include:
facial oedema, swelling of the tongue, internal laryngeal
swelling with constriction of the airways, dyspnoea,
tachycardia, fall of blood pressure to the point of life-
depression, confusion, hallucinations
headache, somnolence, vertigo, fatigue, agitation, dizziness,
Ear and labyrinth
palpitations, heart failure, myocardial infarction, acute
pulmonary oedema, oedema
gastrointestinal disorders, such as heartburn, dyspepsia,
abdominal pain and nausea, vomiting, flatulence, diarrhoea,
gastrointestinal ulcers, sometimes with bleeding and
perforation (see section 4.4), occult blood loss which may lead
to anaemia, melaena, haematemesis, ulcerative stomatitis,
colitis, exacerbation of inflammatory bowel disease,
complications of colonic diverticula (perforation, fistula),
oesophagitis, pancreatitis, intestinal strictures
Increase of blood urea nitrogen, serum transaminases and
liver dysfunction, liver damage, especially in long-term use,
liver failure, acute hepatitis, jaundice
severe forms of skin reactions (erythema multiforme,
exfoliative dermatitis, bullous reactions including
Stevens-Johnson syndrome and toxic epidermal necrolysis,
alopecia, necrotising fascitis
Renal and urinary
development of oedema especially in patients with arterial
hypertension or renal insufficiency, nephrotic syndrome,
interstitial nephritis which can be associated with renal failure
renal papillary necrosis in long-term use (see section 4.4)
decrease in haemoglobin and haematocrit values, inhibition of
platelet aggregation, prolonged bleeding time, decrease of
serum calcium, increase in serum uric acid
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, dizziness,
vertigo and gastrointestinal bleeding may also occur. 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. Children may also develop myoclonic cramps. In
serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged,
probably due to the actions of circulating clotting factors. Acute renal failure, liver damage,
hypotension, respiratory depression and cyanosis may occur. Exacerbation of asthma is possible in
Treatment should be symptomatic and supportive and include the maintenance of a clear airway and
monitoring of cardiac and vital signs until stable. Gastric emptying or oral administration of
activated charcoal is indicated if the patient presents within one hour of the ingestion of more than
400 mg per kg of body weight. If the Brufen has already been absorbed, alkaline substances should
be administered to promote the excretion of the acid ibuprofen in the urine. If frequent or prolonged,
convulsions should be treated with intravenous diazepam or lorazepam. Other measures may be
indicated by the patient's clinical condition. Bronchodilators should be given for asthma. No specific
antidote is available.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts. 5
Pharmacotherapeutic classification: Anti-inflammatory and antirheumatic products, non-steroids;
propionic acid derivatives. ATC code: M01AE01
Mechanism of action
Ibuprofen is a NSAID that possesses anti-inflammatory, analgesic and antipyretic activity. Animal
models for pain and inflammation indicate that ibuprofen effectively inhibits the synthesis of
prostaglandins. In humans, ibuprofen reduces pain possibly caused by inflammation or connected
with it, swelling and fever. Ibuprofen exerts an inhibitory effect on prostaglandin synthesis by
inhibiting the activity of cyclo-oxygenase. In addition,ibuprofen has an inhibitory effect on ADP
(adenosine diphosphate) or collagen-stimulated platelet aggregation.
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
400 mg was taken within 8 hour before or within 30 min after immediate release acetylsalicylic acid
dosing (81 mg), 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 inhibits prostaglandin synthesis in the uterus, thereby reducing intrauterine rest and active
pressure, the periodic uterine contractions and the amount of prostaglandins released into the
circulation. These changes are assumed to explain the alleviation of menstrual pain. Ibuprofen
inhibits renal prostaglandin synthesis which can lead to renal insufficiency, fluid retention and heart
failure in risk patients (see section 4.3).
Prostaglandins are connected with ovulation and the use of medicinal products inhibiting
prostaglandin synthesis may therefore affect the fertility of women (see section 4.4, 4.6 and 5.3). 5.2
Ibuprofen is rapidly absorbed from the gastrointestinal tract with a bioavailability of 80-90%. Peak
serum concentrations occurred 1.7 hours (median value) after administration of ibuprofen in the
fasted state. If administered with food, peak serum concentrations were 34% lower and achieved
approximately 2 hours later than when taken on an empty stomach. Food does not markedly affect
Ibuprofen is extensively bound to plasma proteins (99%). Ibuprofen has a small volume of
distribution being about 0.12-0.2 L/kg in adults. Biotransformation
Ibuprofen is rapidly metabolized in the liver through cytochrome P450, preferentially CYP2C9, to
two primary inactive metabolites, 2-hydroxyibuprofen and 3-carboxyibuprofen. Following oral
ingestion of the drug, slightly less than 90% of an oral dose of ibuprofen can be accounted for in the
urine as oxidative metabolites and their glucuronic conjugates. Very little ibuprofen is excreted
unchanged in the urine. Elimination
Excretion by the kidney is both rapid and complete. The elimination half-life is approximately 2
hours. The excretion of ibuprofen is virtually complete 24 hours after the last dose. Special populations
Given that no renal impairment exists, there are only small, clinically insignificant differences in the
pharmacokinetic profile and urinary excretion between young and elderly.
The systemic exposure of ibuprofen following weight adjusted therapeutic dosage (5mg/kg to 10
mg/kg bodyweight) in children aged 1 year or over, appears similar to that in adults.
Children 3 months to 2.5 years appeared to have a higher volume of distribution (L/kg) and
clearance (L/kg/h) of ibuprofen than did children >2.5 to 12 years of age.
For patients with mild renal impairment increased unbound (S)-ibuprofen, higher AUC values for
(S)-ibuprofen and increased enantiomeric AUC (S/R) ratios as compared with healthy controls have
In end-stage renal disease patients receiving dialysis the mean free fraction of ibuprofen was about
3% compared with about1% in healthy volunteers. Severe impairment of renal function may result
in accumulation of ibuprofen metabolites. The significance of this effect is unknown. The
metabolites can be removed by haemodialysis (see sections 4.2, 4.3 and 4.4).
Alcoholic liver disease with mild to moderate hepatic impairment did not result in substantially
altered pharmacokinetic parameters.
In cirrhotic patients with moderate hepatic impairment (Child Pugh’s score 6-10) treated with
racemic ibuprofen an average 2-fold prolongation of the half-life was observed and the enantiomeric
AUC ratio (S/R) was significantly lower compared to healthy controls suggesting an impairment of
metabolic inversion of (R)-ibuprofen to the active (S)-enantiomer (see sections 4.2, 4.3 and 4.4).
Preclinical safety data
As a well established and widely used product, the pre-clinical safety of ibuprofen is well
Ibuprofen's subchronic and chronic toxicity was mainly shown by animal tests as gastric tract
damage and ulcers.
The vitro and in vivo tests have not shown any clinically significant signs about ibuprofen's
mutagenicity. Furthermore, no carcinogenic effects have been observed in mice and rats.
Ibuprofen inhibits ovulation in rabbits and impairs implantation in various animal species (rabbit,
rat, and mouse). In reproduction tests undertaken with rats and rabbits, ibuprofen passed across the
placenta. When using doses toxic to the mother, malformations occur more frequently (i.e.
ventricular septum defects). 6
List of excipients
Anhydrous sodium carbonate
Sodium hydrogen carbonate
Sodium lauril sulfate 6.2
Not applicable. 6.3
2 years 6.4
Special precautions for storage
Store below 25C. Store in the original package in order to protect from light and moisture. 6.5
Nature and contents of container
Sachet consisting of a paper/polyethylene/aluminium foil and polyethylene laminate.
Pack sizes: 20, 30 or 40 sachets. Not all pack sizes may be marketed 6.6
Special precautions for disposal <and other handling>
No special requirements
Any unused product or waste material should be disposed of in accordance with local requirements. 7
MARKETING AUTHORISATION HOLDER
2132 JD Hoofddorp
088 822 2688
MARKETING AUTHORISATION NUMBER
DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
20 december 2012 10
DATE OF REVISION OF THE TEXT