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BRUFEN 400 MG EFFERVESCENT GRANULES

Active substance(s): IBUPROFEN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Brufen 400 mg Effervescent Granules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

One sachet contains 400 mg ibuprofen.
Excipients with known effect
One sachet also contains 2222 mg sucrose and 131 mg sodium.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Effervescent granules.
White granules, with orange flavour.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

- Acute mild to moderate pain, such as headache and dental pain
- Primary dysmenorrhoea.
- Fever

4.2

Posology and method of administration

Posology
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 and adolescents should not exceed 400 mg of ibuprofen.
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.
More than 400 mg at a time does not give a better analgesic effect.
The maximum daily dose should not exceed 1200 mg.
Adolescents
If in adolescents this medicinal product is required for more than 3 days or if symptoms
worsen a
doctor should be consulted.
Adults
The patient should consult a doctor if symptoms worsen, or persist for more than 3 days in
case of fever and 5 days in case of pain.
Paediatric population
Brufen 400 mg Effervescent Granules are not suitable for use in children under 12 years.
Other more appropriate ibuprofen formulations are available for this population.
Elderly
NSAIDs should be used with particular caution in elderly patients who are more prone to
adverse events (see sections 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).
Method of administration
In order to achieve a faster onset of action, the dose may be taken on an empty stomach.
It is recommended that patients with sensitive stomachs take ibuprofen with food.
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.

4.3

Contraindications

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 NSAID 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 (NYHA Class IV) 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). Higher than recommended doses may cause serious risks.
Brufen should only be administered under strict consideration of the benefit-risk ratio in the
following conditions:
-

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
Lactation

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
Hepatic dysfunction
Disturbed haematopoiesis
Blood coagulation defects
Allergies, hay fever, chronic swelling of nasal mucosa, adenoids, chronic obstructive
airway disease or bronchial asthma as an increased risk of allergic reactions occurring
in these patients. These allergic reactions may present as asthma attacks (so-called
analgesic asthma) Quincke’s oedema or urticaria
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 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 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
withdrawn.
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.
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 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). Overall, epidemiological studies do not suggest that low
dose ibuprofen (e.g. ≤ 1200 mg/day) is associated with an increased risk ofarterial thrombotic
events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), 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 also be exercised before initiating long-term treatment of
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.
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.
Renal effects
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.
There is a risk of renal impairment in dehydrated adolescents and the elderly
Allergic reactions
Severe acute hypersensitivity reactions (for example anaphylactic shock) are observed very
rarely. At the first signs of hypersensitivity reaction after taking the/administering Brufen,
therapy must be stopped. Medically required measures, in line with the symptoms, must be
initiated by specialist personnel.
Caution is required in patients who have had hypersensitivity or allergic reactions as they
could be at an increased risk of hypersensitivity reactions occurring with Brufen.
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 diseases.
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 painrelieving 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 disease).
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 gastrointestinal
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).

This product contains sucrose. 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.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of
ibuprofen with:

Possible effects:

Other NSAIDs including
cyclooxygenase-2 selective
inhibitors

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).
NSAIDs may exacerbate cardiac failure, reduce GFR and
increase plasma levels of cardiac glycosides. Monitoring of
serum digoxin is recommended.
Increased risk of gastrointestinal ulceration or bleeding (see
section 4.4).
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).

Cardiac glycosides
(Digoxin)
Corticosteroids
Anticoagulants

Antiplatelet-agents
(e.g. clopidogrel and
ticlopidine)

Acetylsalicylic acid

Selective serotonin
reuptake inhibitors (SSRI)
Lithium

Ticlopidine
Potassium sparing diuretics
Captopril
Antihypertensive drugs
(Diuretics, ACE inhibitors,
angiotensin-II-antagonists)

Methotrexate

Concomitant administration of ibuprofen and acetylsalicylic
acid is not generally recommended because of the potential of
increased adverse effects.
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).
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.
Concomitant use may cause hyperkalaemia (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
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.
NSAIDs inhibit 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.

Ciclosporin

Tacrolimus
Zidovudine

Quinolone antibiotics

CYP2C9 inhibitors
(e.g. voriconazole or
fluconazole)

Sulphonylureas

Cholestyramine

Aminoglycosides
Herbal extracts
Alcohol

Mifepristone

4.6

The risk of kidney damage by ciclosporin is increased by the
concomitant administration of certain NSAIDs. This effect can
not be ruled out for the combination of ciclosporin and
ibuprofen either.
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 NSAIDs can increase the risk of
convulsions associated with quinolone antibiotics. Patients
taking NSAIDs and quinolones may have an increased risk of
developing convulsions.
Concomitant administration of ibuprofen with CYP2C9
inhibitors may increase the exposure to ibuprofen (CYP2C9
substrate). In a 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 interval.
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

Pregnancy
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
hypertension)
− 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 low doses
− 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 (see section 4.4).

4.7

Effects on 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.

4.8

Undesirable effects

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, haematemesis, ulcerative stomatits, exacerbation of colitis and Crohn’s disease (see
section 4.4) have been reported following administration. Less frequently, gastritis has been
observed.

A transient sensation of burning in the mouth or throat may occur with Brufen Effervescent
Granules.
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.
Hypersensitivity reactions have been reported following treatment with NSAIDs. These may
consists of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity
comprising asthma, aggravated asthma, bronchospasm or dyspnoea or (c) assorted skin
disorders including rashes of various types, pruritus, urticaria, purpura, angioedema and, very
rarely erythema multiforme and bullous dermatoses (including Stevens-Johnson syndrome,
toxic epidermal necrolysis).
Exacerbation of infection-related inflammations (e.g. development of necrotising fasciitis)
coinciding with the use of NSAIDs has been described. If signs of an infection occur or get
worse
during use of Brufen, the patient is recommended to go to a doctor without delay.
In exceptional cases, severe skin infections and soft-tissue complications may occur during a
varicella infection.
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).
Oedema, hypertension, and cardiac failure, have been reported in association with NSAID
treatment.
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

Frequ
ency

Adverse Reaction

Infections and
infestations

Unco
mmon

Rhinitis

Meningitis aseptic

Blood and lymphatic
system disorders

Very
rare
Very
rare

Leucopoenia, thrombocytopenia, neutropenia,
agranulocytosis ,aplastic anaemia and haemolytic
anaemia. The first symptoms or signs may include: fever,
sore throat, superficial mouth ulcers, flu-like symptoms,
severe exhaustion ,unexplained bleeding and bruising.

Immune system
disorders

Psychiatric disorders

Nervous system
disorders

Uncom
mon

Hypersensitivity reactions such as urticaria, pruritus,
purpura and exanthema as well as asthma attacks
(sometimes with hypotension)

Rare

Lupus erythematosus syndrome

Very
rare

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-threatening shock.
Anxiety

Uncom
mon
Rare
Comm
on

Unco
mmon
Eye disorders

Ear and labyrinth
disorders

Cardiac disorders
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders

Hepatobiliary disorders

Skin and subcutaneous
tissue disorders

Rare
Uncom
mon
Rare
Comm
on

Depression, confusional state, hallucinations
Headache, somnolence, agitation, dizziness, insomnia
,irritability
Paraesthesia

Optic neuritis
Visual impairment
Toxic optic neuropathy
Vertigo

Unco
mmon

Hearing impaired

Rare
Very
rare
Very
rare
Uncom
mon

Tinnitus
Palpitations, heart failure, myocardial infarction, acute
pulmonary oedema, oedema
hypertension

Comm
on

Dyspepsia, diarrhoea, nausea, vomiting, abdominal
pain, flatulence, constipation , melena,
haematemesis, gastrointestinal haemorrhage

Uncom
mon
Very
rare

Gastritis, duodenal ulcer, gastric ulcer, mouth ulceration,
gastrointestinal perforation
Oesophagitis, pancreatitis, intestinal strictures

Asthma, bronchospasm , dyspnoea

Not
Colitis and Crohn’s disease
known
Unco
Hepatitis, jaundice, hepatic function abnormal
mmon
Rare
Liver injury
Very
Hepatic failure
rare
Uncom
mon
Very
rare

Rash, urticaria, pruritus, purpura, photosensitivity
reaction
Bullous dermatoses, including Stevens-Johnson syndrome,
toxic epidermal necrolysis and erythema multiforme

Renal and urinary
disorders

Very
rare

General disorders
and administration
site conditions

Comm
on
Rare

exfoliative dermatitis, alopecia, necrotising fasciitis
Tubulointerstitial nephritis, nephrotic syndrome and renal
failure
Acute renal failure, papillary necrosis (especially in
long-term use associated with increased serum urea)
Fatigue

Oedema

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 Yellow

Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose

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, 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 asthmatics.


Treatment

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

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic classification: Anti-inflammatory and antirheumatic products, nonsteroids; 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.
Pharmacodynamic effects
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose
acetylsalicylic acid on platelet aggregation when they are dosed concomitantly.Some
pharmacodynamic studies show that when single doses of ibuprofen 400 mg were taken
within 8 h 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. 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 4.5).
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 sections 4.4, 4.6 and
5.3).

5.2

Pharmacokinetic properties

Absorption
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 total bioavailability.
Distribution

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 metabolised in the liver through cytochrome P450, preferentially
CYP2C9, to two primary inactive metabolites, 2-hydroxyibuprofen and 3carboxyibuprofen. 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
Elderly
Given that no renal impairment exists, there are only small, clinically insignificant
differences in the pharmacokinetic profile and urinary excretion between young and
elderly.
Children
The systemic exposure of ibuprofen following weight adjusted therapeutic dosage (5
mg/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.
Renal impairment
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 been reported.
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).
Hepatic impairment
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).

5.3

Preclinical safety data
As a well established and widely used product, the pre-clinical safety of ibuprofen is
well documented.
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

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Anhydrous sodium carbonate
Croscarmellose sodium
Malic acid
Microcrystalline cellulose
Sodium saccharin
Sodium hydrogen carbonate
Sucrose
Povidone
Orange flavour
Sodium laurilsulfate

6.2

Incompatibilities
Not applicable.

6.3
3 years

Shelf life

6.4

Special precautions for storage
Store below 25°C. 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: 12,15, 20, 30 or 40 sachets. Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
BGP Products Ltd.
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 43900/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/01/2013

10

DATE OF REVISION OF THE TEXT
25/11/2015

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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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