IBUPROFEN 600 MG TABLETS

Active substance: IBUPROFEN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Apsifen-F
Ibuprofen 600 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 600 mg Ibuprofen Ph. Eur.

3

PHARMACEUTICAL FORM
Pink, capsule shaped film-coated tablets, plain on one side and coded "600/0531" on
the reverse.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Ibuprofen is indicated for rheumatoid arthritis including Still's disease,
osteoarthrosis, seronegative (non-rheumatoid) arthropothies, ankylosing
spondylitis, non-articular rheumatic conditions, soft-tissue injuries and mild to
moderate pain (such as dysmenorrhoea, dental and post-operative pain).

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).
For oral administration.

Adults:

Initially 1200 mg per day in divided doses.
In severe conditions up to 1800 mg per day may be given until the acute
phase of the condition has been brought under control.
Some patients may be maintained on doses in the range of 600 - 1200
mg per day.
Under no circumstances should the dose of ibuprofen exceed 2400 mg
in any 24 hours.

Children:
The Elderly:

4.3

600 mg tablets are not recommended for children.
The elderly are at increased risk of the serious consequences of adverse
reactions. If an NSAID is considered necessary, the lowest dose should
be used and the patient should be monitored for GI bleeding for 4 weeks
following initiation of NSAID therapy.

Contraindications
Ibuprofen is contraindicated in patients with hypersensitivity to the active
substance or to any of the excipients.
Ibuprofen should not be used in patients who have previously shown
hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) after
taking aspirin or other NSAID’s.
Ibuprofen is also contraindicated in patients with a history of gastrointestinal
bleeding or perforation, related to previous NSAID therapy. Ibuprofen should
not be used in patients with active, or history of, recurrent peptic ulcer or
gastrointestinal haemorrhage (two or more distinct episodes of proven
ulceration or bleeding).
Ibuprofen should not be given to patients with conditions involving an
increased tendency to bleeding.
Ibuprofen is contraindicated in patients with severe heart failure, hepatic failure
and renal failure (see section 4.4)
Ibuprofen is contraindicated in last trimester of pregnancy (see section 4.6).

4.4

Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the
shortest duration necessary to control symptoms (see section 4.2, and GI and
cardiovascular risks below).
As with other NSAIDs, ibuprofen may mask the signs of infection.
The use of Ibuprofen with concomitant NSAIDs, including cyclooxygenase-2
selective inhibitors, should be avoided due to the increased risk of ulceration
or bleeding (see section 4.5).
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).
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 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 aspirin, or other drugs likely to increase
gastrointestinal risk (see below and section 4.5).
Patients with a history of gastrointestinal disease, particularly when elderly,
should report any unusual abdominal symptoms (especially gastrointestinal
bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications
which could increase the risk of ulceration or bleeding, such as oral
corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake
inhibitors or anti-platelet agents such as aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving Ibuprofen, the
treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of ulcerative
colitis or Crohn's disease as these conditions may be exacerbated (see section
4.8).
Respiratory disorders
Caution is required if ibuprofen is administered to patients suffering from, or
with a previous history of, bronchial asthma since NSAID’s have been reported
to precipitate bronchospasm in such patients.

Cardiovascular, renal and hepatic impairment
The administration of an NSAID 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 also section 4.3).
Ibuprofen should be given with care to patients with a history of heart failure or
hypertension since oedema has been reported in association with ibuprofen
administration.
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 a 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).
Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤
1200 mg daily) is associated with an increased risk of arterial thrombotic events,
particularly myocardial infarction.
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, smoking).
Renal effects
Caution should be used when initiating treatment with ibuprofen in patients
with considerable dehydration.
As with other NSAIDs, long-term administration of ibuprofen has resulted in
renal papillary necrosis and other renal pathologic changes. Renal toxicity has
also been seen in patients in whom renal prostaglandins have a compensatory
role in the maintenance of renal perfusion. In these patients, administration of
an NSAID 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 this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is
usually followed by recovery to the pre-treatment state.
SLE and mixed connective tissue disease
In patients with systemic lupus erythematosus (SLE) and mixed connective
tissue disorders there may be an increased risk of aseptic meningitis (see
below and section 4.8).

Dermatological effects
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 within the first month of treatment
in the majority of cases. Ibuprofen should be discontinued at the first
appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Haematological effects
Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and has
been shown to prolong bleeding time in normal subjects.
Aseptic meningitis
Aseptic meningitis has been observed on rare occasions in patients on
ibuprofen therapy. Although it is probably more likely to occur in patients
with systemic lupus erythematosus and related connective tissue diseases, it
has been reported in patients who do not have an underlying chronic disease.
Impaired female fertility
The use of Ibuprofen 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 Ibuprofen
should be considered.
4.5

Interaction with other medicinal products and other forms of interaction
Care should be taken in patients treated with any of the following drugs such as
interactions have been reported in some patients.
Anti-hypertensives, beta-blockers and diuretics:
NSAID’s may reduce the effect of anti-hypertensive, such as ACE inhibitors,
beta-blockers and diuretics..
Diuretics can also increase the risk of nephrotoxicity of NSAIDs.
Cardiac glycosides:
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma
glycoside levels.
Cholestyramine:
The concomitant administration of ibuprofen and cholestyramine may reduce
the absorption of ibuprofen in the gastrointestinal tract. However, the clinical
significance is unknown.
Lithium:
Decreased elimination of lithium.
Methotrexate:

NSAIDs may inhibit the tubular secretion of methotrexate and reduce
clearance of methotrexate.
Ciclosporin:
Increased risk of nephrotoxicity.
Mifepristone:
NSAIDs should not be used for 8 - 12 days after mifepristone administration as
NSAIDs can reduce the effect of mifepristone. Limited evidence suggests that
co-administration of NSAIDs on the day of prostaglandin administration does
not adversely influence the effects of mifepristone or the prostaglandin on
cervical ripening or uterine contractility and does not reduce the clinical
efficacy of medicinal termination of pregnancy.
Other analgesics and cyclooxygenase-2 selective inhibitors:
Avoid concomitant use of two or more NSAIDs including Cox-2 inhibitors, as
this may increase the risk of adverse effects (see section 4.4).
Aspirin: As with other products containing NSAIDs, concomitant
administration of ibuprofen and aspirin is not generally recommended because
of the potential of increased adverse effects.
Corticosteroids:
Increased risk of gastrointestinal ulceration or bleeding with NSAID’s (see
section 4.4).
Anticoagulants:
NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See
section 4.4).
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.
Experimental data suggests that ibuprofen may inhibit the effect of low dose
aspirin on platelet aggregation when they are used 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).
Sulfonylureas:
NSAIDs may potentiate the effects of sulfonylurea medications. There have
been rare reports of hypoglycaemia in patients on sulfonylurea medications
receiving ibuprofen.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):
Increased risk of gastrointestinal bleeding with NSAIDs (see section 4.4).

Tacrolimus:
Possible increased risk of nephrotoxicity when NSAIDs are given with
tacrolimus.
Zidovudine:
Increased risk of haematological toxicity when NSAIDs are given with
zidovudine. There is evidence of an increased risk of haemarthroses and
haematoma in HIV(+) haemophiliacs receiving concurrent treatment with
zidovudine and ibuprofen.
Aminoglycosides:
NSAIDs may decrease the excretion of aminoglycosides.
Herbal extracts:
Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.
CYP2C9 Inhibitors:
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.
4.6

Pregnancy and lactation
Pregnancy
Inhibition of prostaglandin synthesis may adversely affect the pregnancy
and/or 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. In
animals, the 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 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 or 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 the following:


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



Renal dysfunction, which may progress to renal failure with
oligohydramnios.

At the end of pregnancy, prostaglandin synthesis inhibitors may expose the
mother and the neonate to the following:



Possible prolongation of bleeding time, an anti-aggregating effect
which may occur even at very low doses.
Inhibition of uterine contractions, which may result in delayed or
prolonged labour.

Consequently, Ibuprofen is contraindicated during the third trimester of
pregnancy.
Lactation
In the limited studies so far available, ibuprofen appears in the breast milk in
very low concentrations and is unlikely to adversely affect the breast-fed infant.
NSAIDs should, if possible, be avoided when breastfeeding.
See section 4.4 Special warnings and precautions for use, 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
Gastro-intestinal:
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 stomatitis and gastrointestinal haemorrhage
exacerbation of colitis and Crohn's disease (see section 4.4) have been reported
following administration. Less frequently, gastritis, duodenal ulcer, gastric ulcer,
and gastrointestinal perforation have been observed. Pancreatitis has also been
reported very rarely.
Immune system disorders: Hypersensitivity reactions have been reported
following treatment with NSAIDs. These may consist 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, pruritis, urticaria,
purpura, angioedema and, more rarely, exfoliative and bullous dermatoses

(including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema
multiforme).
Cardiac disorders and vascular disorders: Oedema, hypertension and cardiac
failure have been reported in association with NSAID treatment. Clinical trial
and epidemiological data suggest that use of ibuprofen, particularly at high 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).
Other adverse events reported less commonly and for which causality has not
necessarily been established include:
Blood and lymphatic system disorders: Leukopenia, thrombocytopenia,
neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia
Psychiatric disorders: Insomnia, anxiety, depression, confusional state,
hallucination
Nervous system disorders: Optic neuritis, headache, paraesthesia, dizziness,
Somnolence
Infections and infestations: Rhinitis and aseptic meningitis (especially in
patients with existing autoimmune disorders, such as systemic lupus
erythematosus and mixed connective tissue disease) with symptoms of stiff
neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).
Eye disorders: Visual impairment and toxic optic neuropathy
Ear and labyrinth disorders: Hearing impaired, tinnitus and vertigo
Hepatobiliary disorders: Abnormal liver function, hepatitis and jaundice.
Skin and subcutaneous tissue disorders: Bullous reactions, including StevensJohnson syndrome and toxic epidermal necrolysis (very rare), and
photosensitivity reaction.
Renal and urinary disorders: Impaired renal failure and Nephrotoxicity in
various forms, including interstitial nephritis, nephrotic syndrome and renal
failure.
General disorders and administration site conditions: Malaise, fatigue.
4.9

Overdose
Toxicity
Signs and symptoms of toxicity have generally not been observed at doses
below 100 mg/kg in children or adults. However, supportive care may be
needed in some cases.

In children ingestion of more than 400 mg/kg may cause symptoms. In adults
the dose response effect is less clear cut. The half-life in overdose is 1.5-3
hours.
Symptoms:
Most patients who have ingested clinically important amounts of NSAIDs will
develop symptoms within 4 to 6 hours. The most frequently reported
symptoms of overdose include nausea, vomiting, abdominal pain, lethargy and
drowsiness. Central nervous system (CNS) effects include headache, tinnitus,
dizziness, convulsion, and loss of consciousness. Nystagmus, metabolic
acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea,
diarrhoea and depression of the CNS and respiratory system have also been
rarely reported. Disorientation, excitation, fainting and cardiovascular toxicity,
including hypotension, bradycardia and tachycardia have been reported. In
cases of significant overdose, renal failure and liver damage are possible.
Prothrombin time/INR may also be prolonged, probably due to interference
with the actions of circulating clotting factors. Large overdoses are generally
well tolerated when no other drugs are being taken. 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
The active ingredient is a non-steroidal anti-inflammatory agent with analgesic and
anti-pyretic activity. The analgesic activity of ibuprofen is thought to be due to
inhibition of prostaglandin synthesis.
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 hours before or within 30 minutes after
immediate release aspirin dosing (81 mg), a decreased effect of aspirin on the
formation of thromboxane or platelet aggregation occurred. However, the limitations
of these data and the uncertainties regarding extrapolation of ex vivo data to the
clinical situation imply that no firm conclusions can be made for regular ibuprofen
use, and no clinically relevant effect is considered to be likely for occasional
ibuprofen use.

5.2.

Pharmacokinetic Properties
Ibuprofen is well absorbed (>80%) from the gastro-intestinal tract. Peak
plasma levels occur 1 or 2 hours after ingestion with a half life of 2
hours (+/- 0.5 hours). It is extensively bound to plasma proteins (>99%).
It is rapidly excreted in the urine mainly as metabolites and their
conjugates.

5.3.

Preclinical Safety Data
Preclinical information has not been included because the safety profile
of ibuprofen has been established after many years of clinical use.
Please refer to section 4.

Pharmaceutical Particulars
6.1.

List of Excipients

The tablet contains Maize Starch Ph. Eur., Pregelatinised Maize Starch Ph. Eur.,
Colloidal Silicon Dioxide USNF, Sodium Starch Glycollate Ph. Eur. and Stearic Acid
BP.
The coating contains opaspray pink (hydroxypropyl methylcellulose (E464), titanium
dioxide (E171), erythrosine (E127)) and Talc Ph. Eur.

6.2.

Incompatibilities
None known.

6.3.

Shelf Life
36 months.

6.4.

Special Precautions for Storage
Store in a dry place at or below 25°C. Protect from light.

6.5.

Nature and Contents of Container

HDPE or polypropylene containers with caps or child resistant closures
in packs of 100, 250, 500 and 1000 tablets.
PVDC coated PVC film with hard temper aluminium foil blister strips in
packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150,
160 and 168 tablets.
Polypropylene container with HDPE child resistant caps in pack sizes of
84 tablets.

6.6.

Instruction for Use/Handling
Not applicable.

7

MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG

8.

MARKETING AUTHORISATION NUMBER
PL 000289/0280

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29.11.1993 / 04.03.2009

10

DATE OF REVISION OF THE TEXT
20/01/2012

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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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