4.1. Therapeutic indications

Brufen Retard is indicated for its analgesic and anti-inflammatory effect in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies.

In the treatment of non-articular rheumatic conditions, Brufen Retard is indicated in the peri-articular conditions such as frozen shoulder (capsulitis), bursitis, tendinitis, tenosynovitis and low back pain; Brufen Retard can also be used in soft-tissue injuries such as sprains and strains.

Brufen Retard is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental and post-operative pain and for symptomatic relief of headache including migraine headache.

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).

Adults and children over 12 years of age: Two tablets taken as a single daily dose, preferably in the early evening well before retiring to bed. The tablets should be swallowed whole with plenty of fluid and not chewed, broken, crushed or sucked on to avoid oral discomfort and throat irritation. In severe or acute conditions, total daily dosage may be increased to three tablets in two divided doses.

Children: Not recommended for children under 12 years.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4).

Elderly: The elderly are at increased risk of serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. If renal or hepatic function is impaired, dosage should be assessed individually.

Renal impairment:

Patients with mild to moderate renal impairment, (see section 4.4 - Special warnings and precautions for use) and patients with severe renal insufficiency (see section 4.3 –

Contraindications).

Hepatic impairment:

For patients with mild to moderate hepatic impairment (see section 4.4 Special warnings and precautions for use) and patients with severe hepatic dysfunction (see section 4.3- Contraindications).

For oral administration. It is recommended that patients with sensitive stomachs take Brufen with food. If taken shortly after eating, the onset of action of Brufen may be delayed. To be taken preferably with or after food.

4.3. Contraindications

Brufen is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

Brufen should not be used in patients who have previously shown hypersensitivity reactions (e.g. asthma, urticaria, angioedema or rhinitis) after taking ibuprofen, aspirin or other NSAIDs.

Brufen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy. Brufen 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).

Brufen should not be given to patients with conditions involving an increased tendency to bleeding.

Brufen is contraindicated in patients with severe heart failure (NYHA Class IV), hepatic failure and renal failure (see section 4.4).

Brufen is contraindicated during the 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 Brufen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding (see section 4.5).

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 analgesic medication. Patients with medication overuse headache should not be treated by increasing the dose of the analgesic. In such cases the use of analgesics should be discontinued.

The concomitant consumption of excessive alcohol with NSAIDs, including ibuprofen, may increase the risk of adverse effects on the gastrointestinal tract, such as GI haemorrhage or the central nervous system possibly due to the additive effect.

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).

Paediatric population

There is a risk of renal impairment in dehydrated children and adolescents.

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 Brufen, 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 and hypersensitivity reactions

Caution is required if Brufen is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since NSAIDs have been reported to precipitate bronchospasm, urticaria or angioedema in such patients.

Cardiac, renal and hepatic impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. The habitual concomitant intake of various similar painkillers further increases this risk. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. For these patients, use the lowest effective dose, for the shortest possible duration and monitor renal function especially in long-term treated patients (see also section 4.3).

Brufen 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 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 such as myocardial infarction or stroke. Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200mg/day) is associated with an increased risk of arterial 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 (2400mg/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 (2400mg/day) are required.

Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

Renal effects

Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration. There is a risk of renal impairment especially in dehydrated children, adolescents and the elderly.

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-dependant reduction in prostaglandin formation and, secondarily, in renal blood flow, which may cause renal failure. 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.

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

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).

Severe cutaneous adverse reactions (SCARs)Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with the use of ibuprofen (see section 4.8). Most of these reactions occurred within the first month. If signs and symptoms suggestive of these reactions appear ibuprofen should be withdrawn immediately and an alternative treatment considered (as appropriate).

In exceptional cases, 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 Ibuprofen in case of varicella.

Haematological effects

Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and 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 Brufen 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 Brufen should be considered.

Masking of symptoms of underlying infections

Brufen retard can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Brufen retard is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In nonhospital settings, the patient should consult a doctor if symptoms persist or worsen.

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 as interactions have been reported in some patients.

Antihypertensives, beta-blockers and diuretics: NSAIDs may reduce the effect of anti-hypertensives, such as ACE inhibitors, angiotensin-II receptor antagonists, 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 cardiac 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: A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of NSAIDs. Limited evidence suggests that coadministration 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 (Acetylsalicylic acid): As with other products containing NSAIDs, concomitant administration of ibuprofen and aspirin 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 aspirin 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 use (see section 5.1).

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding with NSAIDs (see section 4.4).

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, 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.

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. Fertility, 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. The risk is believed to increase with dose and duration of therapy. 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. From the 20th week of pregnancy onward, Brufen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Brufen should not be given unless clearly necessary. If Brufen 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days from gestational week 20 onward. Brufen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to the following:

• Cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension)

• Renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

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

• Possible prolongation of bleeding time

• Inhibition of uterine contractions, which may result in delayed or prolonged labour.

Consequently, Brufen is contraindicated during the third trimester of pregnancy.

Lactation

In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations . 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

Gastrointestinal disorders: 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, gastrointestinal haemorrhage and exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following ibuprofen administration. Less frequently, gastritis, duodenal ulcer, gastric ulcer and gastrointestinal perforation have been observed.

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reaction 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, bullous dermatoses (including Stevens- Johnson syndrome and toxic epidermal necrolysis ).

Cardiac disorders and vascular disorders: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical studies suggest that use of ibuprofen, particularly at high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section 4.4).

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).

Exacerbation of infection-related inflammations coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of Ibuprofen the patient is therefore recommended to go to a doctor without delay.

Skin and subcutaneous tissue disorders: In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also “Infections and infestations”)

The following adverse reactions possibly related to ibuprofen and displayed by MedDRA frequency convention and system organ classification. Frequency groupings are classified according to the subsequent conventions: 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

Frequency

Adverse reaction

Infections and infestations

Uncommon

Rhinitis

Rare

Meningitis aseptic (see section 4.4)

Blood and lymphatic system disorders

Rare

Leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia , haemolytic anaemia

Immune system disorders

Uncommon

Hypersensitivity

Rare

Anaphylactic reaction

Psychiatric disorders

Uncommon

Insomnia, anxiety

Rare

Depression, confusional state

Nervous system disorders

Common

Headache, dizziness

Uncommon

Paraesthesia, somnolence

Rare

Optic neuritis

Eye disorders

Uncommon

Visual impairment

Rare

Toxic optic neuropathy

Ear and labyrinth disorders

Uncommon

Hearing impaired , tinnitus, vertigo

Respiratory, thoracic and mediastinal disorders

Uncommon

Asthma, bronchospasm, dyspnoea

Gastrointestinal disorders

Common

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

Uncommon

Gastritis, duodenal ulcer, gastric ulcer, mouth ulceration, gastrointestinal perforation

Very rare

Pancreatitis

Not known

Exacerbation of Colitis and Crohn´s disease

Hepatobiliary disorders

Uncommon

Hepatitis, jaundice, hepatic function abnormal

Very Rare

Hepatic failure

Skin and subcutaneous tissue disorders

Common

Rash

Uncommon

Urticaria, pruritus, purpura, angioedema, photosensitivity reaction

Very rare

Severe cutaneous adverse reactions (SCARs) (including Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

Not Known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Acute generalised exanthematous pustulosis (AGEP)

Fixed Drug Eruption

Renal and urinary disorders

Uncommon

Nephrotoxity in various forms e.g.Tubulointerstitial nephritis, nephrotic syndrome and renal failure

Not known

Renal tubular acidosis*

General disorders and administration site conditions

Common

Fatigue

Rare

Oedema

Cardiac disorders

Very rare

Cardiac failure, myocardial infarction (also see section 4.4)

Not Known

Kounis Syndrome

Vascular disorders

Very rare

Hypertension

Metabolism and Nutritional Disorders

Not known

Hypokalaemia*

*Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses.

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

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. Children have been observed to manifest signs and symptoms of toxicity after ingestion of 400 mg/kg or greater.

Symptoms

Most patients who have ingested significant amounts of ibuprofen will manifest 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. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. 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. Large overdoses are generally well tolerated when no other drugs are being taken.

Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

Therapeutic measures

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.