Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
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 events.
Caution is required in patients with renal, hepatic or cardiac impairment since the use of NSAIDs may result in deterioration of renal function. The habitual concomitant intake of similar painkillers further increases this risk. For patients with renal, hepatic or cardiac impairment, use the lowest effective dose, for the shortest possible duration (see Section 4.3)
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.
The use of Brufen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the potential for additive effects. On prolonged use of any painkillers, headache may occur that must not be treated with increased doses of the medicinal product.
Through concomitant consumption of alcohol, active substance-related undesirable effects, particularly those that concern the gastrointestinal tract or the central nervous system, may be increased on use of NSAIDs.
Elderly patients have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
NSAIDs should be given with care to patients with a history of peptic ulceration and other gastrointestinal disease since their conditions may be exacerbated (see section 4.2).
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 acetylsalicylic acid/aspirin, or other drugs likely to increase gastrointestinal risk (See section 4.5).
The concomitant administration of Brufen and other NSAIDs, including cyclooxygenase-2 (Cox-2) selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding (See section 4.5).
Patients with a history of GI disease, 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, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid/aspirin (See section 4.5).
When GI bleeding or ulceration occurs in patients receiving Brufen, the treatment should be withdrawn.
Caution is required if ibuprofen is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since ibuprofen has been reported to cause bronchospasm, urticaria or angioedema in such patients.
Appropriate monitoring and advice arerequired 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 (for example 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.
Caution should be used when initiating treatment with Brufen 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 Brufen has resulted in renal papillary necrosis and other renal pathological 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 NSAIDs may cause a dose-dependant reduction in prostaglandins 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 who are taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID drug therapy is usually followed by recovery to the pre-treatment state.
As NSAIDs can interfere with platelet function and may prolong bleeding time, Brufen should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.
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. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Brufen should 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 Ibuprofen in case of varicella.
Brufen 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 is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.
Aseptic meningitis has been observed on rare occasions in patients with Brufen therapy. Although it is probably more likely to occur in patients with systematic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease.
Brufen 400mg film-coated tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially sodium free.
It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.
Care should be taken in patients treated with any of the following drugs as interactions have been reported:
| Concomitant use of ibuprofen with: | Possible effects: |
|---|---|
| Other NSAIDs including cyclooxygenase-2 selective inhibitors | Concomitant use with other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the potential for additive effects |
| Cardiac glycosides | NSAIDs may exacerbate heart failure, reduce glomerular filtration rate and increase plasma levels of cardiac glycosides |
| Corticosteroids | Increased risk of gastrointestinal ulceration or bleeding with NSAIDs |
| Anticoagulants | NSAIDs may enhance the effects of anticoagulants, such as warfarin |
| Antiplatelet agents & selective serotonin-reuptake inhibitors (SSRIs), e.g. clopidogrel and ticlopidine | Increased risk of gastrointestinal bleeding with NSAIDs |
| Acetylsalicylic acid/aspirin | As with other products containing NSAIDs, concomitant administration of ibuprofen and acetylsalicylic acid/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 acetylsalicylic acid/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 aspirin (acetylsalicylic acid) cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1) |
| Lithium | NSAIDs may decrease elimination of lithium |
| Anti-hypertensive, 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 |
| Methotrexate | NSAIDs may inhibit the tubular secretion of methotrexate and reduce clearance of methotrexate. |
| Cyclosporine | Increased risk of nephrotoxicity with NSAIDs |
| Tacrolimus | Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus |
| Zidovudine | Increased risk of haematological toxicity with NSAIDs are given with zidovudine. There is evidence of an increased risk of hemarthrosis and hematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen |
| 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. |
| 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. |
| Sulfonylureas | NSAIDs may potentiate the effects of sulfonylurea medications. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen. |
| Cholestyramine | The concomitant administration of ibuprofen and cholesytramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown. |
| Aminoglycosides | NSAIDs may decrease the excretion of aminoglycosides. |
| Herbal extracts | Ginkgo biloba may potentiate the risk of bleeding with NSAIDs. |
| Mifepristone | A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of NSAIDs including acetylsalicylic acid. 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. |
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.
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, ibuprofen 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, 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days from gestational week 20 onward. Ibuprofen 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 mother and the neonate, at the end of pregnancy, to:
Consequently, ibuprofen is contraindicated during the third trimester of pregnancy (see section 4.3 and 5.3).
Administration of ibuprofen is not recommended during labour and delivery. The onset of labour may be delayed and the duration increased with a greater bleeding tendency in both mother and child.
In limited studies to date, ibuprofen appears in breast milk in very low concentrations. Brufen is not recommended for use in nursing mothers.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. Following treatment with ibuprofen, the reaction time of patients may be affected. This should be taken into account where increased vigilance is required e.g. when driving a car or operating machinery. This applies to a greater extent in combination with 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, haematemesis, ulcerative stomatitis, 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.
Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © 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).
Exacerbation of skin 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 the use of ibuprofen, the patient is therefore recommended to go to a doctor without delay.
In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also “Infections and infestations” and section 4.4)
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 (for example myocardial infarction or stroke) (see section 4.4). The following are adverse reactions possibly related to ibuprofen, 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 and haemolytic anaemia |
| Immune system disorders | Uncommon | Hypersensitivity |
| Rare | Anaphylactic reaction | |
| Phychiatric disorders | Uncommon | Insomnia, anxiety |
| Rare | Depression, confusional state | |
| Nervous system disorder | 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, dyspnea |
| Gastrointestinal disorders | Common | Dyspepsia, diarrhoea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, hematemesis, 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 | Common | Rash |
| Uncommon | Urticaria, pruritus, purpura, angioedema, photosensitivity reaction | |
| Very Rare | Severe forms of skin reactions (e.g. Erythema multiforme, bullous reactions including Stevens-Johnson syndrome, and toxic epidermal necrolysis). | |
| Not known | Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Acute generalised exanthematous pustulosis (AGEP) | |
| Renal and urinary disorders | Uncommon | Nephrotoxicity in various forms, e.g. Tubulointerstitial nephritis, nephrotic syndrome and renal failure |
| General disorders and administration site conditions | Common | Fatigue |
| Rare | Edema | |
| Cardiac disorders | Very Rare | Cardiac failure, myocardial infarction (see also section 4.4) |
| Vascular disorders | Very Rare | Hypertension |
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 HPRA Pharmacovigilance. Website: www.hpra.ie
Not applicable.
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