Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Accord Healthcare Limited, Sage House, 319 Pinner Road, North Harrow, Middlesex HA1 4HF, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active gastric or duodenal ulcer or a history of recurrent gastrointestinal ulcer/bleeding (two or more clear episodes of demonstrable ulceration or bleeding).
Severe hepatic failure.
Severe heart failure (NYHA Class IV) or coronary heart disease.
Severe renal failure (glomerular filtration below 30 mL/min).
Conditions involving an increased tendency to bleeding.
Gastrointestinal bleeding or perforation in connection with previous treatment with NSAIDs.
The third trimester of pregnancy (see section 4.6).
Because of cross-reactions, ibuprofen should not be given to patients who have developed hypersensitivity reactions, including symptoms of asthma, rhinitis or urticaria after taking acetylsalicylic acid or other NSAIDs.
In patients with cerebrovascular or other acute bleeding.
Hematologic diseases (e.g. hemorrhagic diathesis, hematopoetic disorder).
In patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake).
Colitis ulcerosa.
The 600 mg tablets are contraindicated in children aged less than 12 years.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal and cardiovascular effects below).
As with other NSAIDs, ibuprofen may mask the signs of infection.
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.
Ibuprofen tablets contain lactose monohydrate and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
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.
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate heart failure as fluid retention and oedema have been reported in association with NSAID therapy. NSAIDs might decrease the effect of diuretics and other antihypertensive agents (see section 4.5).
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 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 (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.
There is a strong link between the dose and severe gastrointestinal bleeding. The concomitant administration of ibuprofen and other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors should be avoided.
Elderly patients are at greater risk of experiencing undesirable effects when treated with an NSAID, especially gastrointestinal bleeding and perforation, which may be fatal.
Potentially fatal gastrointestinal bleeding, ulceration and perforation have been reported in connection with treatment with all types of NSAID and have occurred at any time during treatment, with or without warning symptoms or previous episodes of severe gastrointestinal events.
The risk of gastrointestinal bleeding, ulceration or perforation is higher at increased doses of NSAIDs in patients with a history of ulcer, especially if complicated with bleeding or perforation (see section 4.3), and in the elderly. Patients with the above-mentioned risk factors should commence treatment at the lowest possible dose.
Treatment with mucosa-protective drugs (e.g. misoprostol or proton pump inhibitors) should be considered for these patients as well as for patients on low doses of a acetylsalicylic acid or other drugs that may increase the risk of undesirable gastrointestinal effects (see below and section 4.5).
Patients with a history of gastrointestinal reactions, particularly elderly patients, should be told to watch out for any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly at the start of the treatment and, if such symptoms occur, to seek medical help.
Caution should be exercised in patients receiving concomitant medication which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or antiplatelet drugs such as acetylsalicylic acid (see section 4.5).
Treatment with ibuprofen should be withdrawn if the patient suffers from gastrointestinal bleeding or ulceration.
NSAIDs should be given with care to patients with a history of gastrointestinal disease, e.g. ulcerative colitis and Crohn’s disease, as these conditions may be exacerbated (see section 4.8).
Caution should be exercised with regard to dehydrated patients. There is a risk of renal impairment in dehydrated children and adolescents.
As with other NSAIDs, the long-term administration of ibuprofen has resulted in papillary necrosis and other pathological changes in the kidney. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of normal renal perfusion. In these patients the administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may cause kidney failure. Those who are at greatest risk of this are patients with renal impairment, heart failure, hepatic dysfunction, the elderly and patients on diuretics or ACE inhibitors. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
Ibuprofen can cause fluid and sodium and potassium retention in patients who have never suffered from renal disorders due to its effects on renal perfusion. This can cause oedema or heart failure or hypertension in predisposed subjects.
In general, regular use of analgesics, especially combinations of various analgesic agents, has the potential to cause permanent renal damage including the risk of renal failure (analgesics nephropathy).
Ibuprofen can inhibit platelet aggregation, resulting in prolongation of bleeding time. Hence, careful monitoring of patients with coagulation disorders or taking anticoagulants is recommended.
Caution is required if ibuprofen is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic disease since ibuprofen have been reported to cause bronchospasm, urticaria or angioedema in such patients.
Severe skin reactions, some with a fatal outcome, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in connection with the use of NSAIDs (see section 4.8). The risk of such reactions occurring is greatest at the start of the treatment, the majority of cases occurring during the first month. Treatment with ibuprofen should be withdrawn at the first signs of skin rash, mucosal lesions or other signs of hypersensitivity and if visual disorders or persistent signs of hepatic dysfunction appear.
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).
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.
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.
Analgesics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) can cause potentially serious hypersensitivity reactions, including anaphylactic reactions, even in subjects with no previous exposure to this type of drug. The risk of hypersensitivity after ibuprofen intake appears to be higher in patients who have previously exhibited hypersensitivity to other analgesic agents, antipyretics, NSAIDs and in patients with bronchial hyper-responsiveness (asthma), hay fever, nasal polyps or chronic obstructive pulmonary disease or previous episodes of angioedema (see sections 4.3 and 4.8). The allergic reactions may present as asthma attacks (so-called analgesic asthma), Quincke’s oedema or hives.
Severe hypersensitivity reactions (e.g. anaphylactic shock) have been rarely reported. The treatment with ibuprofen should be immediately withdrawn at the first sign of hypersensitivity reaction.
In patients with renal, cardiac, or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration of renal function. This risk is further increased in patients taking combinations of different analgesic agents regularly. The lowest effective dose for the shortest period of time and periodic monitoring of clinical and laboratory parameters, especially in case of prolonged treatment, is recommended in patients with renal, cardiac, or hepatic impairment (see section 4.3).
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.
Patients with gastrointestinal problems, SLE, haematological or coagulation disorders and asthma should be treated with care and be closely monitored during NSAID treatment, since their condition may be exacerbated by the NSAID.
The dicumarol group: NSAIDs may increase the effect of anticoagulants such as warfarin Experimental studies show that ibuprofen reinforces the effects of warfarin on bleeding time. NSAIDs and the dicumarol group are metabolised by the same enzyme, CYP2C9.
Anti-platelet agent: NSAIDs should not be combined with antiplatelet agents such as ticlopidine due to the additive inhibition of the platelet function (see below).
Methotrexate: NSAIDs inhibit the tubular secretion of methotrexate and some metabolic interaction with reduced clearance of methotrexate may also occur as a result. Accordingly, in high-dose treatment with methotrexate one should always avoid prescribing NSAIDs (see below).
Acetylsalicylic acid: 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).
Cardiac glycosides: NSAIDs can exacerbate heart failure, reduce glomerular filtration and increase plasma cardiac glycoside (e.g. digoxin) levels.
Mifepristone: A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid. 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 medical termination of pregnancy
Sulfonylureas: NSAIDs may potentiate the effects of sulfonylurea medications. There are rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen.
Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Antihypertensives: NSAIDs can reduce the effect of diuretics and other antihypertensive agents.
Aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides.
Children: Care should be taken during concomitant treatment with ibuprofen and aminoglycosides.
Lithium: Ibuprofen reduces the renal clearance of lithium, as a result of which serum lithium levels may rise. The combination should be avoided unless frequent checks of serum lithium can be carried out and a possible reduction in the dose of lithium made.
ACE inhibitors and angiotensin-II antagonists: There is an increased risk of acute renal failure, usually reversible, in patients with renal impairment (e.g. dehydrated and/or elderly patients) when treatment with ACE inhibitors or angiotensin-II antagonists is given at the same time as NSAIDs, including selective cyclooxygenase-2 inhibitors. The combination should, therefore, be given with care to patients with renal impairment, especially elderly patients. Patients should be adequately hydrated and a check of renal function should be considered after the initiation of combination treatment and at regular intervals during treatment (see section 4.4).
Beta-blockers: NSAIDs counteract the antihypertensive effect of beta-adrenoceptor blocking drugs.
Selective serotonin re-uptake inhibitors (SSRIs): SSRIs and NSAIDs each entail an increased risk of bleeding, e.g. from the gastrointestinal tract. This risk is increased by combination therapy. The mechanism may possibly be linked to reduced uptake of serotonin in the platelets (see section 4.4).
Cyclosporine: The concomitant administration of NSAIDs and cyclosporine is thought to be capable of increasing the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney. Accordingly, in the event of combination treatment, renal function must be monitored closely.
Captopril: Experimental studies indicate that ibuprofen counteracts the effect of captopril on sodium excretion.
Colestyramine: The concomitant administration of ibuprofen and colestyramine retards and reduces (by 25%) the absorption of ibuprofen. These drugs should be given at an interval of at least 2 hours.
Thiazides, thiazide-related preparations and loop diuretics: NSAIDs can counteract the diuretic effect of furosemide and bumetanide, possibly through inhibition of prostaglandin synthesis. They can also counteract the antihypertensive effect of thiazides.
Tacrolimus: Concomitant administration of NSAIDs and tacrolimus is thought to be capable of increasing the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney. Accordingly, in the event of combination treatment, renal function should be monitored closely.
Methotrexate: The risk of a potential interaction between an NSAID and methotrexate should also be taken into account in connection with low-dose treatment with methotrexate, especially in patients with renal impairment. Whenever combination treatment is given, renal function should be monitored. Caution should be exercised if both an NSAID and methotrexate are given within 24 hours, as the plasma levels of methotrexate can increase, resulting in increased toxicity (see above).
Corticosteroids: Concomitant treatment gives rise to an increased risk of gastrointestinal ulceration or bleeding.
Antiplatelet drugs: Increased risk of gastrointestinal bleeding (see above).
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.
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).
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.
Ritonavir: It is a possible increase in the concentration of NSAIDs.
Probenecid: It slows the excretion of NSAIDs, with possible increase of their plasma concentrations.
Pemetrexed: An interaction with pemetrexed as there is an increased risk of its toxicity by decreased renal clearance. In patients with an impaired renal function displaying a creatinine clearance between 45-80 ml/min, this combination is to be avoided. In patients with normal renal function, a precaution for use is sufficient based on laboratory tests of the renal function.
Interaction studies have only been performed on adults.
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 gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of 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 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, has also been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimesters of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive or during the first and second trimester, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester, 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 last trimester of pregnancy.
Ibuprofen is excreted in breast milk, but with therapeutic doses during short term treatment the risk for influence on infant seems unlikely. If, however, longer treatment is prescribed, early weaning should be considered.
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 investigation of infertility, withdrawal of ibuprofen should be considered.
Following treatment with ibuprofen, the reaction time of certain patients may be affected. This should be taken into account where increased vigilance is required. Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
The undesirable effects are mainly associated with the pharmacological effect of ibuprofen on prostaglandin synthesis. The most common effects are dyspepsia and diarrhoea, which are estimated to occur in about 10–30% of treated patients.
Adverse events at least possibly related to ibuprofen are displayed by MedDRA frequency convention and system organ class database. The following frequency groupings are used: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10000 to <1/1000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data).
Uncommon: Rhinitis
Rare: Aseptic meningitis
Uncommon: Leukopenia, thrombocytopenia, agranulocytosis, neutropenia, aplastic anaemia and haemolytic anaemia
Rare: Anaphylactic reaction
Uncommon: Insomnia, anxiety
Rare: Depression, confusional state
Common: Headache, dizziness
Uncommon: Paraesthesia, somnolence
Rare: Optic neuritis
Uncommon: Visual impairment
Rare: Toxic optic neuropathy
Uncommon: Hearing impaired
Rare: Tinnitus, vertigo
Uncommon: Asthma, bronchospasm, dyspnoea
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
Uncommon: Hepatitis, jaundice, abnormal hepatic function
Rare: Liver injury
Very rare: Hepatic failure
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)
Uncommon: Nephrotoxity in various forms e.g. tubulointerstitial nephritis, nephrotic syndrome and renal failure
Common: Fatigue
Rare: Oedema
Not known: Cardiac failure, myocardial infarction (also see section 4.4)
Not known: Hypertension
Cardiac disorders and vascular disorders: Oedema, hypertension and heart failure have been reported in association with NSAID treatment. 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 (see section 4.4).
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).
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 © 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).
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 (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 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”).
Ibuprofen can cause prolongation of bleeding time through reversible inhibition of platelet aggregation.
Deterioration of ulcerative colitis and Crohn’s disease have been reported in connection with NSAID treatment.
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, Website: www.mhra.gov.uk/yellowcard.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
