Indications
Rheumatoid arthritis, osteoarthritis. Dysmenorrhea without organic cause. Mild to moderate pain. Fever in adults and adolescents.
Children aged 6 to 12 years (weighing more than 20 kg): acute pain and fever associated with the common cold. The indications for children apply only to medicinal products containing ibuprofen 200 mg.
Dosage
Doses
Treatment should be initiated with the lowest dose expected to be effective, which may be subsequently adjusted according to the therapeutic response and the occurrence of any adverse reactions. In long-term treatment, a low maintenance dose should be considered.
Adverse reactions may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Adults and adolescents over 12 years of age (weighing ≥ 40 kg):
Rheumatic diseases
One 400 mg tablet three times a day or a medicine containing 600 mg ibuprofen three times a day. An interval of at least 4-6 hours should be ensured between doses. For a faster improvement in morning stiffness, the first dose can be administered on an empty stomach. The dose should be reduced in case of renal insufficiency. The maximum daily dose is 2400 mg.
Dysmenorrhea
One 400 mg tablet taken once to three times a day, as needed. An interval of at least 4-6 hours should be ensured between doses. Treatment should be initiated at the first sign of menstrual disorders.
Mild to moderate pain: one tablet containing 200 mg ibuprofen or one 400 mg tablet, as a single dose or three to four times a day. An interval of at least 4-6 hours should be allowed between doses. Single doses exceeding 400 mg have been shown to have no additional analgesic effect.
Fever in adults and adolescents
One tablet containing 200 mg ibuprofen or one tablet containing 400 mg once to three times daily, as needed.
Children and adolescents
Children aged 6 to 12 years (weighing more than 20 kg) Acute pain and fever associated with the common cold
One tablet containing 200 mg ibuprofen once to three times daily. An interval of at least 4-6 hours should be allowed between doses.
The use of the film-coated tablet form is not recommended for children under 6 years of age.
Elderly
The elderly are at increased risk of serious adverse reactions. If a non-steroidal anti-inflammatory drug (NSAID) is required, the lowest effective dose should be used for the shortest possible duration. During treatment with an NSAID, the patient should be monitored regularly for gastrointestinal bleeding. If renal or hepatic function is impaired, the dose should be adjusted individually.
Renal impairment
In patients with renal impairment, ibuprofen should be administered with caution. The dose should be adjusted individually. The dose should be kept as low as possible and renal function should be monitored (see sections 4.3, 4.4 and 5.2).
Hepatic impairment
In patients with hepatic impairment, the dose should be administered with caution. The dose should be adjusted individually and kept as low as possible (see sections 4.3, 4.4 and 5.2).
Method of administration
To obtain a more rapid onset of action, the dose may be administered on an empty stomach. It is recommended that patients with stomach disorders take ibuprofen with food. Brufen film-coated tablets should be taken with a glass of water. Brufen tablets should be swallowed whole, without chewing, breaking, crushing or sucking, to avoid discomfort in the oral cavity and irritation in the pharynx.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active gastric or duodenal ulcer or history of recurrent gastrointestinal ulcer/bleeding (two or more distinct episodes of proven ulceration or bleeding).
Severe hepatic impairment.
Severe heart failure (NYHA class IV).
Severe renal impairment (glomerular filtration rate below 30 ml/min). Conditions that cause an increased tendency to bleed.
Gastrointestinal bleeding or perforation related to previous NSAID therapy. Third trimester of pregnancy.
Due to cross-reactions, Brufen should not be administered to patients who have had symptoms of bronchial asthma, rhinitis or urticaria after the use of acetylsalicylic acid or other NSAIDs.
Warnings
General precautions
Adverse reactions can be minimized by administering the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and gastrointestinal and cardiovascular risks presented below).
With prolonged use of any type of analgesic, headache may occur which should not be missed with high doses of this medicine.
The concomitant use of alcohol and NSAIDs may potentiate the adverse reactions of the active substance, especially in the gastrointestinal tract or central nervous system.
There is some evidence that drugs that inhibit cyclooxygenase/prostaglandin synthesis may cause fertility disorders in women through an effect on ovulation. This effect is reversible after discontinuation of treatment.
Cardiovascular effects
In patients with a history of hypertension and/or mild to moderate heart failure, appropriate monitoring and advice are necessary, as reports have shown that treatment with NSAIDs is associated with fluid retention and edema.
Clinical studies suggest that the use of ibuprofen, especially in high doses (2400 mg per day) may be associated with a slightly increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). In general, epidemiological studies do not suggest that a lower dose of ibuprofen (e.g. ≤ 1200 mg per day) is associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), stable angina pectoris, peripheral arterial disease and/or cerebrovascular disease should be treated with ibuprofen only after careful consideration and higher doses (2400 mg per day) should be avoided. Careful consideration should be given before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) especially if high doses of ibuprofen (2400 mg per day) are required.
Caution is advised when treating patients with a history of hypertension and/or heart failure, as fluid retention and oedema have been reported in association with NSAID treatment.
Gastrointestinal bleeding, ulceration and perforation
There is a close relationship between the dose administered and severe gastrointestinal bleeding. Concomitant administration of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.
Elderly patients are at increased risk of adverse reactions when treated with NSAIDs, especially the risk of gastrointestinal bleeding and perforation, which can be fatal.
Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported with all types of NSAIDs and have occurred at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.
The risk of gastrointestinal bleeding, ulceration or perforation is greater with higher doses of NSAIDs, in patients with a history of ulcer, particularly if complicated by haemorrhage or perforation (see section 4.3), and in the elderly. Patients with the above risk factors should start treatment with the lowest possible dose.
In these patients, and also in patients receiving low-dose acetylsalicylic acid or other drugs that may increase the risk of gastrointestinal adverse reactions, combination therapy with gastric protectors (e.g. misoprostol or proton pump inhibitors) should be considered (see below and section 4.5).
Patients with a history of gastrointestinal adverse reactions, particularly the elderly, should be warned to monitor for any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly at the start of treatment, and to seek medical advice if such symptoms occur.
Caution is advised in patients receiving concomitant treatment with medicinal products that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid (see section 4.5).
Treatment with ibuprofen should be discontinued if the patient experiences gastrointestinal bleeding or ulceration.
NSAIDs should be administered with caution to patients with a history of gastrointestinal disease, e.g. ulcerative colitis and Crohn’s disease, as they may exacerbate these conditions (see section 4.8).
Renal effects
Caution should be exercised in dehydrated patients. There is a risk of renal failure, particularly in dehydrated adolescents and the elderly.
As with other NSAIDs, long-term administration of ibuprofen has been associated with renal papillary necrosis and other pathological renal changes.
Renal function plays a compensatory role in maintaining normal renal perfusion. In these patients, NSAIDs may cause, firstly, a dose-dependent reduction in prostaglandin synthesis and, secondly, a decrease in renal blood flow, which may lead to renal failure. From this point of view, the greatest risk is in patients with renal failure, heart failure, liver failure, the elderly and patients taking diuretics or ACE inhibitors. Symptoms are usually reversible after discontinuation of NSAID treatment.
In patients with renal, liver or heart failure, it is recommended to use the lowest effective dose for the shortest possible period and renal function should be monitored, especially in patients on long-term treatment (see section 4.3).
Haematological effects
Ibuprofen may inhibit platelet aggregation, resulting in prolonged bleeding time. Respiratory disorders
Caution should be exercised when ibuprofen is administered to patients with, or a history of, asthma, chronic rhinitis or allergic diseases, as bronchospasm, urticaria or angioedema have been reported in these patients.
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). The greatest risk of these reactions is at the initiation of treatment, with most cases occurring within the first month of treatment. Cases of acute generalised exanthematous pustulosis (AGEP) have been reported in association with ibuprofen-containing medicinal products. Ibuprofen should be discontinued at the first sign of rash, mucosal lesions or other signs of hypersensitivity.
Infections and infestations
In exceptional cases, chickenpox can cause serious skin complications and soft tissue infections.
It cannot be ruled out that NSAIDs may contribute to the aggravation of these complications. Therefore, it is recommended to avoid treatment with Brufen in cases of chickenpox.
Masking of symptoms of pre-existing infections
Brufen may mask the symptoms of an infection, which may lead to a delay in initiating appropriate treatment and, consequently, to aggravation of the effects of the infection. This has been observed in the case of community-acquired pneumonia of bacterial etiology and bacterial complications of chickenpox. When Brufen is administered for fever or to relieve pain associated with an infection, monitoring of the infection is recommended. In the case of administration outside a hospital setting, the patient should seek medical advice if symptoms persist or worsen.
Aseptic meningitis
In rare cases, aseptic meningitis has been observed in patients treated with ibuprofen. Although it is more likely to occur in patients with systemic lupus erythematosus and associated connective tissue diseases, this condition has been reported in patients without underlying chronic disease.
Patients with gastrointestinal disorders, systemic lupus erythematosus, haematological and coagulation disorders and bronchial asthma should be treated with caution and should be closely monitored during treatment with NSAIDs, as pre-existing conditions may be exacerbated by NSAIDs.
Information on excipients
Brufen film-coated tablets contain lactose monohydrate and should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
Interactions
The following combinations with Brufen should be avoided:
Dicumarol class: NSAIDs may increase the effect of anticoagulants such as warfarin. Experimental studies indicate that ibuprofen potentiates the effects of warfarin on bleeding time. NSAIDs and drugs of the dicumarol group are metabolized by the same enzyme, CYP2C9.
Antiplatelet drugs: NSAIDs should not be combined with antiplatelet drugs such as ticlopidine due to the risk of additive effects on platelet function inhibition (see below).
Methotrexate: NSAIDs inhibit the renal tubular secretion of methotrexate and, as a result, some metabolic interactions with decreased methotrexate clearance may also occur. Thus, in the case of treatment with high-dose methotrexate, the prescription of NSAIDs should always be avoided (see below).
Acetylsalicylic acid: Concomitant administration of ibuprofen with acetylsalicylic acid is not recommended due to the increased potential for adverse reactions.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Although there is uncertainty regarding the extrapolation of these data to the clinical situation, it cannot be excluded that regular and long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. No clinically relevant effect is likely to be associated with occasional use of ibuprofen (see section 5.1).
Cardiotonic glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate and increase plasma concentrations of cardiac glycosides (e.g. digoxin).
Mifepristone: Theoretically, a decrease in the efficacy of the drug may occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. Limited evidence suggests that concomitant administration of NSAIDs on the day of prostaglandin administration does not adversely affect the effects of mifepristone or prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of drugs used for termination of pregnancy.
Sulfonylureas: rarely, cases of hypoglycemia have been reported in patients taking ibuprofen concomitantly with sulfonylureas.
Zidovudine: there is evidence of an increased risk of haemarthrosis and haematoma in HIV-positive haemophiliac patients receiving concomitant treatment with zidovudine and ibuprofen.
The following drugs used concomitantly with Brufen may require dose adjustment:
NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. Diuretics may also increase the risk of nephrotoxicity of NSAIDs.
NSAIDs may reduce the elimination of aminoglycosides. Children: Caution is advised during concomitant treatment with ibuprofen and aminoglycosides.
Lithium: ibuprofen reduces the renal clearance of lithium and therefore serum lithium concentrations may increase. The combination should be avoided unless frequent monitoring of serum lithium levels can be performed and a reduction in the lithium dose is possible.
ACE inhibitors and angiotensin II antagonists
There is an increased risk of acute renal failure, usually reversible, in patients with compromised renal function (e.g. dehydrated and/or elderly patients) when ACE inhibitors or angiotensin II antagonists are administered concomitantly with NSAIDs, including cyclooxygenase-2 selective inhibitors. Therefore, concomitant administration should be undertaken with caution in patients with renal impairment, particularly the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant treatment and also at regular intervals during treatment (see section 4.4).
Beta-blockers: NSAIDs antagonize the antihypertensive effect of beta-adrenergic blockers.
Selective serotonin reuptake inhibitors (SSRIs)
Both SSRIs and NSAIDs are associated with an increased risk of bleeding, e.g. from the gastrointestinal tract. This risk is increased with concomitant treatment.
The mechanism may be related to reduced platelet serotonin uptake (see section 4.4).
Ciclosporin: Concomitant administration of NSAIDs with ciclosporin is thought to increase the risk of nephrotoxicity due to decreased renal prostacyclin synthesis. Therefore, renal function should be closely monitored during concomitant treatment.
Captopril: Experimental studies indicate that ibuprofen counteracts the effect of captopril on sodium excretion.
Cholestyramine: Co-administration of ibuprofen with cholestyramine delays and reduces (by 25%) the absorption of ibuprofen. These drugs should be administered at least 2 hours apart.
Thiazides, thiazide-related diuretics and loop diuretics: NSAIDs may counteract the diuretic effect of furosemide and bumetanide, possibly by inhibiting prostaglandin synthesis. They may also counteract the antihypertensive effect of thiazides.
Tacrolimus: Concomitant administration of NSAIDs and tacrolimus is considered to increase the risk of nephrotoxicity due to decreased renal prostacyclin synthesis. Therefore, renal function should be monitored closely during concomitant treatment.
Methotrexate: The risk of a potential interaction between an NSAID and methotrexate should also be considered in the case of treatment with low-dose methotrexate, especially in patients with renal dysfunction. Whenever concomitant treatment is administered, renal function should be monitored.
Corticosteroids: Concomitant treatment is associated with an increased risk of gastrointestinal ulceration or bleeding.
Antiplatelet agents: Increased risk of gastrointestinal bleeding (see above).
CYP2C9 inhibitors: Concomitant use of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increase in the exposure to S(+) ibuprofen- by approximately 80 to 100% was shown. A reduction in the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, especially when high doses of ibuprofen are administered with voriconazole or fluconazole.
Interaction studies with other medicinal products have only been performed in adults.
Pregnancy
Inhibition of prostaglandin synthesis may have a negative influence on pregnancy and/or embryonal/foetal development. Data from epidemiological studies suggest an increased risk of spontaneous abortion and of cardiac malformations and gastroschisis after administration of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is assumed to increase in proportion to the dose and duration of treatment. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in an increase in the number of pre- and post-implantation loss of pregnancies and embryo-foetal lethality. In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals exposed to a prostaglandin synthesis inhibitor during organogenesis. During the first and second trimesters of pregnancy, Brufen should not be used unless clearly necessary. If Brufen is used by a woman attempting to conceive or by a woman in the first and second trimesters of pregnancy, the dose should be as low and the duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with oligohydramnios.
Prostaglandin synthesis inhibitors may expose the mother and the neonate, at the end of pregnancy, to:
prolonged bleeding time;
inhibition of uterine contractions, resulting in delayed or prolonged labour. Brufen is therefore contraindicated in the last trimester of pregnancy.
Breast-feeding
Ibuprofen is excreted in breast milk, but at therapeutic doses during short-term treatment, the risk of harm to the infant seems unlikely. However, if long-term treatment is recommended, permanent cessation of breast-feeding should be considered.
Fertility
The use of ibuprofen may impair fertility and is not recommended in women attempting to conceive. Discontinuation of ibuprofen should be considered in women who have difficulty conceiving or who are undergoing investigation of infertility.
Driving
After treatment with ibuprofen, the reaction time of some patients may be impaired. This should be taken into account when increased alertness is required, for example when driving a vehicle and applies to a greater extent if Brufen is used concomitantly with alcohol. No studies have been performed.
Adverse reactions
The adverse reaction profile reported for ibuprofen is similar to that of other NSAIDs.
Gastrointestinal disorders
The most frequently observed adverse events are gastrointestinal in nature. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, gastrointestinal haemorrhage and exacerbation of colitis and Crohn’s disease have been reported with ibuprofen (see section 4.3). Gastritis, duodenal and gastric ulcers and gastrointestinal perforation have been observed less frequently.
Gastrointestinal ulcers, perforations or bleeding may sometimes be fatal, particularly in the elderly (see section 4.4).
Skin and subcutaneous tissue disorders
Severe infectious complications of the skin and connective tissue have exceptionally occurred in cases of varicella infection. Exacerbation of inflammation caused by infections (e.g. development of necrotising fasciitis) has been described, coinciding with the use of NSAIDs.
Cardiac and vascular disorders
Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg per day), may be associated with a slightly increased risk of cardiovascular events.
In the context of NSAID treatment, oedema, hypertension and heart failure have been observed.
Blood and lymphatic system disorders
Ibuprofen may prolong bleeding time by reversible inhibition of platelet aggregation.
Infections and infestations
In the majority of cases where aseptic meningitis has been reported, there was some underlying autoimmune disease (especially systemic lupus erythematosus and related connective tissue diseases).
Adverse reactions at least possibly associated with ibuprofen administration are presented by system organ class and frequency using the MedDRA convention. The following frequency groups are used: very common (more than or equal to 1/10), common (more than or equal to 1/100 and less than 1/10), uncommon (more than or equal to 1/1000 and less than 1/100), rare (more than or equal to 1/10000 and less than 1/1000), very rare (less than 1/10000) and unknown frequency (which cannot be estimated from the available data).
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