Pharmacology: Pharmacodynamics: Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and anti-pyretic activity. The drug's therapeutic effects are thought to result from its inhibitory effect on the enzyme cyclooxygenase, which results in a marked reduction in prostaglandin synthesis.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400 mg were taken within 8 h before or within 30 min after immediate release aspirin dosing (81 mg), a decreased effect of acetylsalicylic acid/aspirin on the formation of thromboxane or platelet aggregation occurred. 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/aspirin cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see Interactions).
Pharmacokinetics: Ibuprofen is rapidly absorbed from the gastrointestinal tract, peak serum concentrations occurring one to two hours after administration. The elimination half-life is approximately two hours.
Ibuprofen is metabolized in the liver to two inactive metabolites and the kidney excretes these, together with unchanged ibuprofen, either as such or as conjugates. Excretion by the kidney is both rapid and complete.
Ibuprofen is extensively bound to plasma proteins.
Brufen is indicated for its anti-inflammatory and analgesic effect in the treatment of rheumatoid arthritis, osteoarthritis and allied conditions, non-articular rheumatism and soft tissue injuries. Brufen is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental pain, post-operative pain and in the relief of migraine headache. Its antipyretic activity is effective in reducing fever.
Adults and adolescents older than 12 years (≥ 40kg):
The recommended initial dosage is 1200mg - 1800mg daily in divided doses. Some patients can be maintained on 600 - 1200mg daily. Generally, the maximum daily dose of Brufen should not exceed 2400mg in divided doses.
The dose is 20-40 mg/kg of bodyweight in divided doses according to the severity of the disease.
This can be achieved by using the 20mg/ml suspension as follows: (See Table 1.)
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In juvenile rheumatoid arthritis, up to 40mg/kg body weight per day in divided doses may be taken. Not recommended for children weighing less than 7kg.
No special dosage modifications are required for elderly patients unless renal or hepatic function is impaired, in which case the dosage should be assessed individually.
Method of administration:
In order to achieve a faster onset of action, the dose may be taken on an empty stomach. It is recommended that patients with sensitive stomachs take ibuprofen with food.
Ensure the bottle is thoroughly shaken before use. A transient sensation of burning in the mouth or throat may occur with Brufen suspension.
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, apnea and depression of the CNS and respiratory system have also been rarely reported. Cardiovascular toxicity, including hypotension, bradycardia and tachycardia, has 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. In serious poisoning metabolic acidosis may occur.
Treatment: There is no specific antidote for ibuprofen overdose. Gastric emptying followed by supportive measures is recommended if the quantity ingested exceeds 400 mg/kg within the previous hour. For the most current information, contact the local poison control center.
Known hypersensitivity to the active substance or to any of the inactive ingredients.
Ibuprofen should not be given to patients who have experienced asthma, urticaria or allergic type reactions after taking acetylsalicylic acid/aspirin or other NSAIDs.
Severe heart failure (NYHA IV).
Severe liver failure.
Severe renal failure (glomerular filtration below 30 mL/min).
Conditions involving an increased tendency or active bleeding.
History of gastrointestinal bleeding or perforation, related to previous NSAID therapy.
Active, or a history of, ulcerative colitis, Crohn's disease, recurrent peptic ulceration or gastrointestinal hemorrhage (defined as two or more distinct episodes of proven ulceration or bleeding).
During the third trimester of pregnancy.
General Precautions: Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see Dosage & Administration and Gastrointestinal and cardiovascular risks as follows).
As with other NSAIDs, ibuprofen may mask the signs of infection.
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.
Information Related to Excipients: Brufen suspension contains sucrose and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. This should also be taken into account in patients with diabetes mellitus. May be harmful to the teeth. Brufen suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. May cause allergic reactions (possibly delayed). Brufen suspension contains sunset yellow (E110). May cause allergic reactions.
Gastrointestinal Bleeding, Ulceration and Perforation: 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 Contraindications).
Gastrointestinal bleeding, ulceration or perforation has been reported with all NSAIDs at any time during treatment. These adverse events can be fatal and may occur with or without warning symptoms or a previous history of serious gastrointestinal events.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing ibuprofen doses in patients with a history of ulcers, particularly if complicated with hemorrhage or perforation, 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, as well as patients requiring concomitant low dose acetylsalicylic acid/aspirin, or for other drugs likely to increase gastrointestinal risk (see Interactions).
The concomitant administration of ibuprofen and other NSAIDs, including cyclooxygenase-2 (Cox-2) selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding (see Interactions).
Patients with a history of gastrointestinal disease, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) in the initial stages of treatment.
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/aspirin (see Interactions).
If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Respiratory Disorders: 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.
Cardiac, Renal and Hepatic Impairment: 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 various painkillers further increases this risk. For patients with renal, hepatic or cardiac impairment, use the lowest effective dose, for the shortest possible duration and monitor renal function especially in long-term treated patients (see Contraindications).
Cardiovascular and Cerebrovascular Effects: Ibuprofen should be given with care to patients with a history of heart failure or hypertension since edema has been reported in association with ibuprofen administration.
Non-selective NSAIDs may be associated with a small increase in the absolute risk of cardiovascular events (e.g. myocardial infarction and stroke), especially when used at high doses for long-term treatment.
Clinical studies suggest that use of ibuprofen, particularly at a high dose (2,400 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. ≤1,200 mg/day) is associated with an increased risk of arterial thrombotic events, particularly myocardial infarction. All NSAIDs should be prescribed at the lowest effective dose and the duration of treatment should be periodically reviewed and kept as short as possible.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic 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, hyperlipidemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400mg/day) are required.
All NSAIDs should not be used perioperatively in patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures.
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. Patients appear to be at highest risk of these reactions early in the course of therapy. In the majority of cases, the onset of the reaction occurs within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs 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.
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 NSAIDs may cause a dose dependent 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 NSAIDs therapy is usually followed by recovery to the pretreatment state.
Hematological Effects: Ibuprofen, like other NSAIDs, can inhibit 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.
Effects on ability to drive and to 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. This applies to a greater extent in combination with alcohol.
Use in the Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.
Pregnancy: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/fetal 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/fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
During the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first or second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to the following: Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension).
Renal dysfunction, which may progress to renal failure with oligohydramnios.
At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to the following: Possible prolongation of bleeding time.
Inhibition of uterine contractions, which may result in delayed or prolonged labor.
Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.
Labor and Delivery: Administration of ibuprofen is not recommended during labor and delivery.
The onset of labor may be delayed and the duration increased with a greater bleeding tendency in both mother and child.
Breast-feeding: In the limited studies so far available, ibuprofen appears in the breast milk in very low concentrations. Ibuprofen is not recommended for use in nursing mothers.
Female Fertility: The use of ibuprofen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of ibuprofen should be considered.
The pattern of adverse events reported for ibuprofen is similar to that for other NSAIDs.
The most commonly observed adverse events are gastrointestinal in nature. Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, gastrointestinal hemorrhage and exacerbation of colitis and Crohn's disease (see Contraindications) have been reported following ibuprofen administration. Less frequently, gastritis, duodenal ulcer and gastric ulcer, and gastrointestinal perforation have been observed.
A transient sensation of burning in the mouth or throat may occur with Brufen suspension or granules.
Immune system disorders:
Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of non-specific allergic reaction and anaphylaxis, respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnea, 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:
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 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 as follows).
Cardiac and vascular disorders:
Clinical studies suggest that use of ibuprofen (particularly at a high dose of 2400mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke, see Precautions).
The following adverse reactions possibly related to ibuprofen ad 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). (See Table 2.)
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Care should be taken in patients treated with any of the following drugs as interactions have been reported in some patients: Anti-hypertensives, 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.
Lithium: NSAIDs may decrease elimination of lithium.
Methotrexate: NSAIDs may inhibit the tubular secretion of methotrexate and reduce clearance of methotrexate.
Anti-coagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) (e.g. clopidogrel and ticlopidine): Increased risk of gastrointestinal bleeding with NSAIDs.
Aminoglycosides: NSAIDs may decrease the excretion of aminoglycosides.
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 acetylsalicylic acid cannot be excluded.No clinically relevant effect is considered to be likely for occasional ibuprofen use (see Pharmacology: Pharmacodynamics under Actions).
Cardiac Glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate 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.
Cyclosporine: Increased risk of nephrotoxicity with NSAIDs.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding with NSAIDs.
Cox-2 Inhibitors and other NSAIDs: Concomitant use with other NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive effects (see Precautions).
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. 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.
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 hypoglycemia in patients on sulfonylurea medications receiving ibuprofen.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of hematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of hemarthroses and hematoma in HIV(+) hemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
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.
Do not store above 30°C.
Shelf life: 2 years.
M01AE01 - ibuprofen ; Belongs to the class of propionic acid derivatives of non-steroidal antiinflammatory and antirheumatic products.
Oral susp 20 mg/mL x 60 mL.