Instructions Ibuprofen 400 film-coated tablets 400 mg No. 20
Composition
active ingredient: ibuprofen;
1 tablet contains 200 mg or 400 mg of ibuprofen;
Excipients: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, colloidal anhydrous silica, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide (E 171), talc, macrogol 4000.
Dosage form
Film-coated tablets.
Main physicochemical properties:
200 mg tablets: film-coated tablets, straight solid cylinders, white or almost white in color, with convex end surfaces;
400 mg tablets: film-coated tablets, oblong in shape, white or almost white in color, with convex upper and lower surfaces.
Pharmacotherapeutic group
Drugs affecting the musculoskeletal system. Anti-inflammatory and antirheumatic drugs. Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Ibuprofen.
ATX code M01A E01.
Pharmacological properties
Pharmacodynamics
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which exerts a directed effect against pain, fever and inflammation by inhibiting the synthesis of prostaglandins - mediators of pain and inflammation. In addition, ibuprofen reversibly inhibits platelet aggregation.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when these drugs are used concomitantly. Some pharmacodynamic studies have shown that single doses of ibuprofen 400 mg administered within 8 hours before and within 30 minutes after administration of acetylsalicylic acid/aspirin immediate-release (81 mg) reduced the effect of acetylsalicylic acid/aspirin on thromboxane formation or platelet aggregation. Although there is uncertainty regarding the extrapolation of the data to the clinical situation, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid/aspirin. Such a clinically significant effect is unlikely with non-systematic use of ibuprofen (see section 4.5).
Pharmacokinetics
Absorption
Ibuprofen is rapidly absorbed mainly in the small intestine and binds to plasma proteins. After oral administration of 200–600 mg ibuprofen, maximum plasma concentrations of 15–55 μg/ml (Cmax) are reached on average in 1–2 hours (tmax).
If the drug is taken after meals, the absorption of ibuprofen is much slower and the maximum plasma concentrations will be lower.
After oral administration of a single dose of 400 mg ibuprofen, peak plasma concentrations of 8–13 μg/ml are reached after 6 hours.
Distribution
99% of ibuprofen binds to blood plasma proteins. Binding is reversible.
Metabolism
More than 50–60% of an oral dose of ibuprofen is metabolized in the liver to two inactive metabolites. The metabolism of ibuprofen is similar in children and adults.
Appearance
The plasma half-life is 1½–2 hours. The short half-life means that even after repeated administration of ibuprofen, there is no accumulation. Ibuprofen and its metabolites are almost completely excreted by the kidneys within 24 hours of administration.
No significant differences in the pharmacokinetic profile are observed in elderly patients.
Indication
Symptomatic treatment of mild to moderate pain of various origins (headache, toothache, painful menstruation), including colds and fever.
Contraindication
Hypersensitivity to ibuprofen or to any of the components of the drug.
History of hypersensitivity reactions (e.g. bronchial asthma, rhinitis, angioedema or urticaria) following previous use of ibuprofen, acetylsalicylic acid/aspirin or other NSAIDs.
Gastric and/or duodenal ulcer or gastrointestinal bleeding in active form, or history of recurrence (two or more severe episodes of ulcer or bleeding in the past).
Acute or previous inflammatory bowel diseases (such as Crohn's disease, ulcerative colitis).
History of gastrointestinal bleeding or perforation associated with previous NSAID use.
Increased tendency to bleed.
Severe renal failure (creatinine clearance <30 ml/min).
Severe liver failure (cirrhosis, ascites).
Severe heart failure (class III-IV according to the NYHA (New York Heart Association) classification).
Treatment of postoperative pain after coronary artery bypass grafting (or use of a cardiopulmonary bypass machine).
Last trimester of pregnancy (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other types of interactions
Other NSAIDs, including selective cyclooxygenase-2 inhibitors: the simultaneous use of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect. Therefore, the concomitant use of ibuprofen with other NSAIDs should be avoided (see section "Special warnings and precautions for use");
corticosteroids: increase the risk of ulcers and bleeding in the gastrointestinal tract (see section "Special instructions for use");
alcohol: increases gastrointestinal side effects, increases the risk of gastrointestinal bleeding;
Antihypertensives, β-blockers and diuretics: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs such as ACE inhibitors, angiotensin II antagonists and β-blockers. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the concomitant use of an ACE inhibitor or angiotensin II antagonist and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If long-term treatment is necessary, the patient should be adequately hydrated and the need for monitoring of renal function should be determined at the beginning of the combination treatment and thereafter. Diuretics increase the risk of nephrotoxicity of NSAIDs;
Probenecid and sulfinpyrazone: may delay the excretion of ibuprofen, the uricosuric effect of probenecid and sulfinpyrazone is weakened;
Anticoagulants: NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin (see section "Special warnings and precautions for use");
Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding when used with NSAIDs (see section "Special warnings and precautions for use");
Aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides;
Acetylsalicylic acid/aspirin: should not be used in combination with ibuprofen as this increases the risk of adverse reactions. Experimental data suggest that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when used concomitantly. However, uncertainty regarding the extrapolation of these data to the clinical situation prevents definitive conclusions being drawn that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid/aspirin. Such clinically significant effects are considered unlikely with non-systematic use of ibuprofen (see section 4.4);
Sulfonylureas: The effect of oral antidiabetic agents (sulfonylureas) may be enhanced by ibuprofen and other NSAIDs. Hypoglycemia has been reported rarely in patients receiving ibuprofen in combination with a sulfonylurea. Blood glucose levels should be monitored regularly and the dose of antidiabetic agents adjusted if necessary.
Histamine H2 antagonists: no clinically significant interaction of ibuprofen with cimetidine or ranitidine has been established;
Digoxin: NSAIDs may increase the plasma concentration of digoxin;
Phenytoin: NSAIDs may increase the plasma concentration of phenytoin;
Lithium: NSAIDs may reduce the excretion of lithium;
Methotrexate: NSAIDs may inhibit the tubular secretion of methotrexate and reduce the clearance of methotrexate;
Baclofen: the use of NSAIDs increases the toxicity of baclofen;
Cholestyramine: Concomitant use with cholestyramine may reduce the absorption of ibuprofen from the gastrointestinal tract, but the clinical significance of this is unknown.
cyclosporine: increased risk of nephrotoxicity;
tacrolimus: increased risk of nephrotoxicity;
herbal extracts: ginkgo biloba may potentiate the risk of bleeding associated with NSAIDs;
Mifepristone: a reduction in the efficacy of the medicinal product is theoretically possible due to the antiprostaglandin properties of NSAIDs. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not alter the effect of mifepristone or prostaglandins on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical abortion;
Quinolone antibiotics: Animal studies have shown that quinolone-associated seizures may occur more frequently in association with NSAIDs. Concomitant use with ibuprofen increases the risk of seizures.
Zidovudine: There is an increased risk of haematological toxicity with concomitant use of zidovudine and NSAIDs. There is evidence of an increased risk of haemarthrosis and haematoma in HIV-infected patients with haemophilia when zidovudine and ibuprofen are used concomitantly.
simultaneous use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia (serum potassium testing is recommended);
Cardiac glycosides: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma glycoside levels.
Application features
General warnings
The side effects of ibuprofen can generally be reduced by using the lowest effective dose necessary to treat symptoms for the shortest period of time (see section “Dosage and Administration” and gastrointestinal, cardiovascular risks below).
Long-term use of any painkiller for headache may worsen this condition. If this condition is suspected or confirmed, consult a doctor and discontinue treatment. A diagnosis of medication overuse headache should be considered in patients who suffer from frequent or daily headaches despite (or because of) regular use of headache medications.
For some selective COX-2 inhibitors, an increased risk of thrombotic cardiovascular and cerebrovascular events has been reported in placebo-controlled studies. It is not yet known whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs. As there are currently no comparable clinical trial data for ibuprofen at maximum doses and long-term therapy, a similar increased risk cannot be excluded. Until such data are available, ibuprofen should be used in clinically proven ischemic disease, cerebrovascular disease, peripheral arterial disease or in patients with significant risk factors (e.g. high blood pressure, hyperlipidemia, diabetes mellitus, smoking) only after careful risk-benefit assessment. Also because of this risk, the lowest effective dose for the shortest duration of therapy should be given.
Renal effects of NSAIDs include fluid retention with oedema and/or hypertension. Therefore, ibuprofen should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention. Caution should also be exercised in patients taking diuretics or ACE inhibitors concomitantly, and in patients at increased risk of hypovolaemia.
When NSAIDs are used concomitantly with alcohol, side effects related to the active substance, particularly those affecting the gastrointestinal tract or central nervous system (CNS), may increase.
Masking of symptoms of underlying infections. Ibuprofen may mask the symptoms of an infectious disease, which may delay the initiation of appropriate treatment and thereby complicate the course of the disease. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. If ibuprofen is used for fever or for pain relief in an infection, monitoring for the infectious disease is recommended. In the context of treatment outside a medical institution, the patient should consult a doctor if symptoms persist or worsen.
Respiratory disorders: Ibuprofen should be administered with caution to patients with or a history of bronchial asthma, chronic rhinitis, allergic diseases, as ibuprofen has been reported to cause bronchospasm, urticaria, or angioedema in such patients.
Impaired cardiac, renal, or hepatic function: NSAIDs should be used with caution in patients with impaired renal, hepatic, or cardiac function, as this may lead to deterioration of renal function.
Habitual concomitant use of such painkillers further increases this risk.
Patients with impaired renal, hepatic or cardiac function should use the lowest effective dose for the shortest period of time and renal function should be monitored, especially in the case of long-term treatment (see section "Contraindications").
Other NSAIDs: Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, increases the risk of adverse reactions and should be avoided.
Elderly patients: Elderly patients have an increased incidence of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal.
Gastrointestinal bleeding, ulcers, perforations. NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section "Contraindications").
The risk of gastrointestinal bleeding, perforation, ulceration increases with increasing doses of NSAIDs in patients with a history of ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with minimal doses. Caution should be exercised when treating patients receiving concomitant medications that increase the risk of gastrotoxicity or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), SSRIs or antiplatelet agents such as acetylsalicylic acid/aspirin (see section “Interaction with other medicinal products and other forms of interaction”). With prolonged treatment for these patients, as well as for patients who require concomitant use of low doses of acetylsalicylic acid/aspirin or other drugs that increase the risk for the gastrointestinal tract, the doctor may need to prescribe combination therapy with misoprostol or proton pump inhibitors.
Patients with a history of gastrointestinal disorders, especially elderly patients, should report any unusual gastrointestinal symptoms (predominantly bleeding), especially gastrointestinal bleeding at the beginning of treatment.
In the event of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.
Ibuprofen should only be prescribed under strict indications and under medical supervision for gastrointestinal complaints and liver dysfunction, as their condition may worsen (see "Adverse reactions").
Cardiovascular and cerebrovascular effects: Patients with uncontrolled hypertension and a history of congestive heart failure (NYHA class II) should be cautious when initiating long-term treatment (consultation with a doctor is necessary), as fluid retention, hypertension and oedema have been reported with ibuprofen, as with other NSAIDs.
Clinical trial data suggest that ibuprofen use, particularly at high doses (2400 mg/day), may be associated with an increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen use (e.g. ≤ 1200 mg/day) is associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg/day) should be avoided. The clinical assessment should also be carefully considered before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg/day) are required.
Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with narrowing of the coronary arteries, potentially leading to myocardial infarction.
Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced eosinophilia with systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with ibuprofen (see section 4.8). Most of these reactions occurred within the first month of treatment.
If signs and symptoms suggestive of these reactions occur, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary).
In exceptional cases, chickenpox can cause severe skin and soft tissue infections. At present, it cannot be ruled out that NSAIDs may worsen these infections, and it is therefore recommended that ibuprofen be avoided in cases of chickenpox.
Patients at high risk for this reaction include patients with renal impairment, heart failure, liver dysfunction, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAIDs is usually accompanied by a return to pre-treatment status.
Habitual use of analgesic drugs, especially combinations of several analgesics, may lead to persistent renal impairment with the risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration.
Hematological effects: Ibuprofen may temporarily inhibit platelet function (affect platelet aggregation) and increase bleeding time. Therefore, careful monitoring of patients with coagulation disorders is recommended.
Aseptic meningitis, systemic lupus erythematosus and mixed connective tissue diseases. Ibuprofen should be used with caution in patients with systemic lupus erythematosus and mixed connective tissue diseases due to the increased risk of aseptic meningitis. However, symptoms of aseptic meningitis have also occurred with ibuprofen in patients without any of these chronic diseases.
Effects on female fertility. There is some evidence that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible after discontinuation of treatment. Long-term use (at doses of 2400 mg/day and for treatment durations exceeding 10 days) of ibuprofen may impair female fertility and is not recommended in women attempting to conceive. This medicinal product should not be used in women who have difficulty conceiving or who are undergoing investigation for infertility.
Porphyrin metabolism: Caution should be exercised in patients with congenital disorders of porphyrin metabolism (e.g. acute intermittent porphyria).
Surgery: Caution should be exercised immediately following major surgery.
Other. Severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed very rarely. At the first signs of a hypersensitivity reaction after use of the drug, therapy should be discontinued. In such cases, both symptomatic and specialized therapy should be carried out.
With long-term use of the drug, it is necessary to regularly check liver and kidney function indicators, as well as check the blood picture.
This medicinal product contains lactose monohydrate (one Ibuprofen 400 tablet – 26.37 mg, one Ibuprofen 200 tablet – 13.34 mg). Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.
Use during pregnancy or breastfeeding
Fertility
Ibuprofen may impair female fertility and is not recommended for use in women attempting to conceive. If a woman has difficulty conceiving or is undergoing investigation for infertility, discontinuation of ibuprofen should be considered.
Pregnancy
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo/foetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects and gastroschisis after administration of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is thought to increase with increasing dose and duration of therapy. In animals, the use of prostaglandin synthesis inhibitors has been associated with an increased incidence of pre- and post-implantation loss and embryo/foetal lethality. In addition, an increased incidence of various malformations, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.
First and second trimester. From the 20th week of pregnancy, ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur shortly after initiation of treatment and is usually reversible after discontinuation of treatment. In addition, there have been reports of fetal ductus arteriosus narrowing following treatment in the second trimester of pregnancy, which in most cases resolved after discontinuation of treatment. Therefore, ibuprofen should not be given during the first and second trimester of pregnancy unless clearly necessary.
If ibuprofen is used by a woman attempting to conceive, or during the first and second trimesters of pregnancy, the dose should be kept as low and the duration of treatment as short as possible.
Antenatal monitoring for oligohydramnios and narrowing of the ductus arteriosus may be appropriate if exposure to ibuprofen has occurred for several days starting from the 20th week of gestation. The drug should be discontinued if oligohydramnios or narrowing of the ductus arteriosus is detected.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus, leading to the following risks:
cardiopulmonary toxicity (characterized by premature narrowing/closure of the ductus arteriosus and pulmonary hypertension);
kidney dysfunction, which can lead to low amniotic fluid levels and possible complications such as impaired lung maturation and loss of joint movement (limb contractures) in the newborn baby.
At the end of pregnancy, prostaglandin synthesis inhibitors in the mother and newborn may lead to:
prolongation of bleeding time, antiplatelet effect, which can develop even at very low doses;
suppression of uterine contractions, leading to a delay or increase in the duration of labor.
Childbirth. It is not recommended to take ibuprofen during labor. The onset of labor may be delayed and the duration of labor may be prolonged, along with an increased tendency for bleeding in the mother and baby.
Breastfeeding
In some studies, ibuprofen has been found in breast milk at very low concentrations, so it is unlikely that it would have any adverse effects on a breastfed infant. As a precautionary measure, ibuprofen is not recommended for use by nursing mothers.
Ability to influence reaction speed when driving vehicles or other mechanisms
No relevant studies have been conducted. Taking ibuprofen may affect the reaction speed of patients, which should be borne in mind when engaging in activities that require increased concentration, such as driving or working with other mechanisms. The effect on the reaction speed is significantly increased when combined with alcohol.
After taking NSAIDs, undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible. If such effects occur during the use of NSAIDs, patients should not drive or operate other mechanisms.
Method of administration and doses
For oral use. For short-term use only. Undesirable effects can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms.
The tablets should be taken preferably during or after meals, without chewing and with water.
Adults and children over 12 years of age weighing 40 kg or more should take 1 tablet of 400 mg as a single dose or 2 tablets of 200 mg every 6 hours as needed. The maximum daily dose is 1200 mg ibuprofen. Use the lowest effective dose necessary to treat symptoms for the shortest possible time.
If symptoms of the disease worsen in adolescents or persist for more than 3 days, it is necessary to consult a doctor to clarify the diagnosis and adjust the treatment regimen.
If in adults the elevated body temperature persists for more than 3 days or the pain does not go away within 4 days, or the symptoms of the disease worsen, it is necessary to consult a doctor to clarify the diagnosis and adjust the treatment regimen.
The duration of treatment is determined by the doctor individually, depending on the course of the disease and the patient's condition.
Children aged 6 to 11 years with a body weight of 20 kg to 40 kg: usually use at the rate of 20 to 30 mg/kg of body weight per day in several doses. The recommended initial dose is 1 tablet of 200 mg, repeated dose after 6 hours if necessary. The maximum daily dose for children with a body weight of 20 to 30 kg is 600 mg of ibuprofen (3 tablets of 200 mg); for children with a body weight of 30 to 39 kg is 800 mg of ibuprofen (4 tablets of 200 mg).
Elderly patients do not require special dose adjustment, except in cases of severe renal or hepatic insufficiency. Due to the possibility of developing undesirable effects, elderly patients require careful supervision.
Patients with mild to moderate renal impairment do not require dose reduction (for patients with severe renal impairment, see section "Contraindications").
Patients with mild to moderate hepatic impairment do not require dose reduction (for patients with severe hepatic impairment, see section "Contraindications").
Children
200 mg tablets – do not use in children under 6 years of age and weighing less than 20 kg.
400 mg tablets – do not use in children under 12 years of age and weighing less than 40 kg.
Overdose
Symptoms of toxicity have not usually been observed at doses below 100 mg/kg in children and adults. However, supportive measures may be required in some cases. Administration of the drug to children at a dose of more than 400 mg/kg may cause symptoms of intoxication. In adults, the dose effect is less pronounced. The half-life in overdose is 1.5–3 hours.
The most common symptoms of overdose include nausea, vomiting, abdominal pain, lethargy and drowsiness. Central nervous system (CNS) effects include headache, tinnitus, dizziness, convulsions and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, renal symptoms, gastrointestinal bleeding, coma, apnea and CNS and respiratory depression have been reported rarely. Cardiovascular toxicity has been reported, including hypotension, bradycardia and tachycardia.
In case of significant overdose, renal failure and liver damage may develop. Significant overdose is usually well tolerated if no other drugs are taken. In severe poisonings, metabolic acidosis may occur.
Treatment. There is no specific antidote for ibuprofen overdose. Patients should be treated symptomatically if necessary. If the amount ingested exceeds 400 mg/kg, gastric lavage/emptying is recommended within 1 hour of ingestion, followed by symptomatic treatment. Activated charcoal should be administered within 1 hour of ingestion of a potentially toxic amount and the patient should be observed for at least 4 hours.
Treatment should include maintaining a patent airway and monitoring cardiac function and vital signs until the patient's condition is normalized. Ensure adequate diuresis.
Frequent or prolonged seizures should be treated with intravenous diazepam. Other measures may be indicated according to the patient's clinical condition.
Side effects
The following adverse reactions have been observed with short-term use of ibuprofen at doses not exceeding 1200 mg per day. Additional adverse reactions may occur with long-term use in the treatment of chronic diseases.
Adverse reactions that occurred with ibuprofen are listed by organ system and frequency of occurrence.
The frequency of adverse reactions is defined as follows: 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 frequency unknown (cannot be estimated from the available data).
The most frequently observed adverse reactions with NSAIDs are gastrointestinal in nature and are largely dose-dependent, in particular the risk of gastrointestinal bleeding, which depends on the dose and duration of treatment.
Peptic ulcers, perforations or bleeding, sometimes fatal, especially in elderly patients (see section "Special warnings and precautions for use"), nausea, vomiting, diarrhea, flatulence, constipation, indigestion (dyspepsia), abdominal pain, melena, hematemesis may occur.
Ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following use (see Warnings and Precautions). Gastritis is less common. Gastrointestinal perforation has been reported rarely with ibuprofen.
Exacerbation of skin infections caused by infection (e.g. development of necrotizing fasciitis) has been described with concomitant use of NSAIDs. In exceptional cases, severe skin infections and soft tissue complications may occur during varicella infection. If there are any signs of infection or it worsens during the use of ibuprofen, the patient should immediately consult a doctor.
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 arterial thrombotic complications (such as myocardial infarction or stroke) (see section "Special warnings and precautions for use").
Infections and infestations: uncommon - rhinitis; rare - aseptic meningitis (especially in patients with existing autoimmune disorders such as systemic lupus erythematosus and mixed connective tissue diseases) with symptoms of occipital rigidity, headache, nausea, vomiting, fever or disorientation (see section "Special warnings and precautions for use").
Cases of exacerbation of skin inflammation caused by infection (e.g. development of necrotizing fasciitis) have been described during the use of NSAIDs. If signs of infection appear or worsen during the use of ibuprofen, the patient should immediately consult a doctor.
From the blood and lymphatic system: rarely - aplastic anemia, leukopenia, thrombocytopenia, neutropenia, agranulocytosis, hematopoiesis.
