Revmalgin solution for injection 10 mg/ml bottle 1.5 ml No. 5

Translation of the instructions can be

Instruction

For medical use of the medicinal product

Revmalgin

(Rheumatol)

Composition:

Active ingredient: meloxicam;

1 tablet contains meloxicam 7.5 mg or 15 mg;

Excipients: sodium citrate, lactose, microcrystalline cellulose, povidone, colloidal anhydrous silica, crospovidone, magnesium stearate.

Dosage form.

Pills.

Main physicochemical properties:

for dosage 7.5 mg: light yellow tablets, round in shape, with a biconvex surface;

for 15 mg dosage: light yellow, round tablets, with a dividing line, with a biconvex surface.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory drugs and antirheumatic drugs.

PBX code M01A C06.

Pharmacological properties.

Pharmacodynamics.

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the enolic acid class, which has anti-inflammatory, analgesic and antipyretic effects. Meloxicam has shown high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, there is a common mechanism of action for all NSAIDs (including meloxicam): inhibition of the biosynthesis of prostaglandins, which are mediators of inflammation.

Pharmacokinetics.

Absorption: Meloxicam is well absorbed from the gastrointestinal tract after oral administration, with an absolute bioavailability of 90%. After a single dose of meloxicam, peak plasma concentrations are reached within 5-6 hours for solid oral dosage forms.

With multiple dosing, steady-state concentrations are reached within 3-5 days. Once-daily dosing results in mean plasma concentrations with relatively small peak fluctuations: in the range of 0.4-1.0 μg/ml for 7.5 mg and 0.8-2.0 μg/ml for 15 mg, respectively (C min and C max at steady state, respectively). Mean plasma concentrations of meloxicam at steady state are reached within 5-6 hours for tablets.

Simultaneous intake of food or use of inorganic antacids does not affect the absorption of the drug.

Distribution. Meloxicam is highly bound to plasma proteins, mainly albumin (99%). Meloxicam penetrates into the synovial fluid, where the concentration is half that in plasma. The volume of distribution is low, averaging 11 l after intramuscular or intravenous administration, and shows individual variations of 7-20%. The volume of distribution after multiple oral doses of meloxicam (7.5 to 15 mg) is 16 l with a coefficient of variation of 11% to 32%.

Biotransformation: Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam have been identified in urine, which are pharmacodynamically inactive. The main metabolite 5'-carboxymeloxicam (60% of the dose) is formed by oxidation of the intermediate metabolite 5'-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of the dose). In vitro studies suggest that CYP 2C9 plays an important role in the metabolism process, while CYP 3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients, possibly responsible for the other two metabolites, contributes to the formation of two other metabolites, which account for 16% and 4% of the administered dose, respectively.

Elimination. Meloxicam is excreted mainly as metabolites in equal parts with urine and feces. Less than 5% of the daily dose is excreted unchanged in the feces, a small amount is excreted in the urine. The half-life varies from 13 to 25 hours after oral, intramuscular and intravenous administration. Plasma clearance is about 7-12 ml / min after a single oral dose, intravenous or rectal administration.

Dose linearity: Meloxicam exhibited linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg after oral and intramuscular administration.

Special groups of patients.

Patients with hepatic/renal insufficiency. Mild to moderate hepatic and renal insufficiency do not significantly affect the pharmacokinetics of meloxicam. In patients with moderate renal insufficiency, total clearance was significantly higher. Reduced binding to plasma proteins was observed in patients with end-stage renal failure. In end-stage renal failure, an increase in the volume of distribution may lead to an increase in the concentration of free meloxicam. The daily dose of 7.5 mg should not be exceeded (see section "Method of administration and dosage").

Elderly patients. In elderly male patients, mean pharmacokinetic parameters were similar to those in young male volunteers. In elderly female patients, AUC values were higher and half-life was longer compared to those in young volunteers of both sexes. Mean steady-state plasma clearance in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indication.

Short-term symptomatic treatment of exacerbation of osteoarthritis.

Contraindication.

Interaction with other drugs and other types of interactions.

Studies regarding interactions have only been conducted with adults.

Risks associated with hyperkalemia.

Some medicinal products or therapeutic groups may contribute to hyperkalaemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, (low molecular weight or unfractionated) heparins, ciclosporin, tacrolimus and trimethoprim.

The onset of hyperkalemia may depend on whether there are associated factors. The risk of developing hyperkalemia increases if the above-mentioned drugs are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid ≥ 3 g/dose. Combination with other NSAIDs is not recommended (see "Special instructions"), including acetylsalicylic acid in doses ≥ 500 mg per dose or ≥ 3 g total daily dose.

Corticosteroids (e.g. glucocorticoids). Concomitant use with corticosteroids requires caution due to an increased risk of bleeding or ulceration in the gastrointestinal tract.

Anticoagulants or heparin. The risk of bleeding is significantly increased due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). The concomitant use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or at therapeutic doses (see section "Special precautions for use").

In other cases (e.g. at prophylactic doses) heparin should be used with caution due to the increased risk of bleeding. Careful monitoring of the INR (international normalized ratio) is necessary if the combination is proven to be unavoidable.

Thrombolytic and antiplatelet drugs: increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors and angiotensin II antagonists. NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), the concomitant use of ACE inhibitors or angiotensin II antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, the combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section 4.4).

Other antihypertensive drugs (e.g. beta-blockers). As with the following drugs, a reduction in the antihypertensive effect of beta-blockers (due to inhibition of prostaglandins with vasodilatory effect) is possible.

Calcineurin inhibitors (e.g. cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be potentiated by NSAIDs due to mediation of the effects of renal prostaglandins. Renal function should be monitored during treatment. Close monitoring of renal function is recommended, especially in elderly patients.

Deferasirox: Concomitant use of meloxicam and deferasirox may increase the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these drugs.

Pharmacokinetic interaction: the effect of meloxicam on the pharmacokinetics of other drugs.

Methotrexate. NSAIDs may reduce the tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high doses of methotrexate (more than 15 mg/week) (see section "Special warnings and precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low doses of methotrexate, in particular in patients with impaired renal function. If combined treatment is necessary, blood tests and renal function should be monitored. Caution should be exercised if NSAIDs and methotrexate are taken for 3 consecutive days, as plasma levels of methotrexate may increase and toxicity may increase. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant treatment with meloxicam, it should be considered that the haematological toxicity of methotrexate may be increased by treatment with NSAIDs (see information above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml/min), meloxicam should be discontinued 5 days before, on the day of, and for 2 days after pemetrexed administration. If the combination of meloxicam and pemetrexed is necessary, patients should be closely monitored, especially for myelosuppression and gastrointestinal adverse reactions. For patients with severe renal impairment (creatinine clearance < 45 ml/min), concomitant use of meloxicam and pemetrexed is NOT recommended. For patients with normal renal function (creatinine clearance ≥ 80 ml/min), doses of 15 mg meloxicam may reduce the elimination of pemetrexed and, therefore, increase the incidence of adverse reactions associated with pemetrexed. Therefore, caution should be exercised when prescribing 15 mg meloxicam with pemetrexed to patients with normal renal function (creatinine clearance ≥ 80 ml/min).

Pharmacokinetic interaction: the effect of other drugs on the pharmacokinetics of meloxicam.

Cholestyramine: Cholestyramine accelerates the elimination of meloxicam due to impaired intrahepatic circulation, so the clearance of meloxicam increases by 50% and the half-life decreases to 13 ± 3 hours. This interaction is clinically significant.

No clinically significant pharmacokinetic interaction was found when co-administered with antacids, cimetidine, and digoxin.

Application features.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section “Method of administration” and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose may be exceeded in case of insufficient therapeutic effect, and additional NSAIDs should not be used, as this may increase toxicity, while the therapeutic benefit has not been proven. The concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam is not suitable for the treatment of patients requiring relief of acute pain.

If there is no improvement after several days, the clinical benefits of treatment should be reassessed.

Attention should be paid to a history of esophagitis, gastritis and/or ulcer in order to ensure that they are completely treated before starting therapy with meloxicam. Regular attention should be paid to the possible manifestation of relapse in patients treated with meloxicam and patients with such cases in history.

Gastrointestinal disorders.

As with other nonsteroidal anti-inflammatory drugs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment with or without previous symptoms or a history of serious gastrointestinal disease.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses in patients with a history of ulcer, especially complicated by bleeding or perforation (see section 4.3), and in elderly patients. These patients should be started on the lowest effective dose. For such patients, it is advisable to consider combination therapy with protective drugs (such as misoprostol or proton pump inhibitors), as well as for patients who require concomitant use of low-dose aspirin or other drugs that increase gastrointestinal risks (see information below and section 4.5).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed of any unusual abdominal symptoms (especially gastrointestinal bleeding), especially during the initial stages of treatment.

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section "Adverse reactions").

Liver disorders.

Up to 15% of patients taking NSAIDs (including meloxicam) may have elevations in one or more liver function tests. These laboratory abnormalities may progress, remain stable, or be transient with continued treatment. Marked elevations in ALT or AST (approximately three or more times the upper limit of normal) have been observed in 1% of patients in clinical trials with NSAIDs. In addition, isolated cases of severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which were fatal, have been reported.

Patients with symptoms of hepatic dysfunction or in whom liver function tests have been abnormal should be evaluated for the development of symptoms of more severe hepatic insufficiency during meloxicam therapy. If clinical signs and symptoms consistent with liver disease develop or if systemic manifestations of the disease occur (e.g. eosinophilia, rash, etc.), meloxicam should be discontinued.

Cardiovascular disorders.

Close observation is recommended in patients with hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAID therapy.

Clinical monitoring of blood pressure is recommended for patients with risk factors at the beginning of therapy, especially at the beginning of treatment with meloxicam.

Research and epidemiological data suggest that the use of some NSAIDs (especially at high doses and in long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g. myocardial infarction or stroke). There are insufficient data to exclude such a risk for meloxicam.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with meloxicam only after careful consideration. Such consideration is necessary before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which may be fatal. The increased risk is related to the duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.

Skin disorders.

Life-threatening severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with meloxicam. Patients should be informed of the signs and symptoms of severe skin reactions and should be closely monitored for skin reactions. The greatest risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis is during the first weeks of treatment. If a patient develops symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g. progressive skin rash, often with blisters or mucosal lesions), meloxicam treatment should be discontinued. It is important to diagnose and discontinue any drugs that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis as soon as possible. This is associated with a better prognosis in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while using meloxicam, the drug should not be restarted at any time in the future.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients with no known history of reaction to meloxicam. Meloxicam should not be used in patients with the aspirin triad. This symptom complex occurs in patients with asthma who have reported rhinitis with or without nasal polyps or who have experienced severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Immediate medical attention should be sought if an anaphylactoid reaction occurs.

Liver parameters and kidney function.

As with most NSAIDs, isolated cases of increased serum transaminases, increased serum bilirubin or other liver function tests, as well as increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. In most cases, these abnormalities were minor and transient. If significant or persistent abnormalities occur, meloxicam should be discontinued and follow-up tests performed.

NSAIDs, by inhibiting the vasodilatory effects of renal prostaglandins, can induce functional renal failure due to a decrease in glomerular filtration. This side effect is dose-dependent. At the beginning of treatment or after increasing the dose, careful monitoring of diuresis and renal function is recommended in patients with the following risk factors:

simultaneous use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section "Interaction with other medicinal products and other types of interactions");

In rare cases, NSAIDs can lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndromes.

The dose of meloxicam for patients with end-stage renal disease on dialysis should not exceed 7.5 mg. In patients with mild to moderate renal impairment (creatinine clearance >25 ml/min), the dose may not be reduced.

Sodium, potassium and water retention.

NSAIDs may increase sodium, potassium and water retention and may interfere with the natriuretic effects of diuretics. In addition, the antihypertensive effect of antihypertensive drugs may be reduced (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure or hypertension may be precipitated or aggravated in susceptible patients. Therefore, clinical monitoring is recommended in patients at risk (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be caused by diabetes mellitus or concomitant use of potassium-sparing medicinal products (see section 4.5). In such cases, potassium levels should be monitored regularly.

Combination with pemetrexed.

In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be suspended 5 days before, on the day of, and for 2 days after pemetrexed administration (see section 4.5).

Other warnings and precautions.

Adverse reactions are often worse tolerated by elderly, frail or debilitated patients who require close supervision. As with other NSAIDs, caution should be exercised in the elderly, who are more likely to have decreased renal, hepatic and cardiac function. Elderly patients have a higher incidence of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.2).

Meloxicam, like any other NSAID, may mask the symptoms of infectious diseases.

Meloxicam may impair reproductive function and is not recommended in women attempting to conceive. Therefore, in women attempting to conceive or undergoing investigation of infertility, discontinuation of meloxicam should be considered (see section "Use during pregnancy and lactation").

REVMALGIN 7.5 mg and 15 mg tablets contain lactose, therefore this drug is not recommended for patients with rare congenital galactose intolerance, lactase deficiency or glucose or galactose malabsorption.

Masking inflammation and fever.

The pharmacological action of meloxicam to reduce fever and inflammation may complicate the diagnosis in suspected non-infectious pain conditions.

Corticosteroid treatment.

REVMALGIN cannot be a likely substitute for corticosteroids in the treatment of glucocorticosteroid insufficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be due to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic, or incompletely described effects on erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit monitored if they develop symptoms of anemia.

NSAIDs inhibit platelet aggregation and may increase bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively smaller, short-lived, and reversible. Patients taking meloxicam who may have adverse effects on platelet function, including coagulation disorders, or patients receiving anticoagulants should be carefully monitored.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which may be fatal. Because of the cross-reactivity between aspirin and other nonsteroidal anti-inflammatory drugs, including bronchospasm, meloxicam should not be used in patients sensitive to aspirin and should be prescribed with caution in patients with pre-existing asthma.

Use during pregnancy or breastfeeding.

Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may have an adverse effect on reproductive function and is not recommended in women attempting to conceive. Therefore, in women planning pregnancy or undergoing investigation of infertility, discontinuation of meloxicam should be considered.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-foetal development. Epidemiological data suggest an increased risk of miscarriage and of cardiac malformations and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations has increased from less than 1% to approximately 1.5%. This risk is believed to increase with increasing dose and duration of treatment.

During the first and second trimesters of pregnancy, meloxicam should not be used unless clearly necessary. If a woman is trying to become pregnant or is using meloxicam during the first and second trimesters of pregnancy, the dosage and duration of treatment should be kept to a minimum.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose a risk to the fetus:

possible risks in the last stages of pregnancy for the mother and newborn:

Therefore, meloxicam is contraindicated in the third trimester of pregnancy.

Breastfeeding.

Although there are no specific data on REVMALGIN, NSAIDs are known to pass into breast milk. Therefore, use is not recommended in breastfeeding women.

The ability to influence the reaction speed when driving vehicles or other mechanisms.

There are no specific studies on the effects of the drug on the ability to drive or use machines. However, based on the pharmacodynamic profile and the adverse reactions observed, it can be assumed that meloxicam is likely to have no or negligible influence on these activities. However, patients who experience visual impairment, including blurred vision, dizziness, drowsiness, vertigo or other central nervous system disorders, are advised to refrain from driving or using other machines.

Method of administration and doses.

Administer orally.

The daily amount of the drug should be taken once, washed down with water or other liquid, during meals.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4). The patient's need for symptomatic relief and response to treatment should be reassessed periodically.

Exacerbation of osteoarthritis:

7.5 mg/day (1 tablet of 7.5 mg or half a tablet of 15 mg). If necessary, the dose can be increased to 15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

Rheumatoid arthritis, ankylosing spondylitis:

15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

See also “Special patient categories” below.

Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day (1 tablet of 7.5 mg or half a tablet of 15 mg).

DO NOT EXCEED THE DOSE OF 15 mg/day.

Special categories of patients.

Elderly patients and patients at increased risk of developing adverse reactions.

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg/day. Patients at increased risk of adverse reactions should start treatment with 7.5 mg/day (see section 4.4).

Kidney failure.

For patients with severe renal insufficiency on dialysis, the dose should not exceed 7.5 mg per day. For patients with mild to moderate renal insufficiency (i.e. patients with creatinine clearance above 25 ml/min), no dose reduction is required (for patients with severe renal insufficiency not on dialysis, see section "Contraindications").

Liver failure.

No dose reduction is required for patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see Contraindications).

Children.

Revmalgin, 7.5 mg and 15 mg tablets, is contraindicated in children under 16 years of age (see the "Contraindications" section).

Overdose.

In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that meloxicam elimination is accelerated by four oral doses of cholestyramine 3 times daily.

Adverse reactions.

Research and epidemiological data suggest that the use of some NSAIDs (especially at high doses and with long-term treatment) is associated with a small increased risk of vascular thrombotic events (e.g. myocardial infarction or stroke) (see section "Special warnings and precautions for use").

Edema, hypertension, and heart failure have been observed with NSAID treatment.

Most of the side effects observed are of gastrointestinal origin. Ulceration, perforation or gastrointestinal bleeding may occur, sometimes fatal, especially in elderly patients (see section "Special warnings and precautions for use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been observed after use (see section "Special warnings and precautions for use"). Gastritis has been observed less frequently.

Severe skin reactions have been reported: Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special warnings and precautions for use"). Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100

From the blood and lymphatic system:

infrequently - anemia;

rarely - deviation of blood test indicators from the norm (including changes in the number of leukocytes), leukopenia, thrombocytopenia.

Very rare cases of agranulocytosis have been reported (see Selected Serious and/or Common Adverse Reactions).

On the part of the immune system:

infrequently - allergic reactions, except anaphylactic and anaphylactoid;

unknown - anaphylactic reaction, anaphylactoid reaction, including shock.

Mental disorders:

rarely - mood swings, nightmares;

unknown - confusion, disorientation, insomnia.

From the nervous system:

often - headache;

infrequently - dizziness, drowsiness.

On the part of the organs of vision:

rarely - visual impairment, including blurred vision, conjunctivitis.

From the side of the organs of hearing and vestibular apparatus:

infrequently - dizziness;

rarely - ringing in the ears.

Cardiac disorders:

rarely - feeling of palpitations.

Heart failure has been reported in association with NSAID treatment.

Vascular disorders:

infrequently - increased blood pressure (see section "Special instructions for use"), hot flashes.

From the respiratory system, chest organs and mediastinum:

rarely - asthma in patients allergic to aspirin and other nonsteroidal anti-inflammatory drugs;

unknown - upper respiratory tract infections, cough.

Gastrointestinal tract:

very often - digestive system disorders: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea;

infrequently - hidden or macroscopic gastrointestinal bleeding, stomatitis, gastritis, belching;

rarely - colitis, gastroduodenal ulcer, esophagitis;

very rarely - gastrointestinal perforation;

unknown - pancreatitis.

Gastrointestinal bleeding, ulceration or perforation may be severe and fatal, especially in elderly patients (see section "Special warnings and precautions for use").

From the hepatobiliary system:

infrequently - impaired liver function (for example, increased transaminases or bilirubin);

very rarely - hepatitis;

unknown - jaundice, liver failure.

Skin and subcutaneous tissue disorders:

infrequently - angioedema, itching, rash;

rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis