Instructions Moviksikam solution for injection 15 mg/1.5 ml ampoule No. 5
Composition
active ingredient: meloxicam;
1 ampoule (1.5 ml) contains 15 mg of meloxicam;
excipients: meglumine, glycofurol, poloxamer 188, sodium chloride, glycine, sodium hydroxide, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent solution of yellow with a greenish tint, practically free of foreign inclusions.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Oxycodone. ATX code M01A C06.
Pharmacoecological properties
Pharmacodynamics
Movixikam® is a non-steroidal anti-inflammatory drug (NSAID) from the oxicam group of substances with anti-inflammatory, analgesic, and antipyretic properties.
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 principle of action for all NSAIDs (including meloxicam): inhibition of the biosynthesis of prostaglandins, which are mediators of inflammation.
Pharmacokinetics
Absorption. Meloxicam is completely absorbed after intramuscular administration. The relative bioavailability compared to oral administration is almost 100%. Thus, dose adjustment when switching from intramuscular to oral administration is not required. 1 hour after intramuscular administration of 15 mg of meloxicam, its maximum concentration in blood plasma was 1.62 μg/ml.
Distribution. Meloxicam is highly protein bound, mainly to albumin (99%). Meloxicam enters the synovial fluid, where its concentration is half that in blood plasma. The volume of distribution is low, averaging 11 l. Individual variation is approximately 7-20%.
Biotransformation. Meloxicam is metabolized by hepatic enzymes. Four different metabolites of meloxicam, which are pharmacodynamically inactive, have been identified in the urine. The main metabolite 5'-carboxymeloxicam (60%) is formed by oxidation of the intermediate metabolite 5'-hydroxymethylmeloxicam. The amount of unchanged 5'-hydroxymethylmeloxicam excreted is 9%. In vitro studies have shown that CYP 2C9 plays an important role in this metabolic pathway with a minor contribution from the CYP 3A4 isoenzyme. The peroxidase activity is probably related to the formation of two other metabolites, which account for 16% and 4% of the administered dose, respectively.
Excretion: Meloxicam is excreted mainly in the form of 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 mean elimination half-life is approximately 20 hours. Total plasma clearance is on average 8 ml/min.
Dose linearity: Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 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. Patients with moderate renal insufficiency had a significantly higher total clearance. 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 (see sections "Contraindications" and "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 the 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 (see section 4.2).
Indication
Short-term symptomatic treatment of acute attacks of rheumatoid arthritis and ankylosing spondylitis when other routes of administration cannot be used.
Contraindication
III trimester of pregnancy (see section "Use during pregnancy or breastfeeding"); children under 18 years of age; hypersensitivity to meloxicam, to other components of the drug or to active substances with a similar effect, such as NSAIDs, acetylsalicylic acid; meloxicam should not be prescribed to patients who have experienced symptoms of asthma, nasal polyps, angioedema or urticaria after taking acetylsalicylic acid or other NSAIDs; gastrointestinal bleeding or perforation associated with previous NSAID therapy in history; active or recurrent peptic ulcer/bleeding in history (two or more separate confirmed cases of ulceration or bleeding); severe hepatic failure; severe renal failure without dialysis; gastrointestinal bleeding, cerebrovascular bleeding in history or other blood clotting disorders; hemostasis disorders or concomitant use of anticoagulants (contraindications related to the route of administration); severe heart failure; treatment of perioperative pain in coronary artery bypass grafting.
Interaction with other medicinal products and other types of interactions
Risks associated with hyperkalemia
Some medicinal products or therapeutic classes may cause hyperkalaemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, NSAIDs (low molecular weight or unfractionated) heparins, cyclosporine, tacrolimus and trimethoprim.
The onset of hyperkalemia may depend on whether there are associated factors. The risk of hyperkalemia is increased if the above-mentioned drugs are used concomitantly with meloxicam.
Pharmacodynamic interactions.
Other NSAIDs and acetylsalicylic acid ≥ 3 g/dose. Combination with other NSAIDs (see section "Special warnings and precautions for use"), acetylsalicylic acid in doses ≥ 500 mg per dose or ≥ 3 g total daily dose is not recommended.
Corticosteroids (e.g. glucocorticoids): Concomitant use with corticosteroids requires caution due to increased risk of gastrointestinal bleeding or ulceration.
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 instructions"). The simultaneous use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or in therapeutic doses (see section "Special instructions"). Intramuscular administration of meloxicam solution for injection is contraindicated in patients receiving anticoagulant treatment (see sections "Contraindications" and "Special instructions").
In other cases of heparin use (e.g., in prophylactic doses), caution is required due to the increased risk of bleeding.
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. β-blockers). As with the following drugs, a reduction in the antihypertensive effect of β-blockers may occur (due to inhibition of vasodilatory prostaglandins).
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be potentiated by NSAIDs through 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, including patients with impaired renal function. If combined treatment is necessary, blood tests and renal function should be monitored. Caution should be exercised when 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 hematological toxicity of methotrexate may be increased by treatment with NSAIDs (see above) (see section "Adverse reactions").
Pemetrexed. When meloxicam is co-administered with pemetrexed in patients with creatinine clearance between 45 and 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, particularly for myelosuppression and gastrointestinal adverse reactions. In patients with severe renal impairment (creatinine clearance below 45 ml/min), the co-administration of meloxicam and pemetrexed is not recommended.
In 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 concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥80 ml/min).
Pharmacokinetic interaction: the effect of other drugs on the pharmacokinetics of meloxicam.
Cholestyramine accelerates the elimination of meloxicam by disrupting 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.
Pharmacokinetic interaction: effect of the combination of meloxicam and other drugs on pharmacokinetics.
Oral antidiabetic agents (sulfonylureas, nateglinide). Meloxicam is almost completely eliminated by hepatic metabolism, approximately two-thirds of which is mediated by cytochrome (CYP) P450 enzymes (primary CYP 2C9 and minor CYP 3A4) and one-third by other pathways, such as peroxidase oxidation. The possibility of pharmacokinetic interactions should be considered when meloxicam is co-administered with medicinal products that are known to inhibit or are metabolised by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 can be expected in combination with medicinal products such as oral antidiabetic agents (sulfonylureas, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients taking meloxicam and sulfonylureas or nateglinide should be closely monitored for the development of hypoglycemia.
Children
Interaction studies were conducted only in adults.
Application features
Adverse reactions can be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section “Dosage and Administration” and information on gastrointestinal and cardiovascular risks below).
The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, nor should additional NSAIDs 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 used to treat patients who require relief of acute pain.
If there is no improvement after several days, the clinical benefit of treatment should be reassessed.
Attention should be paid to a history of esophagitis, gastritis and/or peptic 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 in patients with a history of such cases.
Gastrointestinal disorders
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses in patients with a history of ulcer, particularly complicated by bleeding or perforation (see section 4.3), and in elderly patients. In such patients, treatment should be started at the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered. This also applies to patients who require concomitant low-dose acetylsalicylic acid or other medicinal products 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.
The use of meloxicam is not recommended in patients taking concomitant medications that may increase the risk of ulceration or bleeding, including heparin, as a radical therapy or in geriatric practice, anticoagulants such as warfarin, or other NSAIDs, including acetylsalicylic acid at doses ≥500 mg per dose or ≥3 g total daily dose (see section "Interaction with other medicinal products and other forms of interaction").
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
In patients taking NSAIDs (including meloxicam), one or more liver function tests may be elevated. These laboratory abnormalities may progress, remain stable, or be transient with continued treatment. Elevations of alanine aminotransferase or aspartate aminotransferase (approximately 3 times the upper limit of normal) may occur. Rare 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 abnormal liver function tests should be evaluated for the development of symptoms of more severe hepatic insufficiency during meloxicam therapy. If clinical signs are associated with the development of liver disease or if systemic manifestations of the disease (e.g. eosinophilia, rash) are observed, meloxicam should be discontinued.
Cardiovascular disorders
Close monitoring 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 in 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) is associated with a small increased risk of vascular thrombotic events (e.g. myocardial infarction or stroke). There is 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 are at increased risk of thrombotic events.
Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely with NSAIDs (see section 4.8). The highest risk of such reactions was observed at the beginning of treatment, with the majority of these reactions occurring within the first month of treatment. At the first appearance of signs of severe skin reactions (e.g. skin rash, often progressing to blisters or mucosal lesions) or other symptoms of hypersensitivity, meloxicam should be discontinued. It is important to diagnose skin disorders as soon as possible and to discontinue the use of any drugs that may cause severe skin lesions, as this improves the prognosis for severe skin lesions. If a patient has developed exfoliative dermatitis, Stevens-Johnson syndrome or toxic epidermal necrolysis with meloxicam, its use should not be resumed in the future.
Anaphylactic reactions
As with other NSAIDs, anaphylactic reactions may occur in patients with no known reaction to meloxicam. The drug should not be used in patients with the aspirin triad. This symptom complex is observed in patients with bronchial asthma who have had rhinitis, with or without nasal polyps, or who have experienced severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Emergency measures should be taken if an anaphylactoid reaction occurs.
Liver parameters and kidney function
As with most NSAIDs, isolated cases of increased serum transaminases, serum bilirubin or other liver function parameters, as well as increases in serum creatinine, 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.
Functional renal failure
NSAIDs, by inhibiting the vasodilatory effects of renal prostaglandins, may induce functional renal failure due to decreased glomerular filtration. This adverse effect is dose-dependent. Close monitoring of urine output and renal function is recommended at the beginning of treatment or after dose increases in patients with the following risk factors:
– old age;
– concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section “Interaction with other medicinal products and other types of interactions”);
– hypovolemia (of any origin);
– congestive heart failure;
– renal failure;
– nephrotic syndrome;
– lupus nephropathy;
– severe hepatic dysfunction (serum albumin <25 g/l or ≥10 according to the Child-Pugh classification).
In rare cases, NSAIDs can lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndrome.
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, the dose may not be reduced (creatinine clearance greater than 25 ml/min).
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"). In this regard, edema, heart failure or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended in patients at risk (see sections "Contraindications" and "Method of administration and dosage").
Hyperkalemia
Hyperkalemia may be caused by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, regular monitoring of potassium levels is necessary.
Combination with pemetrexed
In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be suspended for at least 5 days prior to, on the day of, and for at least 2 days following pemetrexed administration (see section 4.5).
Other warnings and precautions
Adverse reactions are often worse tolerated by elderly and debilitated patients who require close monitoring. 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 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 4.6).
Masking inflammation and fever
The pharmacological action of meloxicam to reduce fever and inflammation may complicate the diagnosis of suspected non-infectious pain conditions.
Corticosteroid treatment
Meloxicam cannot be a likely substitute for corticosteroids in the treatment of corticosteroid 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 bleeding, or an incompletely described effect on erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit monitored if there are signs of anemia.
NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. In contrast to acetylsalicylic acid, their effect on platelet function is quantitatively smaller, short-lived and reversible. Patients taking meloxicam who may have adverse effects on platelet function, in particular coagulation disorders, and patients receiving anticoagulants should be carefully monitored.
Use in patients with bronchial asthma
Patients with bronchial asthma may have aspirin-sensitive asthma. The use of acetylsalicylic acid in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which may be fatal. Given the cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, meloxicam should not be used in patients sensitive to acetylsalicylic acid and should be prescribed with caution in patients with bronchial asthma.
Other.
As with other injectable NSAIDs, abscess and necrosis may develop at the injection site.
The drug contains a very small amount of sodium, i.e. it is virtually sodium-free.
Ability to influence 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. Based on the pharmacodynamic profile and the observed adverse reactions, it can be assumed that meloxicam has no or negligible influence on these activities. However, patients who have experienced visual disturbances, including blurred vision, dizziness, drowsiness, vertigo or other central nervous system disorders, are advised to refrain from driving or using machines.
Use during pregnancy or breastfeeding
Fertility: Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may impair reproductive function and is not recommended in women attempting to conceive.
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 thought to increase with increasing dose and duration of treatment.
Meloxicam should not be used during the first and second trimesters of pregnancy unless clearly necessary. If a woman is trying to conceive or is using meloxicam during the first and second trimesters of pregnancy, the dose and duration of treatment should be kept as low as possible.
Meloxicam is contraindicated during the third trimester of pregnancy, as all prostaglandin synthesis inhibitors pose risks to the fetus:
cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligohydramnios.
Risks for the mother (in the last stages of pregnancy) and the newborn:
prolongation of bleeding time, anti-aggregation effect even at very low doses; suppression of uterine contractions, leading to delayed or prolonged labor.
Breastfeeding: Although there are no specific data for meloxicam, NSAIDs are known to pass into breast milk. Therefore, the use of the drug is not recommended in women who are breastfeeding.
Method of administration and doses
Movixikam® should be administered by intramuscular injection.
One injection of 15 mg once daily.
DO NOT EXCEED THE DOSE OF 15 mg per day.
Treatment should be limited to a single injection at the beginning of therapy with a maximum duration of up to 2-3 days in justified exceptional cases (e.g. when oral and rectal routes of administration are not possible). Adverse reactions can be minimized by using the lowest effective dose for the shortest duration of treatment necessary to control symptoms (see section "Special instructions").
Special categories of patients.
The recommended dose for elderly patients is 7.5 mg per day (half a 1.5 ml ampoule).
Patients at increased risk of developing adverse reactions.
Patients at increased risk of adverse reactions, such as those with a history of gastrointestinal disease or risk factors for cardiovascular disease, should start treatment with a dose of 7.5 mg per day (half a 1.5 ml ampoule).
Kidney failure.
This drug is contraindicated in patients with severe renal insufficiency who are not on hemodialysis.
For patients with severe renal insufficiency who are on dialysis, the dose should not exceed 7.5 mg per day (half a 1.5 ml ampoule).
No dose reduction is required in patients with mild to moderate renal impairment (creatinine clearance above 25 ml/min). For patients with severe renal impairment not requiring dialysis, see section 4.3.
Liver failure.
No dose reduction is required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, see section "Contraindications".
Method of application.
For intramuscular use.
The drug should be administered slowly, by deep intramuscular injection into the upper outer quadrant of the buttock, observing strict aseptic technique. In case of repeated administration, it is recommended to change the injection site (alternating between the left and right buttock). Before injection, it is important to check that the needle tip is not in a blood vessel.
The injection should be stopped immediately if severe pain occurs during the injection.
If the patient has a hip prosthesis, the injection should be given in the other buttock.
To continue treatment, oral forms of the drug (tablets) should be used.
Children
The drug is contraindicated in children (under 18 years of age).
Overdose
Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic use of NSAIDs and may also occur with overdose.
In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that meloxicam excretion is accelerated by administration of
4 oral doses of cholestyramine 3 times a day.
Adverse reactions
Research and epidemiological data suggest that the use of some NSAIDs (especially at high doses and with long-term treatment) may be associated with a small increased risk of vascular thrombotic events (such as myocardial infarction or stroke).
Edema, hypertension, and heart failure have been observed with NSAID treatment.
Most of the observed side effects are of gastrointestinal origin. Peptic ulcer, perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur. Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been observed after 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").
Blood system: anemia, blood count abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia. Very rare cases of agranulocytosis have been reported (see Description of selected serious and/or common adverse reactions).
Immune system disorders: allergic reactions, including anaphylactic shock, anaphylactoid reactions, anaphylactic reactions.
On the part of the psyche: mood swings, night terrors, confusion, disorientation, insomnia.
From the nervous system: headache, dizziness, drowsiness.
On the part of the organs of vision: visual function disorders, including blurred vision, conjunctivitis.
On the part of the organs of hearing: vertigo, ringing in the ears.
From the cardiovascular system: palpitations, heart failure, increased blood pressure, hot flashes.
Respiratory system: patients with a history of allergic reactions to acetylsalicylic acid or other NSAIDs may experience asthma attacks; upper respiratory tract infections, cough.
Gastrointestinal: dyspepsia, nausea, vomiting, abdominal pain, diarrhea, occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, constipation, flatulence, belching, colitis, gastroduodenal ulcer, esophagitis, gastrointestinal perforation, pancreatitis. Gastrointestinal bleeding, ulcers or perforation may be severe and potentially fatal, especially in elderly patients.
Skin and subcutaneous tissue disorders: pruritus, rash, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, bullous dermatitis, erythema multiforme, photosensitivity, exfoliative dermatitis.
Urinary system: sodium and water retention, hyperkalemia
