Melbek®

INSTRUCTIONS for medical use of the medicinal product MELBEK®

Composition:

Active substance: meloxicam;

1 tablet contains 7.5 mg or 15 mg of meloxicam;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

7.5 mg tablets: round, light-yellow tablets with a single notch on one side;

15 mg tablets: round, light-yellow tablets with a cross-shaped notch on one side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic drugs. Oxicams. ATC code M01A C06.

Pharmacological Properties

Pharmacodynamics

Meloxicam belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs) known as oxicams and is a selective COX-2 inhibitor with an enolic acid structure. It exerts anti-inflammatory, analgesic, and antipyretic effects. The mechanism of action is based on its ability to inhibit the biosynthesis of prostaglandins, which are mediators of inflammation, through selective inhibition of COX-2.

The mechanism of action is related to selective inhibition of COX-2 compared to COX-1. The therapeutic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with inhibition of COX-2 synthesis, whereas inhibition of COX-1 leads to gastrointestinal and renal toxicity. Compared to non-selective COX inhibitors, meloxicam less frequently causes adverse reactions affecting the gastrointestinal tract and kidneys. Meloxicam does not affect platelet aggregation or bleeding time.

Pharmacokinetics

Absorption

Meloxicam is well absorbed from the gastrointestinal tract, regardless of food intake. The bioavailability of the drug is 89%. Steady-state plasma concentrations are reached by day 3–5 of treatment. Long-term administration (over 6 months) does not lead to an increase in plasma concentration compared to initial levels at the start of therapy.

Distribution

Approximately 99% of the drug is bound to plasma proteins. Meloxicam penetrates into the synovial fluid, where its concentration is about half that in plasma. The volume of distribution averages 11 L.

Metabolism

Biological transformation occurs in the liver via oxidation of methyl groups, resulting in the formation of four inactive metabolites.

Elimination

Excretion of meloxicam occurs predominantly in the form of metabolites. Less than 5% of the daily dose is excreted unchanged in feces, and a small amount is excreted in urine. The elimination half-life of the drug is 20 hours.

Plasma clearance is 8 mL/min and is reduced in elderly individuals.

Dose Linearity
Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg following both oral and intramuscular administration.

Special Patient Populations

Patients with hepatic/renal impairment
Mild to moderate hepatic or renal impairment does not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment showed significantly higher total clearance. Reduced plasma protein binding has been observed in patients with end-stage renal disease. In end-stage renal disease, an increased volume of distribution may lead to higher concentrations of free meloxicam (see sections "Dosage and Administration" and "Contraindications").

Elderly patients
In elderly male patients, average pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of either sex. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis.

Contraindications.

• Hypersensitivity to meloxicam or any of the excipients, or to active substances with similar action, such as NSAIDs, acetylsalicylic acid. Meloxicam should not be administered to patients who have experienced asthma, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
• Third trimester of pregnancy;
• Patient age under 16 years;
• Gastrointestinal bleeding or perforation associated with previous NSAID therapy, in medical history;
• Active or recurrent peptic ulcer/hemorrhage in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• Severe hepatic insufficiency;
• Severe renal insufficiency without dialysis;
• Gastrointestinal bleeding, cerebrovascular hemorrhage in medical history, or other coagulation disorders;
• Severe heart failure;
• Contraindicated for the treatment of perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid ≥ 3 g/dose. Combination with other NSAIDs, including acetylsalicylic acid in anti-inflammatory doses (≥ 1 g – single 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 used in geriatric practice or at therapeutic doses. Significantly increases the risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may potentiate the effects of anticoagulants such as warfarin. Concomitant use of NSAIDs with anticoagulants or heparin in geriatric practice or at therapeutic doses is not recommended.

In other cases of heparin use, caution is required due to increased risk of bleeding. Careful monitoring of INR (International Normalized Ratio) is necessary if such combination cannot be avoided.

Thrombolytic and antiplatelet agents: 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 efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (such as dehydrated patients or elderly patients with compromised renal function), concomitant administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

Other antihypertensive agents (e.g., beta-blockers). As with the medicinal products listed below, a possible reduction in the antihypertensive effect of beta-blockers may occur (due to inhibition of vasodilatory prostaglandins).

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

Intrauterine contraceptive devices. Reduced efficacy of intrauterine contraceptive devices has been reported with NSAID use, but this requires further confirmation.

Pharmacokinetic interaction: effect of meloxicam on the pharmacokinetics of other medicinal products.

Lithium. Data from NSAIDs indicate increased plasma lithium concentrations (due to reduced renal lithium excretion) reaching toxic levels. Concomitant use of lithium and NSAIDs is not recommended. If combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (more than 15 mg per week). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If combination therapy is required, blood parameters and renal function should be monitored. Caution should be exercised if NSAID and methotrexate are taken consecutively for 3 days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg weekly) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase with NSAID therapy (see information above).

Pharmacokinetic interaction: effect of other medicinal products on the pharmacokinetics of meloxicam.

Cholestyramine. Cholestyramine accelerates the elimination of meloxicam due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13 ± 3 hours. This interaction is clinically significant.

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide).

Meloxicam is almost entirely metabolized in the liver, approximately two-thirds via cytochrome P450 (CYP) enzymes (mainly CYP 2C9 and secondary pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when combined with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interaction was observed with concomitant administration of antacids, cimetidine, or digoxin.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Adverse reactions can be minimized 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 if the therapeutic effect is inadequate, and additional NSAIDs should not be used concomitantly, as this may increase toxicity without proven therapeutic benefit. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam is not indicated for the relief of acute pain.

In the absence of improvement after several days of treatment, the clinical benefits of therapy should be re-evaluated.

Particular attention should be paid to a history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. Close monitoring for possible recurrence should be maintained in patients previously treated with meloxicam and in those with such history.

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during therapy, regardless of the presence of prior symptoms or serious gastrointestinal disease history.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risks, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered (see information below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment.

Caution should be exercised in patients receiving concomitant medications that increase the risk of ulceration or bleeding, including heparin, either as radical therapy or in geriatric practice, anticoagulants such as warfarin, or other nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g – single dose or ≥ 3 g – total daily dose).

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 disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated.

Hepatic disorders.

Up to 15% of patients receiving NSAIDs (including Melbek®) may experience elevated levels of one or more liver function tests. These abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately 3 times or more above normal) have been observed in 1% of patients during NSAID studies. Rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, hepatic necrosis, and hepatic failure, some with fatal outcomes, have also been reported.

If hepatic dysfunction is suspected or liver test abnormalities are observed, the patient should be evaluated for signs of more severe hepatic failure during treatment. If symptoms suggestive of hepatic disease develop or systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), Melbek® should be discontinued.

Cardiovascular disorders.

Careful 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 observed during NSAID therapy.

Patients with risk factors should be monitored for blood pressure at the start of therapy, particularly at the beginning of meloxicam treatment.

Available data suggest that the use of some NSAIDs (especially at high doses and during long-term treatment) slightly increases the risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There are insufficient data to exclude such risk with meloxicam use.

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. A similar assessment is necessary before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).

NSAIDs increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. The risk increases with duration of use. Patients with cardiovascular disease or cardiovascular risk factors have an increased risk.

Skin disorders.

Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been observed rarely during NSAID use. The highest risk of such reactions occurs early in treatment, with most cases appearing within the first month of therapy. Meloxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

Cases of fixed drug eruption have been reported with meloxicam use. Meloxicam should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam. Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to Melbek®. Melbek® should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with bronchial asthma who have experienced rhinitis with or without nasal polyps, or who have experienced severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Immediate measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and renal function.

As with treatment with most NSAIDs, isolated cases of elevated serum transaminases, elevated serum bilirubin, or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, have been reported. In most cases, these abnormalities were mild and transient. Meloxicam should be discontinued and follow-up tests performed in cases of significant or persistent abnormalities.

Functional renal impairment.

By inhibiting the vasodilatory effect of renal prostaglandins, NSAIDs may induce functional renal failure due to decreased glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of renal function, including urine output, is recommended at the beginning of treatment or after dose increase in patients with the following risk factors:

• advanced age;
• concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, or diuretics;
• hypovolemia (of any origin);
• congestive heart failure;
• renal impairment;
• nephrotic syndrome;
• lupus nephritis;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

In rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal papillary necrosis, or nephrotic syndrome.

The dose of meloxicam in patients with end-stage renal impairment on dialysis should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 25 mL/min).

Sodium, potassium, and water retention.

NSAIDs may enhance sodium, potassium, and water retention and affect the natriuretic effects of diuretics. Additionally, a reduction in the antihypertensive effect of antihypertensive drugs may occur. As a result, edema, heart failure, or hypertension may worsen in susceptible patients. Therefore, clinical monitoring is recommended in patients with such risks.

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of drugs that increase potassium levels. In such cases, regular monitoring of potassium levels is required.

Other warnings and safety measures.

Adverse reactions are often less well tolerated in elderly, debilitated, or weakened patients, who require careful monitoring. As with other NSAIDs, caution is advised in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

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

The use of meloxicam may negatively affect reproductive function and is not recommended for women wishing to become pregnant. Therefore, discontinuation of meloxicam should be considered for women planning pregnancy or undergoing infertility evaluation.

The formulation contains lactose; therefore, this medicine is not recommended for patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Masking of inflammation and fever.

The pharmacological action of the drug in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Glucocorticoid therapy.

Melbek® cannot be a substitute for glucocorticoids in the treatment of glucocorticoid insufficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including Melbek®. This may be related to fluid retention, gastrointestinal bleeding of unknown origin, or microscopic or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit should be monitored in patients undergoing long-term NSAID therapy, including meloxicam, if symptoms of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively less, short-term, and reversible. Patients taking Melbek® who may have adverse effects on platelet function, including coagulation disorders, and those 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 is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, Melbek® should not be used in patients sensitive to aspirin and should be used cautiously in patients with bronchial asthma.

Use during pregnancy or breastfeeding.

Fertility. Meloxicam, like other drugs inhibiting cyclooxygenase/prostaglandin synthesis, may negatively affect reproductive function and is not recommended for women wishing to become pregnant. Therefore, discontinuation of meloxicam should be considered for women planning pregnancy or undergoing infertility evaluation.

Pregnancy. Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic and fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of heart defects increased from less than 1% to about 1.5%. This risk is believed to increase with increasing dose and duration of treatment.

From the 20th week of pregnancy, the use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after the start of treatment and is usually reversible after discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, most of which resolved after discontinuation. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except when strictly necessary. For women attempting to conceive and during the first and second trimesters of pregnancy, doses and duration of meloxicam treatment should be kept as low as possible.

Monitoring for oligohydramnios and arterial duct constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. Meloxicam treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors pose risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above);

Risks for the mother in late pregnancy and for the newborn:

• potential prolongation of bleeding time, anti-aggregatory effect even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

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

Breastfeeding. Although specific data on the drug are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended for women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No specific studies on the effect of the medicinal product on the ability to drive a vehicle or operate machinery have been conducted. Based on the pharmacodynamic profile and observed adverse reactions, it can be assumed that meloxicam does not affect or has a negligible effect on such activities. However, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, are advised to refrain from driving or operating machinery.

Method of Administration and Dosage.

Dosing.

The total daily dose of the medicinal product should be taken once daily.

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

Osteoarthritis flare-up:

7.5 mg/day (1 tablet of 7.5 mg or half a tablet of 15 mg). If necessary, the dose may 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 section "Special Patient Populations" below.

Depending on the therapeutic effect, the dose may 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 Patient Populations.

Elderly patients.

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg daily (also see subsection "Patients with Increased Risk of Adverse Reactions" below and section "Special Warnings and Precautions for Use").

Patients with increased risk of adverse reactions (see also section "Special Warnings and Precautions for Use").

For patients at increased risk of adverse reactions, e.g., those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg daily.

Renal impairment.

This medicinal product is contraindicated in patients with severe renal impairment who are not on hemodialysis (see section "Contraindications").

For patients with end-stage renal disease on hemodialysis, the dose should not exceed 7.5 mg daily. Dose adjustment is not required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min).

Hepatic impairment.

Dose adjustment is not required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section "Contraindications").

Method of administration.

For oral use.

Melbek®, 7.5 mg and 15 mg tablets, should be taken with water or another liquid during meals.

Children.

Contraindicated in children under 16 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 care. Gastrointestinal bleeding may occur. Severe poisoning may lead to hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that elimination of meloxicam is enhanced by administration of 4 oral doses of cholestyramine given 3 times daily.

Adverse Reactions

Data from clinical studies and epidemiological evidence suggest that the use of certain NSAIDs (especially at high doses and during prolonged 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, arterial hypertension, and heart failure have been observed during NSAID therapy. Most of the adverse effects observed are gastrointestinal in origin. Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease have been reported after administration (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently. Serious 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 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Uncommon – anemia;
Rare – abnormalities in blood test parameters (including changes in leukocyte count), leukopenia, thrombocytopenia.

Rare cases of agranulocytosis have been reported (see "Specific serious and/or common adverse reactions" below).

Immune system disorders:

Uncommon – allergic reactions, excluding anaphylactic or anaphylactoid reactions;
Not known – anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders:

Rare – mood changes, nightmares;
Not known – confusion, disorientation, insomnia.

Nervous system disorders:

Common – headache;
Uncommon – dizziness, somnolence.

Eye disorders:

Rare – visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders:

Uncommon – dizziness;
Rare – tinnitus.

Cardiac disorders:

Rare – palpitations.

Heart failure associated with NSAID treatment has been reported.

Vascular disorders:

Uncommon – increased blood pressure (see section "Special Warnings and Precautions for Use"), flushing.

Respiratory, thoracic and mediastinal disorders:

Rare – asthma in patients with aspirin or other NSAID allergy;
Not known – upper respiratory tract infections, cough.

Gastrointestinal disorders:

Very common – gastrointestinal disturbances: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea;
Uncommon – occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, eructation;
Rare – colitis, gastroduodenal ulcer, esophagitis;
Very rare – gastrointestinal perforation;
Not known – pancreatitis.

Gastrointestinal bleeding, ulceration, or perforation may be severe and potentially fatal, particularly in elderly patients (see section "Special Warnings and Precautions for Use").

Hepatobiliary disorders:

Uncommon – abnormalities in liver function tests (e.g., elevated transaminases or bilirubin);
Very rare – hepatitis;
Not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon – angioneurotic edema, pruritus, rash;
Rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria;
Very rare – bullous dermatitis, erythema multiforme;
Not known – photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), changes in renal function parameters (increased serum creatinine and/or urea);
Very rare – acute renal failure, particularly in patients with risk factors (see section "Special Warnings and Precautions for Use");
Not known – urinary tract infections, disturbances in micturition frequency.

Reproductive system and breast disorders:

Not known – female infertility, delayed ovulation.

General disorders and administration site conditions:

Uncommon – edema, including peripheral edema;
Not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders:

Not known – arthralgia, back pain, signs and symptoms related to joints.

Specific serious and/or common adverse reactions.

Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adverse reactions not observed during use of the medicinal product but typical for other compounds of the class.

Organic kidney damage, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special Warnings and Precautions for Use").

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

15 mg tablets: 4 tablets per blister. 1 blister per cardboard package.

10 tablets per blister. 1 or 3 blisters per cardboard package.

7.5 mg tablets: 10 tablets per blister. 1 or 3 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Address of manufacturer and location of business.

Sankaklar Quarter, Eskisehir Yolu 8. km, No: 299, 81100 Duzce, Turkey.