Meloxicam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Meloxicam (Meloxicam)

Composition:

Active ingredient: meloxicam (meloxicam);

1 tablet contains 7.5 mg or 15 mg of meloxicam;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

for the 7.5 mg dosage: light yellow, round, biconvex tablets;

for the 15 mg dosage: light yellow, round, biconvex tablets with a score line.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory drugs and anti-rheumatic agents. Oxicams.

ATC code M01A C06.

Pharmacological properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class, possessing anti-inflammatory, analgesic, and antipyretic effects.

Meloxicam has demonstrated high anti-inflammatory activity in standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, a common mechanism of action for all NSAIDs (including meloxicam) is inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption. Meloxicam is well absorbed from the gastrointestinal tract; after oral administration (capsules), the absolute bioavailability of the drug is 90%. Tablets, oral suspension, and capsules have shown bioequivalence.

After single administration, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms (capsules and tablets).

With repeated dosing, steady-state concentrations are achieved by day 3–5. Dosing once daily results in average plasma concentrations with relatively small peak fluctuations: within 0.4–1.0 μg/mL for 7.5 mg and 0.8–2.0 μg/mL for 15 mg, respectively (Cmin and Cmax at steady state, respectively).

Average peak plasma concentrations of meloxicam at steady state are reached 5–6 hours after administration of tablets, capsules, or oral suspension. During continuous treatment for periods exceeding one year, plasma concentrations remain comparable to those observed at steady state at the beginning of therapy. Absorption of oral meloxicam is not altered when taken with food or concomitantly with mineral antacids.

Distribution. Meloxicam is highly bound to plasma proteins, primarily albumin (99%). Meloxicam penetrates into synovial fluid, where its concentration is approximately half that in plasma. The volume of distribution is low, averaging 11 L after intramuscular or intravenous administration, with individual variations within 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 ranging from 11% to 32%.

Biological transformation. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam, pharmacodynamically inactive, have been identified in urine. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in the metabolism process, while the CYP3A4 isoenzyme contributes to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Elimination of meloxicam occurs mainly as metabolites, excreted in equal proportions in urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine. The elimination half-life ranges from 13 to 25 hours after oral, intramuscular, and intravenous administration. Plasma clearance is approximately 7–12 mL/min after a single oral dose, intravenous, or rectal administration.

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

Special patient groups.

Patients with hepatic/renal impairment. Mild to moderate hepatic and renal impairment do not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment had significantly higher total clearance. Reduced plasma protein binding has been observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to increased free meloxicam concentration (see section "Method of administration and dosage" 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 longer compared to young volunteers of both sexes. Average plasma clearance at steady state in elderly patients was slightly lower than in young volunteers (see section "Method of administration and dosage").

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

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

Meloxicam, tablets are indicated for the treatment of adults and children aged over 16 years.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• hypersensitivity to active substances with similar actions, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin. Meloxicam should not be administered to patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking aspirin or other NSAIDs;
• third trimester of pregnancy (see section "Use during pregnancy or lactation");
• children under 16 years of age;
• gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• active or recurrent peptic ulcer/bleeding in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• severe hepatic impairment;
• severe renal impairment without dialysis;
• gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
• severe heart failure;
• treatment of perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interaction.

Risks associated with hyperkalemia.

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

The onset of hyperkalemia may depend on whether associated factors are present. The risk of developing hyperkalemia increases if the aforementioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Combination with other NSAIDs is not recommended (see section "Special precautions for use"), including acetylsalicylic acid at 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 gastrointestinal 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 precautions for use"). 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., prophylactic doses), heparin use requires caution due to an increased risk of bleeding. Careful monitoring of INR (International Normalized Ratio) is necessary if this combination cannot be avoided.

Thrombolytics 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 medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combined therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., beta-blockers). As with the medicinal products mentioned below, a 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 potentiated by NSAIDs due to mediation of renal prostaglandin effects. Renal function should be monitored during treatment. Careful 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 medicinal products.

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

Lithium. Data exist for NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the start 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 (over 15 mg/week) (see section "Special precautions for use"). 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 test parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate administration lasts 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase with NSAID therapy (see information provided above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with creatinine clearance between 45 and 79 mL/min, meloxicam administration should be suspended 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance below 45 mL/min).

For patients with normal renal function (creatinine clearance ≥ 80 mL/min), a 15 mg dose of meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam concurrently with pemetrexed in patients with normal renal function (creatinine clearance ≥ 80 mL/min).

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.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 enzymes (mainly CYP 2C9 and secondarily 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 are potent inhibitors or substrates of CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when combining meloxicam with medicinal products such as oral antidiabetic agents (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 therapeutic effect is inadequate, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

If no improvement is observed after several days, the clinical benefit of treatment should be re-evaluated.

Care should be taken regarding a history of esophagitis, gastritis and/or peptic ulcer to ensure their complete healing before starting meloxicam therapy. Patients treated with meloxicam and those with such history should be regularly monitored for possible recurrence.

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment, with or without previous symptoms or serious gastrointestinal disorders in 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 (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose aspirin or other medicinal products increasing gastrointestinal risks (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 be informed about any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.

Use of meloxicam is not recommended in patients who are concomitantly taking medicinal products that may increase the risk of ulceration or bleeding, such as heparin used as radical therapy or in geriatric practice, anticoagulants such as warfarin, or other non-steroidal anti-inflammatory medicinal products, 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 gastrointestinal disorders in history (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section "Adverse reactions").

Hepatic disorders.

Up to 15% of patients taking NSAIDs (including meloxicam) may experience elevation of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or AST (approximately three times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis and hepatic failure, some with fatal outcome, have been reported.

Patients with symptoms or suspicion of hepatic dysfunction or those with abnormal liver function tests should be evaluated for signs of more severe hepatic failure during meloxicam therapy. If clinical signs and symptoms suggest development of liver disease or if systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), meloxicam should be discontinued.

Cardiovascular disorders.

Careful monitoring is recommended in patients with arterial hypertension and/or history of mild to moderate congestive heart failure, as fluid retention and edema have been observed during NSAID therapy.

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

Data from studies and epidemiological evidence suggest that use of certain NSAIDs (particularly at high doses and during prolonged treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk for meloxicam.

Meloxicam therapy should be initiated only after careful consideration in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease. A similar assessment is required before starting long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

NSAIDs may 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 may have an increased risk.

Skin reactions.

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs 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 involvement), meloxicam treatment should be discontinued. Prompt diagnosis and discontinuation of any drug that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are essential, as early intervention improves prognosis. Meloxicam must not be re-administered at any time in the future if a patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis during its use.

Cases of fixed drug eruption have been reported with meloxicam use.

Meloxicam should not be re-prescribed to patients who have had a history of fixed drug eruption associated with meloxicam.

Potential cross-reactivity may occur with other oxicams.

Anaphylactoid reactions.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known sensitivity to meloxicam. Meloxicam should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have a history of rhinitis with or without nasal polyps, or who have experienced severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Immediate emergency measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and renal function.

As with treatment with most NSAIDs, isolated cases of increased serum transaminases, increased serum bilirubin or other liver function parameters, 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. Meloxicam should be discontinued and follow-up tests performed if such abnormalities are significant or persistent.

Functional renal impairment.

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal impairment due to decreased glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and renal function 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, diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal impairment;
• nephrotic syndrome;
• lupus nephritis;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 on Child-Pugh classification).

In isolated cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal papillary necrosis or nephrotic syndromes.

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 may affect the natriuretic effects of diuretics. Additionally, a reduced antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended in patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of medicinal products 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 required.

Combination with pemetrexed.

In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be withheld for at least 5 days before, on the day of, and 2 days after pemetrexed administration (see section "Interaction with other medicinal products and other forms of interaction").

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 required 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 (see section "Dosage and administration").

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

Meloxicam use may negatively affect fertility and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

The 7.5 mg and 15 mg meloxicam tablets contain lactose (one 7.5 mg meloxicam tablet contains lactose monohydrate equivalent to 38.19 mg anhydrous lactose; one 15 mg meloxicam tablet contains lactose monohydrate equivalent to 76.38 mg anhydrous lactose). Therefore, this medicinal product is not recommended for patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially sodium-free.

Masking of inflammation and fever.

The pharmacological action of meloxicam aimed at reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Corticosteroid therapy.

Meloxicam cannot be considered a substitute for corticosteroids in the treatment of corticosteroid insufficiency.

Hematological effects.

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

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, short-term and reversible. Patients taking meloxicam who may experience adverse effects related to changes in platelet function, such as coagulation disorders, or patients receiving anticoagulants, should be carefully monitored.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of aspirin in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity between aspirin and other NSAIDs, including bronchospasm, meloxicam should not be used in patients sensitive to aspirin and should be used cautiously in patients with asthma.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryofetal 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 cardiac malformations increased from less than 1% to about 1.5%. This risk is considered to increase with increasing dose and duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation losses and embryofetal mortality. Furthermore, in animals receiving a prostaglandin synthesis inhibitor during organogenesis, increased frequency of various developmental abnormalities, including cardiovascular, has been reported.

Use of meloxicam from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after treatment in the second trimester of pregnancy, most of which resolved after discontinuation of treatment. Therefore, meloxicam should not be prescribed during the first and second trimesters unless clearly necessary. If meloxicam is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if exposure to meloxicam occurs for several days starting from the 20th gestational week. Meloxicam should be discontinued if oligohydramnios or ductus arteriosus constriction in the fetus is detected.

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

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios.

Possible risks in late pregnancy for the mother and newborn:

• prolonged 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 meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended in women who are breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, meloxicam is likely to have no effect or only a minor effect on such activities. Nevertheless, patients who experience 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 therapy should be periodically reassessed, especially in patients with osteoarthritis.

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 (see section "Pharmacokinetics").

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg per day (also see section "Method of Administration and Dosage" – "Patients at Increased Risk of Adverse Reactions" and section "Special Warnings and Precautions for Use").

Patients at Increased Risk of Adverse Reactions (see 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 per day.

Renal Impairment (see section "Pharmacokinetics").

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

For patients with end-stage renal failure undergoing dialysis, the dose should not exceed 7.5 mg per day. Dose reduction is not required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min).

Hepatic Impairment (see section "Pharmacokinetics").

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.

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

Children.

Meloxicam tablets 7.5 mg and 15 mg are contraindicated in children under 16 years of age (see section "Contraindications").

Overdose.

Symptoms.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, liver 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.

Treatment.

In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that oral administration of cholestyramine 4 g three times daily accelerates the elimination of meloxicam.

Adverse Reactions

Data from clinical studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during prolonged treatment) may be associated with a small increased risk of thrombotic vascular 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 following 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").

The frequency of adverse reactions listed below is based on reported adverse events recorded in 27 clinical trials with treatment duration of at least 14 days. The information is derived from clinical trials involving 15,197 patients who received oral meloxicam at daily doses of 7.5 or 15 mg in tablet or capsule form for up to one year.

Also included are adverse reactions identified from post-marketing surveillance reports.

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.

Very rare cases of agranulocytosis have been reported (see Specific serious and/or common adverse reactions).

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 disorders: 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 – abnormal liver function tests (e.g., elevated transaminases or bilirubin);
Rare – hepatitis;
Not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon – angioedema, 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 (elevated serum creatinine and/or urea);
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, ovulation delay.

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, joint signs and symptoms.

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 drug use but generally recognized as characteristic of other compounds in the class.

Organic renal damage, potentially leading 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").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

For 7.5 mg dosage: 10 tablets per blister, 2 blisters per pack.

For 15 mg dosage: 10 tablets per blister, 1 or 2 blisters per pack.

Prescription status. Prescription only.

Manufacturer. LLC "FARMEX GROUP".

Manufacturer's address and location of business activity.
100 Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.