Meloktam

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

Composition:

Active substance: meloxicam;

1 tablet contains 7.5 mg or 15 mg of meloxicam;

Excipients: lactose monohydrate, povidone, crospovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of light yellow color.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory drugs and antirheumatic 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 properties.

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

Pharmacokinetics.

Absorption. Meloxicam is well absorbed from the gastrointestinal tract following oral administration, with an absolute bioavailability of 90% (capsules). Tablets, oral suspension, and capsules have been shown to be bioequivalent. After single administration, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms (capsules and tablets).

Steady-state concentrations are achieved by day 3–5 with repeated dosing. Once-daily administration provides mean plasma concentrations with relatively small peak-to-trough fluctuations, ranging from 0.4–1.0 μg/mL at a 7.5 mg dose and 0.8–2.0 μg/mL at a 15 mg dose (Cmin and Cmax at steady state, respectively). Mean maximum plasma concentrations of meloxicam at steady state are reached within 5–6 hours after administration of tablets, capsules, or oral suspension. During continuous treatment lasting more than one year, meloxicam plasma concentrations remain comparable to those observed at steady state at the beginning of therapy.

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

Distribution. Meloxicam is highly bound to plasma proteins, primarily albumin (99%). It 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 (7.5–15 mg) is 16 L, with a coefficient of variation ranging from 11% to 32%.

Biological transformation. Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam, all 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 excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in metabolism, while CYP3A4 isoenzymes contribute 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. Meloxicam is eliminated primarily as metabolites in equal proportions via 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, or intravenous administration. Plasma clearance is approximately 7–12 mL/min after single oral, intravenous, or rectal administration.

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

Special patient groups.

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, 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, mean 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 both sexes. 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 flare-ups.

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

The medicinal product Meloctam, tablets, is indicated for the treatment of adults and children aged 16 years and older.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• 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 breastfeeding");
• not to be used in 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;
• not to be used for the 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, low molecular weight or unfractionated heparins, cyclosporine, tacrolimus, and trimethoprim.

The onset of hyperkalemia may depend on associated factors. The risk of developing hyperkalemia increases if the above-mentioned 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 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 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 of heparin use (e.g., at prophylactic doses), caution is required due to an increased risk of bleeding. Careful monitoring of INR (international normalized ratio) is necessary if this 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 medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), 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, combination therapy should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., beta-blockers). Possible reduction in the antihypertensive effect of beta-blockers (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 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 increases 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 from NSAIDs indicate increased 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 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 (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 are taken for three consecutive days, as plasma methotrexate levels may increase and toxicity may be enhanced. 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 withheld for 5 days before pemetrexed administration, on the day of administration, and for 2 days after administration. 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), 15 mg doses 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 concomitantly 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 (CYP) enzymes (mainly CYP 2C9 and secondary 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 clearly 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 in case of insufficient therapeutic effect, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

If no improvement is observed after several days, the clinical benefits of treatment 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. Patients treated with meloxicam, as well as 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 prior symptoms or history of serious gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased NSAID dosage, 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 agents 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, especially elderly patients, should be informed about all unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

The use of meloxicam is not recommended in patients who are concurrently using medicinal products that may increase the risk of ulceration or bleeding, including heparin as radical therapy or in geriatric practice, anticoagulants such as warfarin, or other non-steroidal anti-inflammatory drugs, 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 disorders (ulcerative colitis, Crohn’s disease), as these conditions may worsen (see section "Adverse reactions").

Hepatic disorders.

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

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

Cardiovascular disorders.

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

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

Data from studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and with 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 a 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 initiating 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 disorders.

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about the 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. Early diagnosis and immediate discontinuation of any drug that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are crucial for a better 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-administered to patients with a history of fixed drug eruption associated with meloxicam. Cross-reactivity with other oxicams may occur.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to meloxicam. Meloxicam should not be used in patients with aspirin triad. This symptom 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 measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and kidney function.

As with treatment with most NSAIDs, isolated cases of elevated 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 mild and transient. If significant or persistent abnormalities are confirmed, meloxicam should be discontinued and follow-up tests performed.

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, 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 nephropathy;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

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

The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg. Dose reduction 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. In addition, a reduction in the 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 for 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 interrupted at least 5 days before, on the day of, and for at least 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 poorly tolerated by elderly, frail, or debilitated 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 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 (see section "Use during pregnancy or breastfeeding").

The 7.5 mg and 15 mg meloxicam tablets contain lactose; therefore, this medicinal product 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 meloxicam in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Glucocorticoid therapy.

Meloxicam cannot substitute for glucocorticoids in the treatment of glucocorticoid 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 incompletely described effects 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. Careful monitoring is required in patients taking meloxicam who may have adverse effects on platelet function, including coagulation disorders, or in patients receiving anticoagulants.

Use in patients with asthma.

Patients with asthma may have aspirin-induced asthma. The use of aspirin in patients with aspirin-induced asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, 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 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 cardiac malformations increased from less than 1% to about 1.5%. This risk is considered to increase with higher doses and longer 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 treated with a prostaglandin synthesis inhibitor during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular defects, was observed.

From the 20th week of pregnancy, the use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after discontinuation. Additionally, there are reports of ductus arteriosus constriction after treatment in the second trimester, most of which resolved after discontinuation. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except when strictly necessary. If a woman is trying to conceive or is using meloxicam during the first or second trimester, the dosage and duration of treatment should be as low as possible.

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to meloxicam for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or ductus arteriosus constriction 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);
• impaired renal function (see above);

and possible risks in late pregnancy for the mother and 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 meloxicam are lacking, NSAIDs are known to pass into breast milk. Meloxicam has been detected in the milk of animals. 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 medicinal product on the ability to drive or operate machinery have been conducted. Based on the pharmacodynamic profile and observed adverse reactions, meloxicam is expected to have no effect or a negligible effect on such activities. However, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, should refrain from driving or operating machinery.

Method of Administration and Dosage.

Dosage.

The total daily dose of the medicinal product should be administered as a single dose.

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 periodically evaluated, especially in patients with osteoarthritis.

Osteoarthritis flare-up:

7.5 mg/day (1 tablet of 7.5 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).

Also see 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).

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 per day (also see subsection "Patients at increased risk of adverse reactions" below 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 diseases, treatment should be initiated at a dose of 7.5 mg per day.

Renal impairment.

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

For patients with end-stage renal disease on haemodialysis, the dose should not exceed 7.5 mg per day. 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.

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

Children.

Meloktam, tablets of 7.5 mg and 15 mg, is 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 and are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial 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.

Treatment.

In case of NSAID overdose, symptomatic and supportive measures are recommended for patients. Studies have shown that the elimination of meloxicam can be accelerated by administering 4 g orally of cholestyramine three times daily.

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 slightly increase the 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 exacerbation of colitis and Crohn’s disease have been reported (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 adverse reactions listed below were recorded in 27 clinical trials with treatment duration of at least 14 days. A total of 15,197 patients participated in these trials, receiving 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 during post-marketing use of the drug.

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 – blood test abnormalities (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"), hot flushes.

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 – liver function test abnormalities (e.g., increased transaminases or bilirubin);
Very 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 tests (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, 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, 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 drug use but characteristic of other compounds in 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").

Reporting of Adverse Reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.
Keep out of the reach and sight of children.

Packaging.

For 7.5 mg and 15 mg dosage: 10 tablets per blister, 1, 2 or 3 blisters (10, 20 or 30 tablets) per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Biofarm Sp. z o.o.

Manufacturer's address and place of business.

Ul. Walbrzyska 13, Poznan 60-198, Poland