Meloxicam

INSTRUCTION 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 silicon dioxide anhydrous; sodium croscarmellose; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: biconvex, round-shaped, light yellow tablets.

Pharmacotherapeutic group. Anti-inflammatory and antirheumatic agents. Nonsteroidal anti-inflammatory and antirheumatic agents. Enolic acids (oxicams). Meloxicam.

ATC code M01A C06.

Pharmacological Properties

Pharmacodynamics

MELOXICAM is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, exhibiting anti-inflammatory, analgesic, and antipyretic effects.

Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its precise mechanism of action remains unknown. However, a common mechanism applies to 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%. After single-dose administration, maximum plasma concentration (Cmax) is reached within 5–6 hours for solid oral dosage forms.

With repeated administration, steady-state concentrations are achieved by day 3–5. With once-daily dosing, average plasma concentrations (with relatively small peak fluctuations) are: 0.4–1.0 µg/mL for the 7.5 mg dose and 0.8–2.0 µg/mL for the 15 mg dose, respectively (minimum plasma concentration [Cmin] and Cmax at steady state, respectively). Average steady-state plasma concentrations of meloxicam are reached within 5–6 hours. During continuous treatment for periods exceeding one year, plasma concentrations remain comparable to those observed at steady state at the beginning of therapy.

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

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 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 excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays a major role in metabolism, while CYP 3A4 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. Elimination of meloxicam occurs primarily 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 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 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 was 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 sections "Contraindications" and "Dosage and Administration").

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.

Clinical characteristics

Indications

• Short-term symptomatic treatment of osteoarthritis exacerbation;
• Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis.

The medicinal product 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;
• Hypersensitivity to active substances with similar actions, 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 (see section "Use during pregnancy or breastfeeding");
• Children under 16 years of age;
• Gastrointestinal bleeding or perforation associated with previous NSAID therapy, in medical history;
• Active or recurrent peptic ulcer / gastrointestinal 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 hemorrhage 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

Certain medicinal products or therapeutic groups may cause hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim.

The development of hyperkalemia may depend on associated risk factors. The risk of hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions

Other NSAIDs and acetylsalicylic acid

Combination with other NSAIDs (see section "Special precautions for use") is not recommended, including acetylsalicylic acid at doses ≥ 500 mg per single 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 platelet function inhibition and gastroduodenal mucosal damage. 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., prophylactic doses), caution is required due to an increased risk of bleeding. Careful monitoring of the international normalized ratio (INR) is necessary if coadministration cannot be avoided.

Thrombolytics and antiplatelet agents

Increased risk of bleeding due to platelet function inhibition and gastroduodenal mucosal damage.

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, such combinations 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., β-blockers)

Possible reduction in the antihypertensive effect of β-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 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 on NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium) exist, 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 when low-dose methotrexate is used, particularly in patients with impaired renal function. If combination therapy is required, blood parameters and renal function should be monitored. Caution is advised when NSAIDs and methotrexate are taken for 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 treatment with meloxicam, hematological toxicity of methotrexate may increase during NSAID treatment (see information above and 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 pemetrexed administration, and for 2 days after pemetrexed administration. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for signs of myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance < 45 ml/min).

In patients with normal renal function (creatinine clearance ≥ 80 ml/min), meloxicam doses of 15 mg 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 the 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 to a lesser extent 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 in combination with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); such interactions 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 interactions were 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 treatment of patients requiring relief from acute pain.

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

Care should be taken regarding a history of esophagitis, gastritis and/or peptic ulcer to ensure complete healing prior to initiating meloxicam therapy. Close monitoring for possible recurrence is required in patients 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 treatment, with or without prior 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 ulceration, 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 acetylsalicylic acid or other medicinal

products increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

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

Use of meloxicam is not recommended in patients who are concurrently using medicinal products that may increase the risk of ulceration or bleeding, such as heparin, as radical therapy or in geriatric practice, anticoagulants such as warfarin, or other NSAIDs, including acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose (see section "Interaction with other medicinal products and other forms of interaction").

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

NSAIDs should be used with caution in patients with 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 treated with 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 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 liver failure, some with fatal outcome, have been reported.

In patients with symptoms or suspicion of hepatic dysfunction or with abnormal liver function tests, assessment for development of more severe hepatic failure should be performed during treatment with MELOXICAM. If clinical signs and symptoms correlate with development of liver disease or if systemic manifestations of disease occur (e.g., eosinophilia, rash), use of 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 data 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). Insufficient data are available to exclude such risk with 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 should be performed before initiating long-term treatment in patients with cardiovascular risk factors (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. 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. 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 in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while taking meloxicam, the drug must not be re-administered in the future.

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

Anaphylactic reactions

As with other NSAIDs, anaphylactic reactions may occur in patients without prior exposure to meloxicam. The drug should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who develop rhinitis, with or without nasal polyps, or who experience severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Emergency measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and kidney function

As with treatment with most NSAIDs, isolated cases of elevated serum transaminase levels, elevated serum bilirubin levels, or other liver function parameters, as well as elevated 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

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal impairment due to reduced 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 on Child-Pugh classification).

In rare cases, NSAIDs may lead to 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 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 such patients (see sections

"Contraindications" and "Dosage and administration").

Hyperkalemia

Hyperkalemia may be caused by diabetes mellitus or concomitant use of medicinal products that increase potassium levels in blood (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 suspended 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 worse tolerated in 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.

Use of meloxicam may negatively affect fertility and is not recommended for women who are trying to conceive. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

Meloxicam 7.5 mg and 15 mg tablets contain lactose; therefore, this medicinal product is not recommended for patients with rare hereditary intolerance to galactose, 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.

Corticosteroid therapy

MELOXICAM cannot be used as a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects

Anemia may occur in patients receiving NSAIDs, including MELOXICAM. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or incompletely described effects on erythropoiesis. During long-term treatment with NSAIDs, including MELOXICAM, hemoglobin or hematocrit levels should be monitored in patients with symptoms and signs of anemia. 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. Close monitoring is required in patients taking MELOXICAM who may have adverse effects on platelet function, particularly coagulation disorders, and in patients receiving anticoagulants.

Use in patients with asthma

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid 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, MELOXICAM should not be used in patients sensitive to acetylsalicylic acid and should be used with caution in patients with asthma.

Use during pregnancy or breastfeeding

Pregnancy

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/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 approximately 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, use of MELOXICAM may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after treatment in the second trimester, which in most cases resolved after treatment cessation. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of urgent need. If meloxicam is used in women attempting 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.

After exposure to MELOXICAM for several days starting from the 20th gestational week, oligohydramnios and ductus arteriosus constriction should be considered in antenatal monitoring. MELOXICAM 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 kidney function, which may progress to renal failure with oligohydramnios (see above).

Risks for the mother at the end of pregnancy and for the newborn:

• possibility of 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 (see section "Contraindications").

Lactation

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 who are trying to conceive. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Ability to influence 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. However, based on the pharmacodynamic profile and observed adverse reactions, it can be assumed that meloxicam has no effect or a negligible 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.

Dosage and Administration

Dosage

The total daily dose should be administered 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 periodically evaluated, especially in patients with osteoarthritis.

Acute exacerbation of osteoarthritis

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). See also subsection "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 a daily dose of 15 mg!

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/day (see sections "Dosage and Administration. Patients at increased risk of adverse reactions" and "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/day.

Renal impairment. 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 disease undergoing dialysis, the daily dose should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal impairment (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.

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

Children

MELOXICAM 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, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Severe poisoning may lead to 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

Symptomatic and supportive measures are recommended in NSAID overdose. Studies have shown that oral administration of cholestyramine at 4 g three times daily accelerates the elimination of meloxicam.

Side effects

Data from studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and during long-term treatment) may be associated with a small increased risk of vascular thrombotic events, such as myocardial infarction or stroke (see section "Special precautions").

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 precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn’s disease have been reported following administration (see section "Special precautions"). Gastritis has been observed less frequently.

Serious skin reactions have been reported: Stevens–Johnson syndrome and toxic epidermal necrolysis (see section "Special precautions").

Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency 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 — agranulocytosis (see below "Specific serious and/or common adverse reactions").

Immune system disorders: uncommon — allergic reactions, excluding anaphylactic or anaphylactoid reactions; frequency not known — anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders: rare — mood changes, night terrors; frequency 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 therapy has been reported.

Vascular disorders: uncommon — increased blood pressure (see section "Special precautions"), flushing.

Respiratory, thoracic and mediastinal disorders: rare — asthma in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs; frequency 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; frequency not known — pancreatitis.

Gastrointestinal bleeding, ulceration, or perforation may be severe and potentially fatal, particularly in elderly patients (see section "Special precautions"). Hepatobiliary disorders: uncommon — liver function test abnormalities (e.g., increased transaminases or bilirubin); very rare — hepatitis; frequency 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; frequency not known — photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special precautions").

Renal and urinary disorders: uncommon — sodium and water retention, hyperkalemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions"), 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 precautions"); frequency not known — urinary tract infections, disturbances in micturition frequency.

Reproductive system and breast disorders: frequency not known — female infertility, ovulation delay.

General disorders and administration site conditions: uncommon — edema, including peripheral edema; frequency not known — influenza-like symptoms.

Musculoskeletal and connective tissue disorders: frequency 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 renal 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 precautions").

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions

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

Packaging

10 tablets in a blister, 2 blisters with the instructions for medical use in a cardboard box.

Or 20 tablets in a bottle, 1 bottle with the instructions for medical use in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations. 5 Budynstryi St., Kyiv, 01013, Ukraine.

Marketing authorization holder. JSC "Lubnifarm", Ukraine.

Address of the marketing authorization holder. 16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.