Aroxican

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

Composition:

Active ingredient: meloxicam;

1 tablet contains 7.5 mg or 15 mg of meloxicam;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

7.5 mg tablets: light-yellow, round, uncoated tablets, with an embossing "F" and "1" on one side and a line between them;

15 mg tablets: light-yellow, round, uncoated tablets, with an embossing "F" and "2" on one side and a line between them.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory drugs and antirheumatic agents. Oxicams. ATC code M01AC06.

Pharmacological properties.

Pharmacodynamics.

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

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, a common mechanism of action 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%. Tablets, oral suspension, and capsules have shown bioequivalence.

After single-dose 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. Once-daily dosing results in average plasma concentrations with relatively small peak fluctuations: within 0.4–1 µg/mL for the 7.5 mg dose and 0.8–2 µg/mL for the 15 mg dose, respectively (Cmin and Cmax at steady state, respectively). Average peak plasma concentrations of meloxicam at steady state are reached within 5–6 hours for tablets, capsules, and oral suspensions, respectively. During continuous treatment 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%). 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 ranging from 7% to 20%. The volume of distribution after repeated oral doses of meloxicam (7.5 mg 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 CYP 2C9 plays a major role in the metabolic process, 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 portions 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 following 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 showed significantly higher total clearance. Reduced plasma protein binding was observed in patients with end-stage renal disease. In end-stage renal disease, an increased volume of distribution may lead to higher concentrations of free meloxicam. The daily dose should not exceed 7.5 mg (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 (see section "Dosage and administration").

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

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

Arcoxia, tablets, is indicated for the treatment of adults and children aged 16 years and older.

Contraindications.

• Hypersensitivity to meloxicam or to any of the excipients of the medicinal product, or to active substances with a similar action, such as NSAIDs, aspirin. Meloxicam should not be prescribed to patients who have experienced symptoms of bronchial asthma, nasal polyps, angioedema or urticaria after taking aspirin or other NSAIDs;

• 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);

• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");

• Children under 16 years of age.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

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 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 single dose or ≥ 3 g total daily dose.

Corticosteroids (e.g. glucocorticoids). Concomitant use with corticosteroids requires caution due to increased risk of bleeding or development of gastrointestinal ulcers.

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., at prophylactic doses), heparin use requires caution due to 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 gastrointestinal 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, 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., beta-blockers). As with the medicinal products listed below, a possible reduction in the antihypertensive effect of beta-blockers may occur (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs due to mediation of effects on renal prostaglandins. Renal function should be monitored during treatment. Close monitoring of renal function is recommended, 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 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 should be exercised if NSAID 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 meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID treatment (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, on the day of, and 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 below 45 ml/min).

In patients with normal renal function (creatinine clearance ≥ 80 ml/min), a dose of 15 mg 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, thus increasing meloxicam clearance by 50% and reducing its half-life to 13±3 hours. This interaction is clinically significant.

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

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 minor pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected in combination 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 in cases of insufficient therapeutic effect, and additional NSAIDs should not be used concomitantly, as this may increase toxicity without proven therapeutic benefit. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Meloxicam is not suitable for treatment of patients requiring relief from acute pain.

If no improvement is observed after several days, the clinical benefits of continued 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 receiving meloxicam, as well as those with such history, should be regularly monitored for possible recurrence.

Gastrointestinal disorders.

As with other NSAIDs, potentially life-threatening gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without warning symptoms or a history of serious gastrointestinal disorders.

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 low-dose aspirin or other drugs that increase 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 all unusual abdominal symptoms (especially gastrointestinal bleeding), particularly during the initial stages of treatment.

Concomitant use of meloxicam is not recommended in patients taking medications that may increase the risk of ulceration or bleeding, such as heparin used as definitive therapy or in geriatric practice, anticoagulants such as warfarin, or other nonsteroidal 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 increased values 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 the upper limit of normal) were observed in 1% of patients during clinical trials with NSAIDs. Rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and hepatic failure, some of which were fatal, have also been reported.

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

Cardiovascular disorders.

Close monitoring is recommended in patients with arterial hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema may occur 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 cardiovascular risk factors. Clinical trial and epidemiological data suggest that use of certain NSAIDs (particularly at high doses and during prolonged treatment) may be associated with a small increase in the risk of vascular thrombotic events (e.g., myocardial infarction or stroke). Insufficient data are available 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 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 of such complications.

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 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 must 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, as prognosis improves with prompt action. Meloxicam must not be re-administered at any time in the future if a patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis while taking it. Cases of fixed drug eruption have been reported with meloxicam use.

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

Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known hypersensitivity to meloxicam. The drug should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with bronchial 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 most NSAIDs, isolated cases of elevated serum transaminases, elevated serum bilirubin, or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. In most cases, these abnormalities were mild and transient. Meloxicam should be discontinued and follow-up tests performed if significant or persistent abnormalities are confirmed.

Functional renal impairment.

NSAIDs may induce functional renal failure by inhibiting the vasodilatory effect of renal prostaglandins, leading to reduced 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 escalation in patients with the following risk factors:

• advanced age;
• concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, or 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 Child-Pugh class ≥ 10).

In isolated cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal papillary necrosis, or nephrotic syndrome. The meloxicam dose 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 fluid retention.

NSAIDs may exacerbate sodium, potassium, and fluid retention and may interfere with 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 for patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, regular monitoring of potassium levels is 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 for 2 days after pemetrexed administration (see section "Interaction with other medicinal products and other forms of interaction").

Other warnings and safety precautions.

Adverse reactions are often more severe in elderly, debilitated, or weakened patients, who require careful monitoring. As with other NSAIDs, caution is advised in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher incidence 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 impair female fertility and is not recommended for women wishing to become pregnant. Therefore, discontinuation of meloxicam should be considered in women planning pregnancy or undergoing infertility evaluation (see section "Use during pregnancy or breastfeeding").

Tablets of 7.5 mg and 15 mg contain lactose and therefore should not be used in patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption.

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

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 serve as 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, occult or macroscopic gastrointestinal bleeding, or an incompletely described effect on erythropoiesis. Hemoglobin or hematocrit should be monitored in patients undergoing long-term NSAID treatment, 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 smaller, transient, and reversible. Close monitoring is required in patients taking meloxicam who are at risk of adverse effects related to platelet function disturbances, including coagulation disorders, or in patients receiving anticoagulants.

Use in patients with bronchial asthma.

Patients with bronchial asthma may have aspirin-sensitive asthma. Aspirin use in patients with aspirin-sensitive 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 hypersensitive to aspirin and should be used cautiously in patients with bronchial asthma.

Use during pregnancy or breastfeeding.

Fertility. Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for women wishing to become pregnant. Therefore, discontinuation of meloxicam should be considered in women planning pregnancy or undergoing infertility evaluation.

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 higher doses and longer duration of treatment. In animal studies, prostaglandin synthesis inhibitors have been shown to increase pre- and post-implantation losses and embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, increased incidence of various developmental abnormalities, including cardiovascular defects, has been reported.

From the 20th week of pregnancy, meloxicam use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction after second-trimester treatment have been reported, most of which resolved after stopping treatment. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If meloxicam is used during the first or second trimester or by women attempting to conceive, the dose and duration of treatment should be as low as possible. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered within several days after exposure to meloxicam, starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, meloxicam should be discontinued.

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

• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios;

potential risks in late pregnancy for mother and newborn:

• possible 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 limited, NSAIDs are known to pass into breast milk. Meloxicam has been detected in the milk of nursing animals. Therefore, use is not recommended in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted on the effect of the drug on the ability to drive or operate machinery. 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 experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system (CNS) disorders, should refrain from driving or operating machinery.

Method of administration and dosage.

Administer orally.

The total daily dose should be taken once, with water or another liquid, during a meal.

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

Osteoarthritis exacerbation: 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 categories" 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 categories.

Elderly patients and patients with an increased risk of adverse reactions. The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg per day.

For patients with an 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 7.5 mg per day (see section "Special instructions").

Renal impairment.

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

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

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

Children.

The drug is contraindicated in children under 16 years of age.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, seizures, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

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

Adverse Reactions

General Description

Data from clinical studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) may be associated with a small increased risk of 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"). Following administration, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations 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 frequency of the 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 reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); 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 section "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 therapy has been reported.

Vascular disorders:

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

Respiratory, thoracic and mediastinal disorders:

Rare – bronchial 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 – abnormalities in liver function tests (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 fluid 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, micturition frequency disorders.

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:

Renal parenchymal injury, 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 Suspected Adverse Reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to 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 in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging

7.5 mg tablets: 10 tablets per blister; 1 or 2 blisters per cardboard pack.

15 mg tablets: 10 tablets per blister; 1 or 2 blisters per cardboard pack.

Prescription Category

Prescription only.

Manufacturer

Aurobindo Pharma Limited - Unit III, India.

Manufacturer's Address and Place of Business

Survey no.: 313, 314 - Block I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India.