Movaris

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOVALIS® (MOVALIS®)

Composition:

Active substance: 1 tablet contains meloxicam 7.5 mg or 15 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: round tablets ranging in color from pale yellow to lemon yellow. One side is convex, with beveled edges and the company's logo. The other side has a score line for breaking in half and a code. The tablet surface may be slightly rough.

MOVALIS 7.5 mg tablets: the score line is intended solely to facilitate splitting for easier swallowing and does not ensure equal dose division.

MOVALIS 15 mg tablets: the tablet can be divided into equal doses.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory drugs and antirheumatic agents. Oxicams.

ATC code M01AC06.

Pharmacological properties.

Pharmacodynamics.

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

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

Pharmacokinetics.

Absorption. Meloxicam is well absorbed from the gastrointestinal tract; after oral administration (capsules), the absolute bioavailability of the drug is 90%. Tablets, oral suspension, and capsules have demonstrated 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 0.4–1.0 µg/mL for 7.5 mg and 0.8–2.0 µg/mL for 15 mg, respectively (Cmin and Cmax at steady state, respectively).

Mean peak plasma concentrations of meloxicam at steady state are reached within 5–6 hours following administration in tablet, capsule, and oral suspension formulations. During continuous treatment over periods exceeding one year, plasma concentrations remain comparable to those observed at steady state at the beginning of therapy. Absorption of oral meloxicam is not altered by concomitant food intake or antacid administration.

Distribution. Meloxicam is highly bound to plasma proteins, primarily to 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 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, 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 also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in the metabolic process, while CYP3A4 contributes to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. 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 following 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 has been observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to elevated free meloxicam concentrations (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.

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

Interaction with other medicinal products and other types of interactions.

Risks associated with hyperkalemia

Certain 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 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 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 potentiate the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Concomitant use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or at therapeutic doses (see section "Special precautions for use").

In other cases (e.g., prophylactic doses), heparin use requires caution due to increased bleeding risk. Careful monitoring of INR (international normalized ratio) is necessary if such a combination cannot be avoided.

Thrombolytic and antiplatelet agents. Increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and angiotensin II antagonists. NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination therapy should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive agents (e.g., beta-blockers). As with the following medicinal products, a reduced 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 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 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. 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.

MTX (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 (>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 parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate are taken for three consecutive days, as methotrexate plasma 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 therapy (see information 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 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).

For patients with normal renal function (creatinine clearance ≥80 ml/min), a 15 mg dose of meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam 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 metabolized in the liver, approximately two-thirds via 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 when combined with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of both agents. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

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

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose should not be exceeded if therapeutic effect is insufficient, 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 of acute pain.

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

Care should be taken regarding history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. Close monitoring for possible recurrence should be maintained in patients 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 disease history.

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

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

Use of meloxicam is not recommended in patients 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 medicinal products, including acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose (see section "Interaction with other medicinal products and other forms of interaction").

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

NSAIDs should be used with caution in patients with gastrointestinal disorders history (ulcerative colitis, Crohn's disease), as these conditions may worsen (see section "Adverse reactions").

Hepatic disorders.

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

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

Cardiovascular disorders.

Careful monitoring is recommended in patients with 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.

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

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

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

Skin reactions.

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment. If a patient develops symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal involvement), meloxicam treatment should be discontinued. Prompt diagnosis and discontinuation of any drug that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—is essential, as this is associated with a better prognosis in severe skin reactions. If a patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis with meloxicam, the drug must not be re-administered at any time in the future.

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.

Anaphylactoid reactions.

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

Liver parameters and renal function.

As with treatment with most NSAIDs, isolated cases of elevated serum transaminases, elevated serum bilirubin or other liver function parameters, as well as elevated serum creatinine and blood urea nitrogen, and other laboratory parameter abnormalities have been described. In most cases, these abnormalities were mild and transient. If significant or persistent abnormalities are confirmed, meloxicam use should be discontinued and follow-up tests performed.

Functional renal failure.

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

• advanced age;
• concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, or diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal insufficiency;
• nephrotic syndrome;
• lupus nephropathy;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

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

The dose of meloxicam in patients with end-stage renal insufficiency on dialysis should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal insufficiency (creatinine clearance level > 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, reduced antihypertensive effect of antihypertensive medicinal products may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure, or hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended in patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be favored 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"). Regular monitoring of potassium levels is required in such cases.

Combination with pemetrexed.

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

Other warnings and safety measures.

Adverse reactions are often less well tolerated in elderly, frail, or debilitated patients, who require careful monitoring. As with treatment 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 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 composition of MOVALIS tablets 7.5 mg and 15 mg includes lactose (one MOVALIS 7.5 mg tablet contains monohydrate lactose equivalent to 22.3 mg anhydrous lactose; one MOVALIS 15 mg tablet contains monohydrate lactose equivalent to 19.0 mg anhydrous lactose); therefore, this medicinal product is not recommended for patients with rare hereditary intolerance to galactose, total lactase deficiency, or glucose-galactose malabsorption.

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

Masking of inflammation and fever.

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

Glucocorticoid therapy.

MOVALIS cannot be a substitute for glucocorticoids in the treatment of glucocorticoid deficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including MOVALIS. This may be related to fluid retention, gastrointestinal bleeding of unknown origin (microscopic or macroscopic), or incompletely described effects on erythropoiesis. Patients undergoing long-term treatment with NSAIDs, including MOVALIS, should have hemoglobin or hematocrit monitored 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. Close monitoring is required in patients taking MOVALIS who may have adverse effects related to changes in platelet function, particularly coagulation disorders, or in patients receiving anticoagulants.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of aspirin in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, MOVALIS 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 congenital heart defects increased from less than 1 % to about 1.5 %. This risk is believed 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 loss and embryofetal mortality. In addition, increased frequency of various developmental abnormalities, including cardiovascular defects, has been reported in animals treated with a prostaglandin synthesis inhibitor during organogenesis.

From the 20th week of pregnancy, use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible after discontinuation of therapy. Additionally, cases of arterial duct constriction after second-trimester treatment have been reported, most of which resolved after treatment 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 become pregnant or uses meloxicam during the first and second trimesters, dosage and duration of treatment should be minimized. Prenatal monitoring for oligohydramnios and arterial duct constriction after meloxicam exposure should be considered within several days starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, meloxicam use should be discontinued.

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

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

possible risks in late pregnancy for mother and newborn:

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

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

Breastfeeding. Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Meloxicam has been detected in milk of lactating 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 use should be considered.

Ability to influence reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive a car or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, it can be assumed that meloxicam is likely to have no effect or only a minor effect on such activities. However, patients who experience visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, are advised to refrain from driving a car or operating machinery.

Method of Administration and Dosage.

Dosing.

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

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use"). The patient's need for symptomatic relief and response to treatment should be periodically evaluated, especially in patients with osteoarthritis.

Exacerbation of osteoarthritis:

7.5 mg/day (1 tablet of 7.5 mg or half a tablet of 15 mg). If necessary, the dose may be increased to 15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

Rheumatoid arthritis, ankylosing spondylitis:

15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

See also section "Special Patient Populations" below.

Depending on the therapeutic effect, the dose may be reduced to 7.5 mg/day (1 tablet of 7.5 mg or half a tablet of 15 mg).

DO NOT EXCEED THE DOSE OF 15 mg/day.

Special Patient Populations.

Elderly patients (see section "Pharmacokinetics").

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

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

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

Renal impairment (see section "Pharmacokinetics").

This medicinal product is contraindicated in patients with severe renal impairment who are not 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 adjustment is not required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min).

Hepatic impairment (see section "Pharmacokinetics").

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

Method of Administration.

For oral use.

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

Children.

MOVALIS, 7.5 mg and 15 mg tablets, 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 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 oral administration of cholestyramine at a dose of 4 g three times daily accelerates the elimination of meloxicam.

Adverse reactions.

General description

Data from studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and with long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., 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 ulcer, 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 (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").

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

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

Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 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 count 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 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 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 precautions").

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 precautions").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"), changes in renal function parameters (increased serum creatinine and/or urea);

Very rare – acute renal failure, particularly in patients with risk factors (see section "Special precautions");

Not known – urinary tract infections, micturition 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.

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 suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report any 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 30 °C in a place inaccessible to children.

Packaging.

For 7.5 mg dosage: 10 tablets per blister, 2 blisters per cardboard box;

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

Prescription status. Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG.

Manufacturer's location and address of place of business.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.

or

Manufacturer.

Boehringer Ingelheim Hellas Single Member S.A.

Manufacturer's location and address of place of business.

5th km Paiania-Markopoulo, Koropi Attiki, 19441, Greece.

or

Manufacturer.

Rottendorf Pharma GmbH.

Manufacturer's location and address of place of business.

Ostenfelder Strasse 51-61, 59320 Ennigerloh, Germany.