Meloxicam-kv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELOXICAM-KV (MELOXICAM-KV)

Composition:

Active substance: meloxicam;

One tablet contains meloxicam 7.5 mg or 15 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: light yellow, flat cylindrical tablets with beveled edges (7.5 mg); light yellow, flat cylindrical tablets with a score line and beveled edges (15 mg).

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory drugs and antirheumatic agents. ATC code M01A C06.

Pharmacological Properties.

Pharmacodynamics.

Meloxicam-KV 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 has been established for all NSAIDs (including meloxicam): inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption.

Meloxicam is well absorbed from the gastrointestinal tract following oral administration, with an absolute bioavailability of 90% (capsules). After single-dose administration, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms.

With repeated dosing, steady-state concentrations are achieved by day 3–5. With once-daily administration, mean 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 (Cmin and Cmax at steady state, respectively). Mean plasma concentrations of meloxicam at steady state are reached within 5–6 hours.

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

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, pharmacodynamically inactive, have been identified in urine. The major 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 metabolism, while CYP3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination.

Excretion of meloxicam occurs primarily in the form of metabolites, equally via urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine. The elimination half-life ranges from 13 to 25 hours after oral administration. Plasma clearance is approximately 7–12 mL/min following a single oral dose.

Dose Linearity.

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

Special patient groups.

Patients with hepatic/renal impairment.

Mild to moderate hepatic or renal impairment does not significantly affect the pharmacokinetics of meloxicam. In patients with moderate renal impairment, total clearance is significantly higher. Reduced plasma protein binding has been observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to increased free meloxicam concentration (see sections "Contraindications" and "Dosage and administration").

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 those in young volunteers of both sexes. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

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

Contraindications.

• Hypersensitivity to meloxicam or to any of the excipients, or to active substances with a 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 during pregnancy or breastfeeding");
• Pediatric patients under 16 years of age;
• Gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• Active or recurrent peptic ulcer/bleeding in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• Severe hepatic impairment;
• Severe renal impairment without dialysis;
• Gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
• Severe heart failure;
• Treatment of perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adults.

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 (see section "Special precautions for use") is not recommended, 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 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 (e.g., prophylactic doses), heparin use requires caution due to increased bleeding risk. Close monitoring of INR (international normalized ratio) is necessary if such combination cannot be avoided.

Thrombolytic 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 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, such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation of combined therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive agents (e.g., beta-blockers). As with the following medicinal products, 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 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 (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 counts and renal function should be monitored. Caution should be exercised when NSAIDs and methotrexate are taken consecutively for 3 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 suspended 5 days before, on the day of, and 2 days after pemetrexed infusion. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance < 45 ml/min).

In 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 meloxicam elimination 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.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide). Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 enzymes (main pathway – CYP 2C9, secondary 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 used in combination 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 hypoglycemia.

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

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 the 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 NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

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

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

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment, with or without previous symptoms or serious gastrointestinal disease in history.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective medicinal products (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 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, especially elderly patients, should be informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially at 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, including heparin as a radical treatment 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 a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may worsen (see section "Adverse reactions").

Hepatic disorders.

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

Patients with symptoms of hepatic dysfunction or suspected hepatic dysfunction, or those with abnormal liver function tests, should be evaluated for the development of more severe hepatic failure during treatment with the medicinal product. If clinical signs and symptoms consistent with the development of liver disease or systemic manifestations of disease (e.g., eosinophilia, rash, etc.) occur, use of Meloxicam-KV 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 have been observed during NSAID therapy.

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

Data from studies and epidemiological data suggest that use of some 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). There are insufficient data to exclude such risk with meloxicam use.

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. Such consideration is also necessary 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. This risk may be increased in patients with cardiovascular diseases or cardiovascular risk factors.

Skin disorders.

There have been reports of life-threatening severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis, 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. It is important to diagnose promptly and discontinue any medicinal products that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis. This is associated with a better prognosis in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while being treated with meloxicam, the drug must never be used again in the future.

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

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

Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to meloxicam. Meloxicam-KV should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have reported rhinitis with or without nasal polyps or who experienced severe, potentially fatal bronchospasm after taking aspirin 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 increased serum transaminase levels, increased serum bilirubin levels or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen and other laboratory parameter abnormalities have been described. In most cases, these abnormalities were minor 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, diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal failure;
• nephrotic syndrome;
• lupus nephropathy;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

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

The dose of meloxicam in patients with end-stage renal failure 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 medicinal products 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 "Contraindications" and "Dosage and administration").

Hyperkalemia.

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

Combination with pemetrexed.

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

Other warnings and safety measures.

Adverse reactions are often poorly tolerated by elderly, frail or debilitated patients who require close monitoring. As with treatment with other NSAIDs, caution is required in elderly patients in whom reduced renal, hepatic and cardiac function is more likely. The frequency of adverse reactions with NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal, is higher in elderly patients (see section "Dosage and administration").

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

Meloxicam use 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 medicinal product contains lactose; therefore, this preparation is not recommended for patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Masking of inflammation and fever.

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

Concomitant corticosteroid therapy.

Meloxicam cannot be considered 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 microscopic or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit should be monitored in patients undergoing long-term NSAID treatment, including meloxicam, if symptoms and signs of anemia are present.

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

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of aspirin in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, meloxicam should not be used in patients sensitive to aspirin and should be used cautiously in patients with existing 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 development of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac defects increased from less than 1% to about 1.5%. This risk is considered to increase with increasing dose and duration of treatment.

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

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause risks:

Risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

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

• possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Meloxicam-KV is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding.

Although specific data on the medicinal product are lacking, it is known that NSAIDs can pass into breast milk. Therefore, use is not recommended for breastfeeding women.

Fertility.

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

Ability to influence reaction speed when driving vehicles or operating machinery.

There are no specific studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery. 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 experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo or other central nervous system disorders, are advised to refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

For oral use.

The total daily dose should be taken once daily, 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 Warnings and Precautions for Use"). The patient's need for symptomatic relief and response to treatment should be reassessed periodically.

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 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.

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, such as those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg per day.

Renal impairment.

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

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

Hepatic impairment.

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

Children.

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

Overdose.

Symptoms.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, 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. Available data indicate enhanced elimination of meloxicam by administration of 4 oral doses of cholestyramine 3 times daily.

Adverse Reactions

Available data suggest that the 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) (see section "Special Warnings and Precautions for Use").

Edema, arterial hypertension, and heart failure have been observed during NSAID therapy.

Most of the adverse effects observed are gastrointestinal in origin. Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn’s disease (see section "Special Warnings and Precautions for Use") have been reported after administration. Gastritis has been observed less frequently.

Serious skin reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special Warnings and Precautions for Use").

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 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 – asthma in patients with aspirin or other NSAID allergy;
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;
Not known – pancreatitis.

Gastrointestinal bleeding, ulceration, or perforation may be severe and potentially fatal, especially in elderly patients (see section "Special Warnings and Precautions for Use").

Hepatobiliary disorders:
Uncommon – liver function test abnormalities (e.g., increased transaminases or bilirubin);
Rare – hepatitis;
Not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders:
Uncommon – angioneurotic edema, 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.

Renal and urinary disorders:
Uncommon – sodium and water retention, hyperkalemia (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), 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 Warnings and Precautions for Use");
Not known – urinary tract infections, disturbances in micturition frequency.

Reproductive system and breast disorders:
Not known – female infertility, ovulation delay.

General disorders and administration site conditions:
Uncommon – edema, including peripheral edema;
Not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders:
Not known – arthralgia, back pain, joint signs and symptoms.

Specific serious and/or common adverse reactions.

Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adverse reactions not observed during drug use but generally recognized as typical for other compounds in the class.

Organic kidney damage, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special Warnings and Precautions for Use").

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 blister per carton.

10 tablets in a blister; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of its business activity.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua