Remoxicam®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REUMOXICAM®

Composition:

Active substance: meloxicam;

1 tablet contains meloxicam – 7.5 mg or 15 mg (calculated as 100% anhydrous substance);

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: yellow, round-shaped tablets with a flat surface, bevel, and score line.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory drugs and antirheumatic agents. ATC code M01AC06.

Pharmacological properties.

Pharmacodynamics.

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

Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact 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 following oral administration, with an absolute bioavailability of 90%. After single-dose administration of meloxicam, maximum plasma concentration (Cmax) is reached within 5–6 hours for solid oral dosage forms.

At steady state, achieved on day 3–5 with repeated dosing, 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 (minimum concentration (Cmin) and Cmax at steady state, respectively). Average meloxicam plasma concentrations 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 7–20%. The volume of distribution after multiple oral doses of meloxicam (7.5 mg to 15 mg) is 16 L, with a coefficient of variation ranging from 11% to 32%.

Metabolism. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam have been identified in urine, all pharmacodynamically inactive. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted but to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in the metabolic process, while CYP3A4 isoenzymes are less significant. Peroxidase is likely responsible for the formation of two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Meloxicam is primarily eliminated 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 unchanged 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 following single oral, intravenous, or rectal doses.

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

Special patient groups.

Patients with hepatic/renal impairment. Mild to moderate hepatic or renal impairment does not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment showed significantly higher total clearance. Reduced plasma protein binding has been observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to higher concentrations of free meloxicam. Daily dose should not exceed 7.5 mg (see section "Dosage and administration").

Elderly patients. In elderly male patients, average pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, the area under the plasma concentration-time curve (AUC) is higher and elimination half-life longer compared to young volunteers of both sexes. Average plasma clearance at steady state in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients, or to other agents with similar action, such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid. Meloxicam should not be administered to patients who have experienced asthma, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");
• Children under 16 years of age;
• Gastrointestinal bleeding or perforation 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 associated with coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interaction.

Risks associated with hyperkalemia

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

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

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Combination with other NSAIDs is not recommended (see section "Special precautions for use"), including acetylsalicylic acid at doses ≥ 500 mg per single 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 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), caution is required when using heparin due to increased bleeding risk. Careful monitoring of the international normalized ratio (INR) is necessary if this combination cannot be avoided.

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

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

Diuretics, ACE inhibitors, and angiotensin II antagonists. NSAIDs may reduce the efficacy of diuretics and other antihypertensive 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 agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination therapy should be used with caution, especially in elderly patients. Patients should receive adequate hydration, 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 medicinal products mentioned 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 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 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 start 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 tests and renal function should be monitored. Caution is advised when NSAID and methotrexate are taken for three consecutive days, as plasma methotrexate levels may increase and 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 provided above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance of 45–79 mL/min), meloxicam administration should be withheld for 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).

For 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, 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 (sulfonylureas, 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 peroxidative oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that clearly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected in combination with medicinal products such as oral antidiabetics (sulfonylureas, 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 hypoglycemia.

No clinically significant pharmacokinetic interaction was observed when this medicinal product was taken concomitantly with antacids, cimetidine, or digoxin.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

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

The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

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

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

Gastrointestinal disorders.

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

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased 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, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction"), combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered.

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

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

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

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

Hepatic disorders.

Up to 15% of patients taking NSAIDs (including Revmoxikam®) may experience elevation 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 or suspicion of hepatic dysfunction or those with abnormal liver function tests should be evaluated for signs of more severe hepatic failure during treatment with Revmoxikam®. If clinical signs and symptoms are consistent with hepatic disease or if systemic manifestations of disease (e.g., eosinophilia, rash, etc.) occur, use of Revmoxikam® should be discontinued.

Cardiovascular disorders.

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

Data from studies 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). There is insufficient data 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.

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. 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 has developed Stevens-Johnson syndrome or toxic epidermal necrolysis while taking 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 use.

Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known reaction to Revmoxikam®. This medicinal product 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 acetylsalicylic acid or other NSAIDs. Immediate measures should be taken if an anaphylactoid reaction is detected.

Liver parameters and kidney 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 test abnormalities have been described. In most cases, these abnormalities were minor and transient. If significant or persistent abnormalities are confirmed, meloxicam should be discontinued and follow-up tests performed.

Functional renal impairment.

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal impairment due to decreased 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 increase in patients with the following risk factors:

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

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

The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg. Dose reduction is not required in patients with mild to moderate renal impairment (creatinine clearance level – more than 25 mL/min).

Sodium, potassium, and water retention.

NSAIDs may enhance sodium, potassium, and water retention and affect the natriuretic effects of diuretics. Additionally, a 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 arterial hypertension may be provoked 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 caused by diabetes mellitus or concomitant use of medicinal products that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, regular monitoring of potassium levels is required.

Combination with pemetrexed.

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

Other warnings and safety measures.

Adverse reactions are often less well tolerated in elderly, debilitated, or weakened 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.

Meloxicam may negatively affect reproductive function and is therefore not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

Tablets Revmoxikam® 7.5 mg and 15 mg contain lactose. In case of intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Masking of inflammation and fever.

The pharmacological action of Revmoxikam® in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Corticosteroid therapy.

Revmoxikam® cannot be a substitute for corticosteroids in the treatment of corticosteroid insufficiency.

Hematological effects.

Anemia may occur in patients taking NSAIDs, including Revmoxikam®. This may be related to fluid retention, occult or massive gastrointestinal bleeding, or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit should be monitored in patients on long-term treatment with Revmoxikam® if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively less, short-term, and reversible. Patients taking Revmoxikam® and those with possible adverse effects on platelet function, including coagulation disorders, or patients receiving anticoagulants should be carefully monitored.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, Revmoxikam® should not be used in patients sensitive to acetylsalicylic acid and should be used cautiously in patients with asthma.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic and fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac defects increased from less than 1% to approximately 1.5%. This risk is considered to increase with increasing dose and duration of treatment.

From the 20th week of pregnancy, use of Revmoxikam® may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, most of which resolved after discontinuation. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except when strictly necessary. If a woman is trying to conceive or is using meloxicam during the first and second trimesters, dosing and duration of treatment should be minimized. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to Revmoxikam® for several days, starting from the 20th gestational week. Use of Revmoxikam® should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

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

Possible risks in late pregnancy for mother and newborn:

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

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

Breastfeeding. Although specific data on Revmoxikam® are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended in women who are breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, meloxicam is likely to have 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 or operating machinery.

Method of Administration and Dosage

Administer orally.

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

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 reassessed.

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 response, 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 and patients at 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 daily. For patients at increased risk of adverse reactions, e.g. those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg daily (see section "Special Warnings and Precautions for Use").

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 undergoing dialysis, the daily dose should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal impairment (patients with creatinine clearance above 25 mL/min).

Hepatic Impairment

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

Children

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

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, convulsions, 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. Studies have shown that meloxicam elimination is accelerated by administration of 4 oral doses of cholestyramine given 3 times daily.

Side effects.

Data from studies and epidemiological data suggest that the use of certain 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 for use").

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

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

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 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 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 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 for use").

Hepatobiliary disorders:

Uncommon – liver function test abnormalities (e.g., increased transaminases or bilirubin);
Very rare – hepatitis;
Not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon – angioedema, pruritus, rash;
Rare – Stevens–Johnson syndrome, toxic epidermal necrolysis, urticaria;
Very rare – bullous dermatitis, erythema multiforme;
Not known – photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special precautions for use").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Special precautions for use" 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 for use");
Not known – urinary tract infections, changes 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 use of the medicinal product but generally recognized as typical for other compounds of 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 for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister. 1 or 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.