Loxidol

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

Composition:

Active substance: meloxicam;

1 tablet contains 15 mg of meloxicam;

Excipients: microcrystalline cellulose; sodium citrate; lactose monohydrate; crospovidone; povidone K30; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat, light-yellow tablets with an engraving "LOX 15" on one side.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) from the oxicam group, with anti-inflammatory, analgesic, and antipyretic properties.

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, there is a common mechanism of action shared by all NSAIDs (including meloxicam): inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics

After oral administration at therapeutic doses, meloxicam exhibits linear pharmacokinetics.

Absorption

Meloxicam is almost completely absorbed from the gastrointestinal tract. Absolute bioavailability after oral administration is 90%. Concomitant food intake or use of inorganic antacids does not affect its absorption.

After a single oral dose, peak plasma concentrations are reached within 5–6 hours. After repeated administration, steady state is achieved within 3–5 days of starting treatment.

Following oral administration of 15 mg meloxicam once daily under fasting conditions, plasma concentrations range from 0.8 to 2.0 mg/L (15 mg) (Cmin–Cmax). Mean plasma concentrations of meloxicam at steady state after oral administration are reached within 5–6 hours.

Distribution

Meloxicam is highly bound to plasma proteins, primarily albumin (99%). Meloxicam penetrates into synovial fluid, where its concentration reaches approximately half of that in plasma.

The volume of distribution after multiple oral doses averages 16 L, with individual variability ranging between 11–32%.

Metabolism

Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam have been identified in urine, all of which are pharmacodynamically inactive. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in this metabolic process, while CYP3A4 isozymes contribute to a lesser extent. Peroxidase activity in patients may be responsible for the formation of two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Excretion

Meloxicam is excreted 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, or intravenous administration. Plasma clearance is approximately 7–12 mL/min after a single oral, intravenous, or rectal dose.

Special patient groups

Elderly patients

In elderly male patients, mean 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 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.

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 free meloxicam concentrations (see sections “Contraindications” and “Dosage and administration”).

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, other components of the medicinal product, or to active substances with similar effects, such as NSAIDs, acetylsalicylic acid.
• History of hypersensitivity reactions (including asthma symptoms, nasal polyps, angioedema, urticaria) to acetylsalicylic acid or to NSAIDs.
• Active recurrent peptic ulcer/bleeding or history of recurrence (two or more distinct episodes of peptic ulcer or bleeding).
• Gastrointestinal bleeding or perforation associated with previous NSAID therapy in medical history.
• Gastrointestinal bleeding, cerebrovascular bleeding, or other coagulation disorders in medical history.
• Severe cardiac, hepatic, or renal insufficiency (without dialysis).
• Treatment of perioperative pain in coronary artery bypass grafting (CABG).
• Third trimester of pregnancy.
• Pediatric age under 16 years.

Interaction with other medicinal products and other forms of interaction.

Risks associated with hyperkalemia

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

The onset of hyperkalemia may depend on whether associated risk factors are present. The risk of hyperkalemia increases if the aforementioned 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 bleeding or gastrointestinal 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), heparin use requires caution 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 gastrointestinal bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

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

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

Other antihypertensive medicinal products (e.g., beta-blockers). As with the medicinal products listed below, a 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 from 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 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 count and renal function should be monitored. Caution is necessary when NSAID and methotrexate administration lasts for 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID 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 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 below 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 the elimination of meloxicam due to disruption of enterohepatic circulation, thus increasing meloxicam clearance by 50% and reducing its half-life to 13 ± 3 hours. This interaction is clinically significant.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 (CYP) enzymes (mainly CYP 2C9, with minor contribution from CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that are strong inhibitors or substrates of CYP 2C9 and/or CYP 3A4. CYP 2C9-mediated interaction may be expected with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of both the antidiabetic agents and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interactions were observed with concomitant administration of antacids, cimetidine, or digoxin.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control the disease.

The recommended maximum daily dose must not be exceeded. In case of insufficient therapeutic effect, 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 should not be used for treatment of patients requiring relief of acute pain.

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

Meloxicam cannot serve as a likely substitute for corticosteroids in the treatment of corticosteroid deficiency.

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

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

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

Gastrointestinal effects

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

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing 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 during the initial stages of treatment.

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

Concomitant use of meloxicam is not recommended in patients taking medications 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.

If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued.

Effects on the liver

Up to 15% of patients receiving NSAIDs (including meloxicam) may experience elevated levels of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or AST (approximately 3 times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions have been reported, including jaundice and fulminant fatal hepatitis, liver necrosis, and hepatic failure, some of which were fatal.

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

Effects on the cardiovascular system

Careful 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.

Patients with risk factors should have clinical monitoring of blood pressure at the beginning of therapy, especially at the start of meloxicam treatment.

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

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

Use of the medicinal product Loksidol 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.

Effects on the skin

Life-threatening severe skin reactions have been reported with meloxicam use: Stevens-Johnson syndrome and toxic epidermal necrolysis. The highest risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment.

Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. 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), treatment should be discontinued. Prompt diagnosis and discontinuation of any drugs that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—is crucial, as early intervention improves prognosis. If a patient develops 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.

The medicinal product Loksidol should not be re-administered to patients who have 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. The drug 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. Emergency measures should be taken if an anaphylactoid reaction occurs.

Effects on liver and kidney function parameters

As with treatment with most NSAIDs, isolated cases of increased plasma transaminase and bilirubin levels or other liver function parameters, as well as increased plasma 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, the drug should be discontinued and follow-up tests performed.

Effects on the kidneys

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.

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

Close 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 of ACE inhibitors, angiotensin II receptor antagonists (ARA II), sartans, or diuretics; hypovolemia (of any origin); congestive heart failure; renal failure; nephrotic syndrome; lupus nephropathy; severe hepatic dysfunction (plasma albumin < 25 g/L or ≥ 10 g/L according to Child-Pugh classification).

The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg (other meloxicam dosage forms with appropriate dosing should be used). Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 25 mL/min).

Effects on water-electrolyte balance

NSAIDs may enhance sodium, potassium, and water retention and may affect the natriuretic effects of diuretics. Additionally, the antihypertensive effect of antihypertensive drugs may be reduced. Consequently, edema, heart failure, or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients with such risks.

Hyperkalemia

Hyperkalemia may also develop, which may be caused by diabetes mellitus or concomitant use of drugs that increase potassium levels. In such cases, regular monitoring of plasma potassium levels is required.

Hematological reactions

Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, gastrointestinal (occult or macroscopic) blood loss, or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit should be monitored during long-term use 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 in whom adverse effects on platelet function are possible, including coagulation disorders, or patients receiving anticoagulants, should be carefully monitored during meloxicam use.

Combination with pemetrexed

In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be withheld 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").

Elderly patients and patients at increased risk of adverse reactions

Adverse reactions are often poorly tolerated in elderly, frail, or debilitated patients, who require careful monitoring. As with treatment with other NSAIDs, the medicinal product Loksidol should be used cautiously in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions with meloxicam use, especially gastrointestinal bleeding and perforations, which may be fatal.

Patients with existing asthma

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid (aspirin) in such patients is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, the drug should not be used in patients sensitive to acetylsalicylic acid and should be used with caution in patients with existing asthma.

Excipients

The medicinal product Loksidol contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The product also contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Effects on fertility

Meloxicam may negatively affect reproductive function and is therefore not recommended for women wishing to become pregnant. Women planning pregnancy or undergoing infertility evaluation should consider discontinuing the drug (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may negatively 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 malformations increased from less than 1% to approximately 1.5%. This risk is believed to increase with higher doses and longer duration of treatment.

From the 20th week of pregnancy, use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting 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 stopping treatment.

The medicinal product Loksidol should not be used during the first and second trimesters of pregnancy, except in cases of urgent need. If a woman is trying to conceive or uses meloxicam during the first and second trimesters, the dose and duration of treatment should be as low as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. The drug 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);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above);

possible risks in late pregnancy for mother and newborn:

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

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

Breastfeeding

Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use of the drug in women during breastfeeding is not recommended.

Fertility

Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, 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 the drug should be considered.

Ability to influence reaction speed when driving or operating machinery.

No specific studies on the effect of meloxicam on the ability to drive a vehicle or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, it can be assumed that meloxicam does not affect or has 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.

Dosage and Administration

Dosing

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

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

Osteoarthritis flare-up:

7.5 mg once daily (use other dosage forms of meloxicam with appropriate dosing). If necessary, the dose may be increased to 15 mg once daily.

Rheumatoid arthritis, ankylosing spondylitis:

15 mg once daily (1 tablet).

See also section "Special Patient Populations" below.

Depending on the therapeutic response, the dose may be reduced to 7.5 mg once daily (use other dosage forms of meloxicam with appropriate dosing).

DO NOT EXCEED THE DOSE OF 15 mg ONCE DAILY.

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 once daily (use other dosage forms of meloxicam with appropriate dosing) (also see section "Dosage and Administration", "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 once daily (use other dosage forms of meloxicam with appropriate dosing).

Renal impairment

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

For patients with end-stage renal disease undergoing hemodialysis, the dose should not exceed 7.5 mg once daily (use other dosage forms of meloxicam with appropriate dosing). No dose adjustment is required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min).

Hepatic impairment

No dose adjustment is required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section "Contraindications").

Route of administration

For oral use.

The medicinal product Loxidol, 15 mg tablets, should be taken with water or another liquid during meals.

Children

Loxidol 15 mg tablets are contraindicated in children under 16 years of age (see section "Contraindications").

Overdose

Symptoms

Symptoms of acute NSAID overdose are usually limited to lethargy, somnolence, 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.

Treatment

In case of overdose, symptomatic and supportive treatment should be initiated. Studies have shown that administration of 4 g of cholestyramine three times daily accelerates the elimination of meloxicam.

Adverse reactions.

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

Edema, arterial hypertension, and heart failure have been observed during treatment with NSAIDs.

Most of the adverse reactions observed are of gastrointestinal origin. Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (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 following 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 reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Uncommon – anemia; rare – blood test abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia.

Very rare 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); frequency not known – anaphylactic/anaphylactoid reactions, including shock.

Psychiatric disorders:

Rare – mood changes, nightmares; frequency not known – confusion, disorientation, insomnia.

Nervous system disorders:

Common – headache; uncommon – dizziness, somnolence.

Eye disorders:

Rare – visual disturbances including blurred vision, conjunctivitis.

Ear and labyrinth disorders:

Uncommon – vertigo; rare – tinnitus.

Cardiac disorders:

Rare – palpitations.

Heart failure has also been reported in association with the use of NSAIDs.

Vascular disorders:

Uncommon – increased blood pressure (see section "Special precautions for use"), flushes.

Respiratory, thoracic and mediastinal disorders:

Rare – asthma in patients with allergic reactions to acetylsalicylic acid or other NSAIDs; frequency not known – upper respiratory tract infections, cough.

Gastrointestinal disorders:

Very common – gastrointestinal disturbances such as dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea; uncommon – occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, belching; rare – colitis, gastroduodenal ulcer, esophagitis; very rare – gastrointestinal perforation; frequency not known – pancreatitis.

Peptic ulcer, perforation, or gastrointestinal bleeding may be severe and potentially fatal, especially in elderly patients (see section "Special precautions for use").

Hepatobiliary disorders:

Uncommon – liver function test abnormalities (e.g., increased transaminase or bilirubin levels); very rare – hepatitis; frequency 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; frequency 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"), renal function test abnormalities (increased plasma creatinine and/or urea levels); very rare – acute renal failure, particularly in patients at increased risk (see section "Special precautions for use"); frequency not known – urinary tract infections, changes in micturition frequency.

Reproductive system and breast disorders:

Frequency not known – female infertility, ovulation delay.

Musculoskeletal and connective tissue disorders:

Frequency not known – arthralgia, back pain, joint-related signs and symptoms.

General disorders:

Uncommon – edema, including peripheral edema; frequency not known – influenza-like 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 previously not observed with meloxicam but typical for other drugs of this pharmacotherapeutic group

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 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 pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging and out of reach of children.

Packaging.

10 tablets per blister; 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.Ш./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of business operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

WORLD MEDICINE, LLC, Ukraine.