Meloxicam-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELOXICAM-DARNYTSIA (MELOXICAM-DARNYTSIA)

Composition:

Active substance: meloxicam;

1 tablet contains meloxicam 7.5 mg or 15 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

7.5 mg tablets – pale yellow to pale yellow with greenish tint, elongated-shaped tablets, beveled on both sides with a score line;

15 mg tablets – pale yellow to pale yellow with greenish tint, round-shaped tablets, convex on one side, beveled edges and a score line on the other side.

Pharmacotherapeutic group

Non-steroidal anti-inflammatory drugs and antirheumatic agents. Oxicams.

ATC code M01AC06.

Pharmacological Properties

Pharmacodynamics

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

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

Pharmacokinetics

Absorption. Meloxicam is well absorbed from the gastrointestinal tract; after oral administration (capsules), the absolute bioavailability of the drug is 90%. Tablets, oral suspension, and capsules have demonstrated bioequivalence.

After single-dose administration, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms (tablets and capsules).

With repeated dosing, steady-state concentrations are achieved by day 3–5. Once-daily dosing results in average plasma concentrations with relatively small peak fluctuations: within 0.4–1.0 µg/mL for 7.5 mg and 0.8–2.0 µg/mL for 15 mg, respectively (Cmin and Cmax at steady state, respectively).

Average peak plasma concentrations of meloxicam at steady state are reached 5–6 hours after administration of tablets, capsules, or oral suspension. During continuous treatment for periods exceeding one year, plasma concentrations remain comparable to those observed at steady state at the beginning of therapy. Absorption of oral meloxicam is not altered when taken with food or concomitantly with mineral antacids.

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 multiple oral doses of meloxicam (7.5–15 mg) is 16 L, with a coefficient of variation between 11% and 32%.

Biological transformation. Meloxicam undergoes extensive biotransformation in the liver.

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

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

Dose linearity. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg after 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 was 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 (see sections "Dosage and administration" and "Contraindications").

Elderly patients. In elderly male patients, average pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Average plasma clearance at steady state in elderly patients was slightly lower than in young volunteers (see section "Dosage and administration").

Clinical characteristics

Indications

Short-term symptomatic treatment of osteoarthritis flare-ups.

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

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

Contraindications

• Hypersensitivity to the active substance or to any of the excipients;
• hypersensitivity to active substances with similar actions, such as 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");
• children under 16 years of age;
• gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• active or recurrent peptic ulcer/hemorrhage in medical history (two or more separate confirmed episodes of ulcers or bleeding);
• severe hepatic insufficiency;
• severe renal insufficiency without dialysis;
• gastrointestinal bleeding, cerebrovascular hemorrhage 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 interaction

Risks associated with hyperkalemia

Certain medicinal products or therapeutic groups may contribute to 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 whether associated factors are present. The risk of developing hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions

Other NSAIDs and acetylsalicylic acid. Combination with other NSAIDs (see section "Special precautions for use"), including acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose, is not recommended.

Corticosteroids (e.g., glucocorticoids). Concomitant use with corticosteroids requires caution due to an 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), heparin use requires caution due to an increased risk of bleeding. Careful monitoring of INR (International Normalized Ratio) is necessary if such 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 impaired renal function), 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. Patients should receive adequate hydration, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive agents (e.g., beta-blockers). As with the above-mentioned agents, 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. Close monitoring of renal function is recommended, especially in elderly patients.

Deferasirox

Concomitant use of meloxicam and deferasirox may increase the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these medicinal products.

Pharmacokinetic interaction: effect of meloxicam on the pharmacokinetics of other medicinal products

Lithium. Data exist for NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium), potentially reaching toxic levels. Concomitant use of lithium and NSAIDs is not recommended. If combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (>15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If combination therapy is required, blood counts and renal function should be monitored. Caution is advised when NSAID and methotrexate administration overlaps for 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (at a dose of 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 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 signs of 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 dose of 15 mg meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, administration of 15 mg meloxicam concomitantly with pemetrexed should be done cautiously in patients with normal renal function (creatinine clearance ≥80 mL/min).

Pharmacokinetic interaction: effect of other medicinal products on the pharmacokinetics of meloxicam

Cholestyramine. Cholestyramine accelerates the elimination of meloxicam due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13±3 hours. This interaction is clinically significant.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 (CYP) enzymes (mainly CYP 2C9 and minor CYP 3A4 pathways) 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 potent inhibitors or substrates of CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when combined with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of both agents. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

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

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use

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

The recommended maximum daily dose should not be exceeded if therapeutic effect is inadequate, and additional NSAIDs should not be used concomitantly, as this may increase toxicity without proven therapeutic benefit. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

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

Particular attention should be paid to a history of oesophagitis, gastritis and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. Patients treated with meloxicam and 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 warning symptoms, or history of serious gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration or perforation is greater with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose aspirin or other 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.

Meloxicam is not recommended for patients who are concurrently using medicinal products that may increase the risk of ulceration or bleeding, such as heparin used as a radical treatment or in geriatric practice, anticoagulants such as warfarin, or other non-steroidal anti-inflammatory drugs, including acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Hepatic disorders

Up to 15 % of patients receiving NSAIDs (including Meloxicam-Darnytsia) may experience elevation of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or AST (approximately three times or more above normal) were observed in 1 % of patients during clinical trials with NSAIDs. 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 with abnormal liver function tests should be evaluated for signs of more severe hepatic failure during treatment with Meloxicam-Darnytsia. If clinical signs and symptoms suggest development of liver disease or if systemic manifestations of disease occur (e.g. eosinophilia, rash), use of Meloxicam-Darnytsia should be discontinued.

Cardiovascular disorders

Careful monitoring is recommended for patients with arterial hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and oedema have been observed during NSAID therapy.

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

Data from studies and epidemiological evidence suggest that use of certain NSAIDs (especially 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.

Meloxicam therapy should be initiated only after careful consideration in patients with uncontrolled arterial hypertension, congestive heart failure, established ischaemic 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, hyperlipidaemia, 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 presents symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal involvement), meloxicam treatment must be discontinued. It is important to diagnose promptly and discontinue any drug 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 using 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 who have had a history of fixed drug eruption associated with meloxicam use. Potential cross-reactivity may occur with other oxicams.

Anaphylactoid reactions

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

Liver parameters and renal function

As with treatment with most NSAIDs, isolated cases of increased serum transaminases, increased serum bilirubin or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. In most cases, these abnormalities were minor and transient. If significant or persistent abnormalities are confirmed, meloxicam use 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 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 impairment;
• nephrotic syndrome;
• lupus nephritis;
• 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 retention of sodium, potassium and water and may affect the natriuretic effects of diuretics. In addition, a reduction in the antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, oedema, heart failure or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalaemia

Hyperkalaemia 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 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 frail patients, who require careful monitoring. As with treatment with other NSAIDs, caution is required in elderly patients, in whom reduced renal, hepatic and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

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

Use of meloxicam may negatively affect fertility 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").

Meloxicam-Darnytsia tablets 7.5 mg and 15 mg contain lactose (one Meloxicam-Darnytsia 7.5 mg tablet contains monohydrate lactose equivalent to 22.3 mg anhydrous lactose; one Meloxicam-Darnytsia 15 mg tablet contains monohydrate lactose equivalent to 19.0 mg anhydrous lactose). Therefore, this medicinal product is not recommended for patients with rare hereditary intolerance to galactose, total lactase deficiency or glucose-galactose malabsorption.

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

Masking of inflammation and fever

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

Treatment with corticosteroids

Meloxicam-Darnytsia cannot be considered a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Haematological effects

Anaemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, gastrointestinal bleeding of unknown origin (microscopic or macroscopic), or an incompletely described effect on erythropoiesis. Patients undergoing long-term treatment with NSAIDs, including meloxicam, should have haemoglobin or haematocrit monitored if symptoms or signs of anaemia 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-Darnytsia who may have adverse effects on platelet function, particularly 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 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-Darnytsia should not be used in patients sensitive to aspirin and should be prescribed with caution to 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 congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations increased from less than 1 % to about 1.5 %. This risk is considered to increase with increasing dose and duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation loss and embryofetal mortality. In addition, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular, has been reported.

From the 20th week of pregnancy, use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment. In addition, cases of arterial duct constriction after treatment in the second trimester have been reported, most of which resolved after discontinuation of treatment. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of compelling need. If a woman is trying to conceive or is using meloxicam during the first and second trimesters of pregnancy, 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 from 20 weeks of pregnancy onwards. If oligohydramnios or arterial duct constriction is detected, meloxicam use should be discontinued.

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

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

possible risks in late pregnancy for mother and newborn:

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

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

Breastfeeding. Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Meloxicam has been detected in milk of lactating animals. Therefore, use is not recommended for 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 influence reaction speed when driving vehicles or operating machinery

No specific studies on the effect of the drug on the ability to drive vehicles or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, meloxicam is likely to have no or negligible effect on such activities. Nevertheless, patients who experience 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

Dosing

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

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

Acute exacerbation of osteoarthritis:

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

Rheumatoid arthritis, ankylosing spondylitis:

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

See also section "Special Patient Populations" below.

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

DO NOT EXCEED THE DOSE OF 15 mg/day

Special Patient Populations

Elderly patients (see section "Pharmacokinetics")

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg daily (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")

Treatment should be initiated at a dose of 7.5 mg daily in patients at increased risk of adverse reactions, for example, those with a history of gastrointestinal disorders or risk factors for cardiovascular disease.

Renal impairment (see section "Pharmacokinetics")

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

Hepatic impairment (see section "Pharmacokinetics")

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

Method of administration

For oral use.

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

Children

Meloxicam-Darnytsia, tablets 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

Symptomatic and supportive measures are recommended for NSAID overdose. Studies have shown that oral administration of cholestyramine 4 g three times daily accelerates the elimination of meloxicam.

Adverse Reactions

General description

Data from clinical trials and epidemiological studies suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) may be associated with a small increased risk of thrombotic events (e.g., myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

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

Most of the adverse effects observed are gastrointestinal in nature. 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 exacerbations of colitis and Crohn’s disease have been reported following administration (see section "Special Warnings and Precautions for Use"). 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").

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

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

All adverse reactions are listed by system organ class and frequency: 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), 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 reaction, anaphylactoid reaction, 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 – dizziness;

Rare – tinnitus.

Cardiac disorders:

Rare – palpitations.

Heart failure associated with NSAID treatment 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;

Frequency 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;

Frequency not known – pancreatitis.

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

Hepatobiliary disorders:

Uncommon – liver function test abnormalities (e.g., elevated transaminases or bilirubin);

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 Warnings and Precautions for Use").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), changes in renal function 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");

Frequency not known – urinary tract infections, micturition disorders.

Reproductive system and breast disorders:

Frequency not known – female infertility, ovulation delay.

General disorders and administration site conditions:

Uncommon – edema, including peripheral edema;

Frequency not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders:

Frequency 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 of the class

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

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions

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

Keep out of the reach of children.

Packaging

7.5 mg – 10 tablets in a blister; 2 blisters per carton;

15 mg – 10 tablets in a blister; 1 or 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity

13, Borispiilska St., Kyiv, 02093, Ukraine.