Meloxicam-darnitsa

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

Composition:

Active substance: meloxicam;

1 ampoule of 1.5 ml solution contains meloxicam 15 mg;

Excipients: meglumine, glycofurol, poloxamer, sodium chloride, glycine, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear yellow solution with a greenish tint.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. ATC code M01A C06.

Pharmacological Properties

Pharmacodynamics

Meloxicam-Darnytsia is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class with 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, there is a common mechanism of action shared by all NSAIDs (including meloxicam): inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics

Absorption. Meloxicam is completely absorbed after intramuscular injection. The relative bioavailability compared to oral administration is nearly 100%. Therefore, dose adjustment is not required when switching from intramuscular to oral administration. After intramuscular injection of 15 mg, the maximum plasma concentration is approximately 1.6–1.8 μg/mL and is reached within 1–6 hours.

Distribution. Meloxicam is highly bound to plasma proteins, primarily to albumin (99%). Meloxicam penetrates into synovial fluid, where its concentration is about half that in plasma. The volume of distribution is low, averaging 11 L after intramuscular or intravenous administration, with individual variations within 7–20%. The volume of distribution after multiple oral doses of meloxicam (7.5 to 15 mg) is 16 L, with a coefficient of variation ranging from 11% to 32%.

Biological Transformation. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam, pharmacodynamically inactive, have been identified in urine. The 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 CYP 2C9 plays a major role in the metabolic process, while the isoenzyme CYP 3A4 is less involved. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Elimination of meloxicam occurs primarily as metabolites in equal proportions in 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, depending on the route of administration (oral, intramuscular, or intravenous). Plasma clearance is approximately 7–12 mL/min after a single oral dose, intravenous, or rectal administration.

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

Special Patient Groups

Patients with Hepatic/Renal Impairment. Mild to moderate hepatic and renal impairment do not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment had 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, mean pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers (see section "Dosage and Administration").

Clinical characteristics

Indications. Meloxicam-Darnitsya, solution for injection, is indicated for short-term symptomatic treatment of acute exacerbations of rheumatoid arthritis and ankylosing spondylitis in adults when other routes of administration are not applicable.

Contraindications

• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");
• Patient age under 18 years;
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Hypersensitivity to active substances with similar actions, such as NSAIDs, aspirin. Meloxicam should not be administered to patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking aspirin or other NSAIDs;
• Gastrointestinal bleeding or perforation associated with 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;
• History of gastrointestinal bleeding, cerebrovascular bleeding, or other coagulation disorders;
• Hemostasis disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
• Severe heart failure;
• Not to be used for the treatment of perioperative pain in coronary artery bypass grafting.

Interaction with other medicinal products and other forms of interaction

Risks associated with hyperkalemia

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

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

Pharmacodynamic interactions

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

Corticosteroids (e.g., glucocorticoids). Concomitant use with corticosteroids requires caution due to increased risk of bleeding or gastrointestinal ulcers.

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. Due to intramuscular administration, meloxicam injection solution is contraindicated in patients undergoing anticoagulant therapy (see sections "Contraindications" and "Special precautions for use").

In other cases (e.g., when prophylactic doses are prescribed), caution is required when using heparin due to an increased risk of bleeding.

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 medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including 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 use of the following medicinal products, a reduction in the antihypertensive effect of beta-blockers may occur (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). NSAIDs may enhance the nephrotoxicity of calcineurin inhibitors by mediating effects on renal prostaglandins. Careful monitoring of renal function is recommended, especially in elderly patients.

Deferasirox. Concomitant use of meloxicam and deferasirox increases 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 indicate that NSAIDs increase plasma lithium concentrations (by reducing renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended. If such combination therapy is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam therapy.

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 taking high-dose (more than 15 mg/week) methotrexate (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients taking low-dose methotrexate, particularly those with impaired renal function. If such combination therapy is necessary, blood test parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate administration occurs 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 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 suspended 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If the 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 below 45 mL/min).

In patients with normal renal function (creatinine clearance ≥ 80 mL/min), meloxicam doses of 15 mg may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing a 15 mg dose of 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 accelerates the elimination of meloxicam by disrupting 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 the 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 secondary 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 clearly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when combined with oral antidiabetic agents (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide preparations should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interaction was observed with concomitant use of antacids, cimetidine, and digoxin.

Children. Interaction studies have been conducted only in adults.

Special precautions for use

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

The recommended maximum daily dose should not be exceeded if the 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 should not be used for the 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.

Caution is advised in patients with a history of esophagitis, gastritis and/or peptic ulcer; ensure complete healing before initiating meloxicam therapy. Patients receiving meloxicam, as well as those with such history, should be monitored regularly for possible recurrence.

Gastrointestinal disorders

At any time during NSAID therapy, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur, with or without prior symptoms or a 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 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. Consider prescribing concomitant protective therapy (e.g., misoprostol or proton pump inhibitors) for these patients, as well as for patients requiring concomitant 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, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment.

Concomitant use of meloxicam is not recommended in patients taking medicinal products that increase the risk of ulceration or bleeding, such as heparin (as definitive therapy or in geriatric practice), anticoagulants such as warfarin, other nonsteroidal anti-inflammatory drugs, or 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 receiving 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 receiving NSAIDs (including the medicinal product Meloxicam-Darnytsia) may experience elevated levels of one or more liver function tests. These abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately three times or more above the upper limit of normal) were observed in 1% of patients during clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant fatal hepatitis, hepatic necrosis, and hepatic failure, sometimes fatal, have been reported during clinical trials with NSAIDs.

Patients presenting symptoms and/or signs of hepatic dysfunction or abnormal liver function tests should be evaluated for progression to more severe hepatic failure during treatment with Meloxicam-Darnytsia. If clinical signs and symptoms suggestive of hepatic disease develop, or if systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), use of Meloxicam-Darnytsia should be discontinued.

Cardiovascular disorders

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should be closely monitored, as fluid retention and edema have been observed during NSAID therapy.

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

Clinical and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and for prolonged periods) is associated with a small increased risk of vascular thrombotic events (such as myocardial infarction or stroke). There are insufficient data to exclude such risk with meloxicam.

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

NSAIDs 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 have an increased risk of thrombotic complications.

Skin reactions

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam. Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment. If a patient develops symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g., progressive skin rash, often with blisters or mucosal involvement), meloxicam treatment should be discontinued. Prompt diagnosis and discontinuation of any drug that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—is critical, as early intervention improves prognosis. Meloxicam must never be re-administered to patients who have experienced Stevens-Johnson syndrome or toxic epidermal necrolysis during meloxicam treatment.

Cases of fixed drug eruption have been reported with meloxicam. Meloxicam should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam. Cross-reactivity with other oxicams may occur.

Anaphylactoid reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to meloxicam. Meloxicam-Darnytsia should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have experienced rhinitis, with or without nasal polyps, or who have had severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. In case of anaphylactoid reaction, emergency measures should be initiated immediately.

Liver parameters and renal function

As with treatment with most NSAIDs, isolated cases of elevated serum transaminases, serum bilirubin, or other liver function parameters, increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. These abnormalities are usually mild and transient. Meloxicam should be discontinued and follow-up tests performed if significant or persistent abnormalities occur.

Functional renal failure

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

• advanced age;
• concomitant use of 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 insufficiency;
• nephrotic syndrome;
• lupus nephritis;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 on Child-Pugh classification).

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

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

Retention of sodium, potassium, and water

NSAIDs may enhance retention of sodium, potassium, and water and may interfere with the natriuretic effects of diuretics. In addition, reduced antihypertensive efficacy of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure, or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients at risk of sodium, potassium, and water retention (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia

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

Combination with pemetrexed

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

Other warnings and safety measures

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

Like any other NSAID, meloxicam may mask symptoms of infectious diseases.

As with intramuscular administration of other NSAIDs, abscess or necrosis may occur at the injection site.

Meloxicam may adversely 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").

The medicinal product contains less than 1 mmol of sodium (23 mg) per 1.5 mL ampoule, i.e., essentially sodium-free.

Masking of inflammation and fever

The pharmacological action of Meloxicam-Darnytsia, aimed at reducing fever and inflammation, may reduce the diagnostic value of clinical findings in identifying complications of suspected non-infectious painful conditions.

Treatment with corticosteroids

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

Hematological effects

Anemia may occur in patients receiving NSAIDs, including Meloxicam-Darnytsia. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or incompletely described effects on erythropoiesis. In patients undergoing long-term treatment with NSAIDs, including Meloxicam-Darnytsia, hemoglobin or hematocrit levels should be monitored if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, transient, and reversible. Patients receiving Meloxicam-Darnytsia who may experience adverse effects on platelet function, such as coagulation disorders, or who are receiving anticoagulants, require careful monitoring.

Use in patients with asthma

Patients with asthma may have aspirin-sensitive asthma. Administration of aspirin to 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 hypersensitive to aspirin and should be used with caution in patients with asthma.

Use during pregnancy or breastfeeding

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/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 higher doses and longer duration of treatment. In animal studies, prostaglandin synthesis inhibitors have been shown to increase pre- and post-implantation loss and embryofetal mortality. In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. Oligohydramnios may occur soon after initiation of treatment and is usually reversible upon discontinuation. In addition, cases of ductus arteriosus constriction after second-trimester treatment have been reported, which mostly resolved after treatment cessation. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except when strictly necessary. If meloxicam is used by a woman attempting to conceive or 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 ductus arteriosus constriction is recommended within several days after meloxicam exposure starting from the 20th week of pregnancy. If oligohydramnios or ductus arteriosus constriction is detected, meloxicam 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 ductus arteriosus and pulmonary hypertension);
• renal impairment (see above);

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

Breastfeeding. Although specific data on Meloxicam-Darnytsia 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 adversely 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 or operating machinery

No specific studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Given the pharmacodynamic profile and observed adverse reactions, meloxicam is expected not to affect or to have a negligible effect on such activities. However, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, should refrain from driving or operating machinery.

Method of Administration and Dosage

Dosing

One injection of 15 mg once daily.

DO NOT EXCEED THE DOSE OF 15 mg/day.

Treatment should be limited to one injection at the beginning of therapy, with a maximum duration of up to 2–3 days only in justified exceptional cases (i.e. when other routes of administration are not feasible). 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 assessed.

Special Patient Categories

Elderly patients (see section "Pharmacokinetics"). The recommended dose for elderly patients is 7.5 mg per day (half of a 1.5 ml vial) (also see subsection "Patients at Increased Risk of Adverse Reactions" below and section "Special Warnings and Precautions for Use").

Patients at Increased Risk of Adverse Reactions (see section "Special Warnings and Precautions for Use"). For patients at increased risk of adverse reactions, such as those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg per day (half of a 1.5 ml vial).

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

For patients with end-stage renal disease on hemodialysis, the dose should not exceed 7.5 mg per day (half of a 1.5 ml vial).

Dose adjustment is not required in patients with mild to moderate renal impairment (i.e. patients with creatinine clearance above 25 ml/min).

Hepatic Impairment. Dose reduction is not required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, see section "Contraindications".

Method of Administration

For intramuscular use only.

Inject 15 mg/1.5 ml solution for injection by deep intramuscular injection into the upper outer quadrant of the buttock, strictly observing aseptic technique. In case of repeated administration, it is recommended to alternate between left and right buttocks. Prior to injection, it is important to ensure that the needle tip has not entered a blood vessel.

If severe pain occurs during injection, administration should be immediately discontinued.

If the patient has a hip prosthesis, the injection should be administered into the opposite buttock.

For continuation of treatment, oral dosage forms of the drug (tablets) should be used.

Children. Meloxicam-Darnitsya, solution for injection 15 mg/1.5 ml, is contraindicated in children (under 18 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 treatment. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

Treatment. In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that oral administration of cholestyramine 4 g three times daily accelerates the elimination of meloxicam.

Adverse Reactions

Clinical studies and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and over prolonged periods) may be associated with a small increased risk of vascular thrombotic events (such as myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

Treatment with NSAIDs has been associated with edema, arterial hypertension, and heart failure.

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

Severe 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 was determined based on data from adverse reactions recorded in 27 clinical trials with treatment duration of at least 14 days. A total of 15,197 patients received oral meloxicam at daily doses of 7.5 mg or 15 mg for up to one year.

Additionally, adverse reactions identified during post-marketing surveillance are included.

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).

Eye disorders:

rare — visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders:

uncommon — dizziness;

rare — tinnitus.

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

Hepatobiliary disorders:

uncommon — liver function abnormalities (e.g., elevated transaminase or bilirubin levels);

very rare — hepatitis;

frequency not known — jaundice, hepatic failure.

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 (elevated creatinine and/or blood urea nitrogen levels);

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.

Nervous system disorders:

common — headache;

uncommon — dizziness, somnolence.

Psychiatric disorders:

rare — mood changes, nightmares;

frequency not known — confusion, disorientation, insomnia.

Cardiovascular disorders:

rare — palpitations.

Heart failure associated with NSAID use has been reported;

uncommon — increased blood pressure (see section "Special Warnings and Precautions for Use"), flushing.

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" below).

Immune system disorders:

uncommon — allergic reactions, excluding anaphylactic or anaphylactoid reactions;

frequency not known — anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, including shock.

Skin and subcutaneous tissue disorders:

uncommon — angioedema, 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").

Musculoskeletal and connective tissue disorders:

frequency not known — arthralgia, back pain, joint signs and symptoms.

Reproductive system and breast disorders:

frequency not known — female infertility, delayed ovulation.

General disorders and administration site conditions:

common — injection site induration, injection site pain;

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 receiving meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adverse reactions not associated with the use of the medicinal product but 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 Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report any suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 1.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Packaging. 1.5 ml in a vial; 5 vials in a blister pack; 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations. 13, Borispilska Street, Kyiv, 02093, Ukraine.