INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELOLGAN (MELOLGAN)

Composition:

Active substance: meloxicam;

1 ampoule (1.5 ml) contains meloxicam 15 mg;

Excipients: meglumine, glycofurole, poloxamer 188, sodium chloride, glycine, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear greenish-yellow solution, free from particles.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. ATC code M01AC06.

Pharmacological Properties

Pharmacodynamics

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class, exhibiting anti-inflammatory, analgesic, and antipyretic effects. Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. The precise mechanism of action of meloxicam, as with other NSAIDs, remains unknown. However, a common mechanism of action for all NSAIDs (including meloxicam) is the inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics

Absorption. Meloxicam is completely absorbed following 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 (Cmax) is approximately 1.6–1.8 µg/mL and is reached within approximately 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%.

Metabolism. 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 CYP 2C9 plays a major role in the metabolism process, while CYP 3A4 isoenzymes play a minor role. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Meloxicam is primarily excreted in the form of metabolites in equal parts via urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine over 13–25 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.

Linearity of Dose. 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 increased free meloxicam concentration (see sections "Contraindications" and "Dosage and Administration").

Elderly patients. In elderly male patients, mean pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, 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 (see section "Dosage and Administration").

Clinical characteristics

Indications.

MELOLGAN, solution for injection, is indicated for short-term symptomatic treatment of acute attacks of rheumatoid arthritis and ankylosing spondylitis when other routes of administration cannot be used.

MELOLGAN, solution for injection, is indicated for treatment of adults.

Contraindications

Third trimester of pregnancy (see section "Use in pregnancy or breastfeeding");
patient age under 18 years;
hypersensitivity to meloxicam or to any of the excipients of the medicinal product, or to active substances with similar action, such as NSAIDs (acetylsalicylic acid); meloxicam should not be administered to patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
gastrointestinal bleeding or perforation related to previous NSAID therapy, in medical history;
active or recurrent peptic ulcer/bleeding in medical history (two or more separate confirmed episodes of ulcer or bleeding);
severe hepatic impairment;
severe renal impairment (without dialysis);
gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
hemostasis disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
severe heart failure.

Do not use for 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 cause hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim. The development of hyperkalemia may depend on whether associated risk factors are present. The risk of hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions

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

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

Anticoagulants or heparin. The risk of bleeding is significantly increased due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Concomitant use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or at therapeutic doses. Due to intramuscular administration, meloxicam solution for injection is contraindicated in patients undergoing anticoagulant therapy (see sections "Contraindications" and "Special precautions for use").

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

Thrombolytics 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 effect of diuretics and other antihypertensive medicinal products. 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 cyclooxygenase-inhibiting medicinal products may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combination 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 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 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 exist for NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning 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 methotrexate (over 15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered if the patient is taking low-dose methotrexate, particularly in the presence of impaired renal function. If combination therapy is required, blood parameters and renal function should be monitored. Caution should be exercised if NSAID and methotrexate administration continues for 3 consecutive days, as plasma methotrexate levels may rise and increase toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate is considered to potentially increase during NSAID therapy (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 withheld for 5 days before, on the day of, and for 2 days after pemetrexed administration. 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 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 concurrently 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 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 (CYP) P450 enzymes (mainly CYP 2C9 and minor pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that clearly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected in combination with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these medicinal products 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 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 symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below). The recommended maximum daily dose should not be exceeded if the therapeutic effect is insufficient, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam should not be used for treatment of patients requiring relief from acute pain. If there is no improvement after several days, the clinical benefits of treatment should be re-evaluated.

Particular attention should be paid to a history of esophagitis, gastritis and/or peptic ulcer to ensure their complete treatment prior to starting meloxicam therapy. Recurrence should be considered possible in patients treated with meloxicam and in those with such history.

Gastrointestinal disorders. As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment, with or without preceding symptoms, regardless of prior gastrointestinal disease (see section "Contraindications"). 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, and in elderly patients. These patients should start treatment with the lowest effective dose. For such patients, consideration should be given to co-prescribing protective agents (e.g., misoprostol or proton pump inhibitors), especially in patients requiring concomitant 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, particularly elderly patients, should be informed about any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly during initial stages of treatment.

Meloxicam is not recommended for patients who are concurrently using medicinal products that increase the risk of ulceration or bleeding, such as heparin (as radical therapy or in geriatric practice), anticoagulants such as warfarin, or other NSAIDs, including acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose (see section "Interaction with other medicinal products and other forms of interaction"). If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

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

Hepatic disorders. Approximately 15% of patients receiving NSAIDs (including meloxicam) may experience elevation of one or more liver function tests. Such laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (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, fulminant fatal hepatitis, liver necrosis and hepatic failure, some with fatal outcome, have been reported during clinical trials with NSAIDs. Patients with symptoms and signs of hepatic dysfunction or abnormal liver test results should be monitored for development of more severe hepatic failure during meloxicam treatment. If clinical signs and symptoms consistent with hepatic disease develop, or if systemic manifestations (e.g., eosinophilia, rash) occur, this medicinal product should be discontinued.

Cardiovascular and cerebrovascular disorders. Patients with 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 beginning of therapy, especially at the start of meloxicam treatment, in patients with cardiovascular risk factors. Data from studies and epidemiological evidence suggest that use of certain NSAIDs, including meloxicam (particularly at high doses and with prolonged treatment), is associated with a certain increased risk of vascular thrombotic events (such as myocardial infarction or stroke). There is insufficient data to exclude such risk with meloxicam use. Meloxicam therapy should be initiated only after careful evaluation in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease. Such evaluation is also necessary before initiating long-term treatment in patients with cardiovascular risk factors (e.g., 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 use. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens–Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment. If a patient develops symptoms or signs of Stevens–Johnson syndrome or toxic epidermal necrolysis (e.g., progressive skin rashes, often with blisters or mucosal involvement), meloxicam treatment should be discontinued. Prompt diagnosis and discontinuation of any medicinal product that may cause severe skin reactions—Stevens–Johnson syndrome or toxic epidermal necrolysis—are crucial for improved prognosis in severe skin reactions. If a patient develops Stevens–Johnson syndrome or toxic epidermal necrolysis during meloxicam use, the drug must never be re-administered in the future. Fixed drug eruptions have been reported with meloxicam use. Meloxicam should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam. Cross-reactivity with other oxicams is possible.

Anaphylactoid reactions. As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to meloxicam.

Meloxicam should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who develop 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 anaphylactoid reactions occur.

Liver parameters and renal function. During 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 observed. Generally, these abnormalities were mild and transient. If significant or persistent abnormalities occur, meloxicam use should be discontinued and follow-up tests performed.

Functional renal failure. Due to inhibition of the vasodilatory effect of renal prostaglandins, NSAIDs may induce functional renal failure by reducing glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and renal function is recommended at the beginning of treatment or after dose increase in patients with risk factors such as:

advanced age;
concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, or 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 nephropathy;
severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 points on Child–Pugh scale).

In rare cases, NSAID use may lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome. The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg. Dose 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 interfere with the natriuretic effects of diuretics. Additionally, 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, 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 "Contraindications" and "Dosage and administration").

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

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

Other warnings and safety measures. Adverse reactions are often poorly tolerated by elderly, frail or debilitated patients, who require careful monitoring. As 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.

Abscess or necrosis may occur at the injection site following intramuscular administration of NSAIDs.

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

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

Glucocorticoid therapy. Meloxicam cannot be a substitute for glucocorticoids in the treatment of glucocorticoid insufficiency.

Hematological effects. Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or an incompletely described effect on erythropoiesis. Hemoglobin or hematocrit levels should be monitored during long-term NSAID treatment, including meloxicam, if symptoms or signs of anemia are present. NSAIDs inhibit platelet aggregation and may lead to prolonged bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively less, short-term and reversible. Close monitoring is required in patients receiving meloxicam who are at risk of adverse reactions related to platelet function changes, such as coagulation disorders, or in patients receiving anticoagulants.

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

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

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 believed to increase with higher doses and longer duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation losses and embryofetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, the frequency of various developmental abnormalities, particularly cardiovascular, was increased.

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. Therefore, the medicinal product should not be used during the first and second trimesters of pregnancy, except in cases of urgent need. If meloxicam is used by a woman trying 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 constriction of the arterial duct is recommended after meloxicam exposure for several days starting from the 20th week of pregnancy. If oligohydramnios or constriction of the arterial duct 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);

and risks to the mother and newborn near term:

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

Therefore, the medicinal product is contraindicated during the third trimester of pregnancy.

Breastfeeding period.

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

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 a vehicle or operate machinery have been conducted. Given the pharmacodynamic profile and observed adverse reactions, meloxicam is expected to have no effect or a negligible effect on such activities. However, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo or other central nervous system disorders, are advised to refrain from driving or operating machinery.

Method of Administration and Dosage

Administer intramuscularly.

Dose — 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 in justified exceptional cases (e.g., when oral and rectal 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 evaluated.

Elderly patients (see section "Pharmacokinetics"). The recommended dose for elderly patients is 7.5 mg per day (half of a 1.5 ml ampoule) (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 ampoule).

Renal impairment. This medicinal product is contraindicated in patients with severe renal impairment who are not on haemodialysis (see section "Contraindications"). For patients with end-stage renal disease on haemodialysis, the dose should not exceed 7.5 mg per day (half of a 1.5 ml ampoule). Dose reduction 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.

The medicinal product MELOLGAN, solution for injection, is administered by deep intramuscular injection into the upper outer quadrant of the buttock, strictly observing aseptic technique. In case of repeated administration, alternating between left and right buttocks is recommended. Prior to injection, it is important to ensure that the needle tip has not entered a blood vessel. The injection should be stopped immediately if severe pain occurs during the procedure. If the patient has a hip prosthesis, the injection should be administered into the opposite buttock. For continuation of treatment, oral dosage forms (tablets) should be used.

Children. The medicinal product is contraindicated in patients under 18 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 care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, seizures, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions, which have occurred during therapeutic use of NSAIDs, may also be observed in overdose.

Treatment. Symptomatic and supportive measures are recommended for patients with NSAID overdose. Studies have shown accelerated elimination of meloxicam with oral doses of cholestyramine 4 g three times daily.

Adverse Reactions

General description

Data from clinical studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) is associated with a small increase in the 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 NSAID therapy.

Most adverse effects of meloxicam are gastrointestinal in origin. Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special precautions for use"). The following have been reported after drug administration: nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn’s disease (see section "Special precautions for use"). Gastritis occurs less frequently. Serious skin reactions have been reported: Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special precautions for use").

List of adverse reactions

The frequency of adverse reactions was determined based on data from 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.

This list also includes adverse reactions reported during post-marketing use.

Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: uncommon — anemia; rare — blood test abnormalities (including changes in white blood cell 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.

Psychiatric disorders: rare — mood changes, night terrors; 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 use has been reported.

Vascular disorders: uncommon — increased blood pressure (see section "Special precautions for use"), flushing.

Respiratory, thoracic and mediastinal disorders: rare — asthma in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs; frequency not known — upper respiratory tract infections, cough.

Gastrointestinal disorders: very common — 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.

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

Hepatobiliary disorders: uncommon — liver function abnormalities (e.g., increased transaminase or bilirubin levels); rare — hepatitis; frequency not known — jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: uncommon — angioedema, pruritus, rash; rare — Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria; very rare — bullous dermatitis, erythema multiforme; 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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"), changes in renal function parameters (increased serum creatinine and/or urea levels); rare — acute renal failure, particularly in patients with risk factors (see section "Special 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: common — injection site induration, injection site pain; uncommon — edema, including peripheral edema; frequency not known — influenza-like symptoms.

Musculoskeletal and connective tissue disorders: frequency not known — arthralgia, back pain, signs and symptoms related to joints.

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 drug but typical for other compounds of the class. Organic kidney damage, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of 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 are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 1.5 ml (15 mg) in ampoules, 5 ampoules per cassette in a carton.

Prescription status. Prescription only.

Manufacturer. HELP S.A.

Manufacturer's address and location of operations. Pedini Yanninon, Yannina, 45500, Greece

Melolgan