Meloktam

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

Composition:

Active substance: meloxicam;

1 ampoule (1.5 ml) contains meloxicam 15 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear greenish-yellow solution.

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

Pharmacological Properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, exhibiting anti-inflammatory, analgesic, and antipyretic effects. Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, 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 an intramuscular injection of 15 mg, the maximum plasma concentration (C_max) 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 ranging from 7% to 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, 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 metabolic process, whereas 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.

Dose linearity. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg after both 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.

For short-term symptomatic treatment of acute attacks of rheumatoid arthritis and ankylosing spondylitis when other routes of administration cannot be used.

The medicinal product Meloctam, solution for injection, is indicated for treatment of adult patients.

Contraindications.

• Third trimester of pregnancy (see section "Use in pregnancy or lactation");
• 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, 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/hemorrhage 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;
• bleeding disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
• severe heart failure;
• not to be used for treatment of perioperative pain in coronary artery bypass grafting.

Interaction with other medicinal products and other types of interactions.

Risks associated with hyperkalemia. Some medicinal products or therapeutic groups may cause hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim. The development of hyperkalemia may depend on associated risk factors. 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"), acetylsalicylic acid at doses ≥ 500 mg (single dose) or ≥ 3 g (total daily dose).

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

Thrombolytic and antiplatelet medicinal products. 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 renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible 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 is possible (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). Nephrotoxicity of calcineurin inhibitors may be potentiated by NSAIDs due to mediation of effects on renal prostaglandins. 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 on NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium) are available, 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.

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 if the patient is receiving low-dose methotrexate, particularly in the presence of renal impairment. If combination therapy is required, blood count and renal function should be monitored. Caution should be exercised if NSAID and methotrexate are taken for 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate is considered to potentially increase with 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 should be withheld 5 days before, on the day of, and 2 days after pemetrexed administration. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance <45 mL/min). For patients with normal renal function (creatinine clearance ≥80 mL/min), a 15 mg dose of meloxicam may reduce pemetrexed elimination, thus increasing the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min).

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

Cholestyramine accelerates the elimination of meloxicam due to disruption of enterohepatic circulation, thus increasing meloxicam clearance by 50% and reducing its half-life to 13 ± 3 hours. This interaction is clinically significant.

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

Oral antidiabetic agents (sulfonylureas, nateglinide). Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 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 clearly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected in combination with medicinal products such as oral antidiabetics (sulfonylureas, nateglinide); this interaction may lead to increased plasma levels of these medicinal products and meloxicam. 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 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 therapeutic effect is inadequate, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. 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. In the absence of improvement after several days, the clinical benefits of treatment should be re-evaluated.

Care should be taken regarding a history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating 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 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. These patients should start treatment with the lowest effective dose. For such patients, consideration should be given to prescribing concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors). This also applies to patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

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

Concomitant use of meloxicam is not recommended in patients taking drugs that increase the risk of ulceration or bleeding, such as heparin (as definitive 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 worsen (see section "Adverse reactions").

Hepatic disorders. Approximately 15% of patients receiving NSAIDs (including Melotam) may experience elevation of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked increases in 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/or signs of hepatic dysfunction or abnormal liver test results should be monitored for development of more severe hepatic failure during treatment with Melotam. If clinical signs and symptoms suggest hepatic disease or if systemic manifestations of disease occur (e.g., eosinophilia, rash), this medicinal product should be discontinued.

Cardiovascular disorders and cerebrovascular disorders.

Careful monitoring is recommended in patients with arterial hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been observed during NSAID therapy. Clinical monitoring of blood pressure is recommended at the start of therapy, especially at the beginning of meloxicam treatment, in patients with 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 some increased risk of vascular thrombotic events (such as myocardial infarction or stroke). Insufficient data are available to exclude such risk with meloxicam use.

Therapy with meloxicam 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 required 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 disorders. 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 skin reactions should be closely monitored. 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 medicinal product that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are essential. A better prognosis is associated with early intervention in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while taking meloxicam, this medicinal product must never be restarted in the future. Cases of fixed drug eruption have been reported with meloxicam use.

Meloxicam should not be re-administered to patients with 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 hypersensitivity to Melotam. Melotam 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. 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 parameter deviations have been reported. In most cases, these deviations were minor and transient. Meloxicam should be discontinued and follow-up tests performed if significant or persistent abnormalities are confirmed.

Functional renal impairment. NSAIDs, due to inhibition of the vasodilatory effect of renal prostaglandins, may induce functional renal impairment 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: advanced age; concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section "Interaction with other medicinal products and other forms of interaction"); hypovolemia (of any origin); congestive heart failure; renal impairment; nephrotic syndrome; lupus nephropathy; severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 on Child-Pugh classification).

In isolated 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 impairment 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).

Retention of sodium, potassium, and water. NSAIDs may enhance retention of sodium, potassium, and water and may affect 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 in 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 drugs 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 pemetrexed administration, on the day of administration, and for at least 2 days after administration (see section "Interaction with other medicinal products and other forms of interaction").

Other warnings and safety measures. Adverse reactions are often less well tolerated in elderly, debilitated, or weakened patients, who require careful monitoring. As with other NSAIDs, caution is advised 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.

As with intramuscular administration of other NSAIDs, abscess or necrosis may occur at the injection site. Meloxicam may negatively affect fertility and is therefore not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

Masking of inflammation and fever. The pharmacological action of Melotam, aimed at reducing fever and inflammation, may reduce the diagnostic value of these signs in identifying complications related to suspected non-infectious painful conditions.

Treatment with corticosteroids. Melotam cannot serve as a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects. Anemia may occur in patients receiving NSAIDs, including Melotam. 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 should be monitored in patients undergoing long-term treatment with NSAIDs, including Melotam, if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively less, short-term, and reversible. Careful monitoring is required in patients receiving Melotam who may have adverse reactions related to platelet function disorders, such as coagulation disorders, or in patients receiving anticoagulants.

Use in patients with asthma. 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 hypersensitive to acetylsalicylic acid and should be used with caution in patients with asthma.

Important information about excipients.

The medicinal product contains less than 1 mmol sodium (23 mg) per 1.5 mL ampoule, i.e., is 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 heart defects increased from less than 1% to approximately 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. Additionally, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, increased frequency of various developmental abnormalities, including cardiovascular, has been reported.

From the 20th week of pregnancy, use of Melotam may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, reports of arterial duct constriction after treatment in the second trimester, most of which resolved after discontinuation, have been documented. Therefore, Melotam should not be prescribed during the first and second trimesters unless necessary. If meloxicam is prescribed to women planning pregnancy or during the first and second trimesters, the lowest possible effective dose should be used for as short a duration as possible. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after meloxicam exposure for several days starting from the 20th week of pregnancy. Melotam should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

for the fetus:

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

risks near term for mother and newborn:

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

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

Lactation period. Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use of this 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 affect 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 not expected to have an effect or only a minor 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

Intramuscular use. 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 Risk of Adverse Reactions" below and section "Special Warnings and Precautions for Use").

Patients at 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 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 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 intramuscular use.

Meloctam, solution for injection 15 mg/1.5 ml, is administered by deep intramuscular injection into the upper outer quadrant of the buttock, strictly observing aseptic technique. In case of repeated injections, it is recommended to alternate between the left and right buttocks. Before injection, it is important to ensure that the needle tip is not within a blood vessel. The injection should be stopped immediately if severe pain occurs during administration. In patients with a hip prosthesis, the injection should be administered into the opposite buttock. For continuation of treatment, oral formulations (tablets) should be used.

Children.

Meloctam, solution for injection 15 mg/1.5 ml, is contraindicated in patients 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 care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in cases of overdose.

In the event of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that meloxicam elimination is accelerated by administration of 4 oral doses of cholestyramine given 3 times daily.

Adverse Reactions

Data from studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) is associated with a modest increase in the risk of vascular thrombotic events (such as 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 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 medicinal product, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease have been reported (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 the adverse reactions listed below is based on reported adverse reactions 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 mg or 15 mg for periods up to one year.

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

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 — anaemia; rare — blood test abnormalities (including changes in white blood cell count), leucopenia, 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 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 — vertigo; rare — tinnitus.

Cardiac disorders: rare — palpitations.

Heart failure associated with NSAID use 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 — 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 test abnormalities (e.g., increased 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 "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), changes in renal function parameters (increased creatinine and/or serum 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: 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, joint signs and 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 characteristic of other compounds in 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 authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 5 years.

Storage conditions. No special storage conditions are required. Keep out of the reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer. HELP S.A.

Manufacturer's address and place of business.

Pedinii Ionninon, Ioannina, 45500, Greece