Melox

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

Composition:

Active substance: meloxicam;

1.5 ml of solution (1 ampoule) contains meloxicam 15 mg;

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

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear yellow or greenish-yellow solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic agents.

ATC code M01A C06.

Pharmacological Properties

Pharmacodynamics

Melox 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 precise 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 following intramuscular injection. Its 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 (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 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 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 metabolism process, while CYP 3A4 isoenzymes play a minor role. Peroxidase activity in patients may be responsible for the formation of two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Meloxicam is primarily excreted 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 between 13 and 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.

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.

Short-term symptomatic treatment of acute attacks of rheumatoid arthritis and ankylosing spondylitis when oral or rectal administration routes cannot be used.

Contraindications.

• Third trimester of pregnancy (see section "Use during 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 actions, 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/bleeding in history (two or more separate confirmed episodes of ulcer or bleeding);
• severe hepatic impairment;
• severe renal impairment (without dialysis);
• gastrointestinal bleeding, cerebrovascular bleeding in history, or other coagulation disorders;
• hemorrhagic disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
• severe heart failure;
• 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 onset of hyperkalemia may depend on associated factors. The risk of developing hyperkalemia increases if the above-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"), 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 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 used), 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 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 combinations should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive 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.

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, particularly in elderly patients.

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

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

Lithium. Data exist for NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium), 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.

Metotrexate. 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 in patients taking low-dose methotrexate, including those with impaired renal function. If combination therapy is required, blood test parameters and renal function should be monitored. Caution should be exercised if NSAID and methotrexate administration lasts for 3 consecutive days, as plasma methotrexate levels may rise 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 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 suspended 5 days before, on the day of, and 2 days after pemetrexed administration. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for signs of myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance < 45 mL/min).

In patients with normal renal function (creatinine clearance ≥ 80 mL/min), a dose of 15 mg meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥ 80 mL/min).

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 (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 enzymes (mainly CYP 2C9 and secondarily CYP 3A4) and one-third via other pathways, such as peroxidative oxidation. Potential pharmacokinetic interactions should be considered when administering meloxicam 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 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 should be closely monitored for signs of hypoglycemia.

No clinically significant pharmacokinetic interaction was observed with concomitant use 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 concomitantly, 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 from acute pain. If no improvement is observed after several days, the clinical benefits of treatment should be re-evaluated.

Caution should be exercised in patients with a history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. The potential for recurrence should always be considered in patients being 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 therapy, with or without preceding symptoms or serious gastrointestinal disease in history. The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products 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.

Concomitant use of meloxicam is not recommended in patients taking medicinal products that may increase the risk of ulceration or bleeding, such as heparin used 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 Melox) may experience increased levels of one or more liver function tests. Such laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or 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 and fulminant fatal hepatitis, liver necrosis, and hepatic failure, some of which were fatal, have been reported during clinical trials with NSAIDs.

Patients with symptoms and/or signs of hepatic dysfunction or with abnormal liver function tests should be evaluated for the development of more severe hepatic failure during treatment with Melox. If clinical signs and symptoms suggest development of liver disease or if systemic manifestations occur (e.g., eosinophilia, rash), use of this medicinal product should be discontinued.

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

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

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

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

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. The risk increases with duration of use. Patients with cardiovascular disease or cardiovascular risk factors may have an increased risk 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 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 medicinal product that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are crucial, as early intervention improves prognosis in severe skin reactions. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during meloxicam use, the drug must never be re-administered in the future.

Fixed drug eruptions (FDE) have been reported with meloxicam use. Meloxicam should not be re-prescribed to patients with a history of FDE associated with meloxicam. Cross-reactivity with other oxicams is possible.

Anaphylactic reactions. As with other NSAIDs, anaphylactic reactions may occur in patients without known prior sensitivity to Melox. Melox should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have a history of rhinitis with or without nasal polyps or who experience severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Immediate measures should be taken if anaphylactic reactions occur.

Liver parameters and kidney 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. If significant or persistent abnormalities are confirmed, meloxicam use should be discontinued and follow-up tests performed.

Functional renal failure. NSAIDs, due to inhibition of the vasodilatory effect of renal prostaglandins, 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 the following risk factors: 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 according to Child-Pugh classification).

In isolated cases, NSAIDs 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 sodium, potassium, and water retention and affect the natriuretic effects of diuretics. In addition, a reduced 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 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 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 in elderly, debilitated, or weakened patients, who require careful monitoring. As with treatment with other NSAIDs, caution is required in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

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

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

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

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

Concomitant corticosteroid therapy. Melox cannot be considered a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects. Anemia may occur in patients receiving NSAIDs, including Melox. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or incompletely described effects on erythropoiesis. Patients undergoing long-term treatment with NSAIDs, including Melox, should have hemoglobin or hematocrit monitored 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. Patients receiving Melox who may be at risk of adverse reactions related to changes in platelet function, such as coagulation disorders, or patients receiving anticoagulants, require careful monitoring.

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, Melox should not be used in patients sensitive to acetylsalicylic acid and should be used with caution in patients with asthma.

Use during pregnancy or breastfeeding.

Fertility. For women attempting to conceive, dosage and duration of treatment should be kept to a minimum.

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 approximately 1.5%. This risk is considered to increase with increasing dose and duration of treatment.

Use of meloxicam from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. In addition, fetal arterial duct constriction has been reported after drug intake during the second trimester of pregnancy, which in most cases resolved after discontinuation of treatment. Therefore, meloxicam should not be taken during the first and second trimesters of pregnancy unless absolutely necessary.

Prenatal monitoring for oligohydramnios and fetal arterial duct constriction may be appropriate if exposure to meloxicam occurs for several days starting from the 20th gestational week. Pregnant women should discontinue meloxicam if oligohydramnios or fetal arterial duct constriction is detected.

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

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

Potential risks in late pregnancy for both mother and fetus:

• 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 Melox are lacking, NSAIDs are known to pass into breast milk. Therefore, use of the medicinal product is not recommended for breastfeeding women.

Ability to affect reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive a vehicle or operate machinery have been conducted. However, based on the pharmacodynamic profile and adverse reactions observed, meloxicam is likely to have no effect or a negligible effect on such activities. Nevertheless, patients who experience visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, are advised to refrain from driving or operating machinery.

Method of Administration and Dosage.

Intramuscular administration. 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 Precautions").

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 daily (half of a 1.5 ml vial) (see section "Method of Administration and Dosage" under 'Patients at increased risk of adverse reactions' and section "Special Precautions").

Patients at increased risk of adverse reactions (see section "Special Precautions"). For patients at increased risk of adverse reactions, e.g., those with a history of gastrointestinal disorders or risk factors for cardiovascular diseases, treatment should be initiated at a dose of 7.5 mg daily (half of a 1.5 ml vial).

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

Administration instructions. The drug should be administered slowly by deep intramuscular injection into the upper outer quadrant of the buttock, strictly following aseptic technique. In case of repeated injections, alternating between left and right buttocks is recommended. Prior to injection, it is important to ensure that the needle tip is not within a blood vessel. The injection should be immediately discontinued 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 dosage forms (tablets) should be used.

Children.

Melox, injection solution 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, seizures, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

In case of NSAID overdose, symptomatic and supportive measures are recommended for patients. Studies have shown accelerated elimination of meloxicam using 4 oral doses of cholestyramine administered 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) may be associated with a small 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 exacerbation of colitis and Crohn’s disease have been observed (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").

Blood and lymphatic system disorders: Uncommon – anemia; isolated cases – blood test abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia.

Very rare cases of agranulocytosis have been reported (see "Specific serious and/or common adverse reactions").

Immune system disorders: Uncommon – allergic reactions, excluding anaphylactic or anaphylactoid reactions; frequency not known – anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders: Isolated cases – mood changes, night terrors; frequency not known – confusion, disorientation, insomnia.

Nervous system disorders: Common – headache; uncommon – dizziness, somnolence.

Eye disorders: Isolated cases – visual disturbances, including blurred vision; conjunctivitis.

Ear and labyrinth disorders: Uncommon – dizziness; isolated cases – tinnitus.

Cardiac disorders: Isolated cases – 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: Isolated cases – 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, eructation; isolated cases – colitis, gastroduodenal ulcer, esophagitis; rare – gastrointestinal perforation; frequency not known – pancreatitis.

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

Hepatobiliary disorders: Uncommon – liver function test abnormalities (e.g., elevated transaminases or bilirubin); rare – hepatitis; frequency not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: Uncommon – angioneurotic edema, pruritus, rash; isolated cases – Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria; 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 tests (increased serum creatinine and/or urea); rare – acute renal failure, particularly in patients with risk factors (see section "Special Warnings and Precautions for Use"); frequency not known – urinary tract infections, altered frequency of urination.

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 edema of the lower limbs; 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 this medicinal product but generally recognized as 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 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 and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging in a place inaccessible to children.

Packaging. Ampoules of 15 mg/1.5 mL: 5 ampoules in a blister pack, 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and place of business.
Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus /
Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus.