Loxidol

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

Composition:

Active substance: meloxicam;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: yellowish-green clear solution, practically free from visible particles.

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

Pharmacological Properties

Pharmacodynamics

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

Meloxicam has demonstrated high anti-inflammatory activity in 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

After intramuscular administration, meloxicam is completely absorbed. 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 at a dose of 15 mg, the maximum plasma concentration is approximately 1.6–1.8 μg/mL and is reached within 1–6 hours.

Distribution

Meloxicam is highly bound to plasma proteins, primarily to albumin (99%). It 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 deviations 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 excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays a significant role in the metabolic process, while the isoenzyme CYP 3A4 is involved to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination

Elimination of meloxicam occurs primarily as metabolites, excreted in equal parts in urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine. The elimination half-life (t1/2) ranges from 13 to 25 hours, depending on the route of administration (oral, intramuscular, or intravenous). Plasma clearance is approximately 7–12 mL/min after a single oral dose, intravenous, or rectal administration.

Dose Linearity

Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 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 has been observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to higher concentrations of free meloxicam. Daily doses exceeding 7.5 mg should not be administered to such patients (see section "Dosage and Administration" and "Contraindications").

Elderly patients. In elderly male patients, mean pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, the area under the concentration-time curve (AUC) is higher and t1/2 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 in adults when other routes of administration cannot be used.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• hypersensitivity to active substances with a similar action, such as NSAIDs, acetylsalicylic acid; meloxicam should not be used in patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
• gastrointestinal bleeding or perforation related to 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;
• disorders of hemostasis or concomitant use of anticoagulants (contraindications related to the route of administration);
• severe heart failure;
• not to be used for the treatment of perioperative pain in coronary artery bypass grafting;
• third trimester of pregnancy (see section "Use in pregnancy or breastfeeding");
• patient age under 18 years.

Interaction with other medicinal products and other types of interactions

Risks associated with hyperkalemia

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

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

Pharmacodynamic interactions

Other NSAIDs and acetylsalicylic acid

Concomitant use of meloxicam with these agents may increase NSAID toxicity. Concomitant use with other NSAIDs (see section "Special instructions for use"), including acetylsalicylic acid at anti-inflammatory doses ≥500 mg per dose or ≥3 g total daily dose, is not recommended.

Corticosteroids (e.g., glucocorticoids)

Concomitant use of meloxicam with these agents increases the risk of gastrointestinal bleeding or ulceration. Concomitant use of these agents requires caution.

Anticoagulants or heparin

Concomitant use of meloxicam with these agents significantly increases the risk of bleeding 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 instructions for use"). Concomitant use of NSAIDs and anticoagulants or heparin in geriatric practice or at therapeutic doses (see section "Special instructions for use") is not recommended. Due to intramuscular administration, meloxicam injection solution is contraindicated in patients undergoing anticoagulant therapy (see sections "Contraindications" and "Special instructions for use"). In other cases, use of heparin (e.g., at prophylactic doses) requires caution due to increased risk of bleeding.

Thrombolytic and antiplatelet agents

Concomitant use of meloxicam with these agents increases the risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs)

Concomitant use of meloxicam with these agents increases the risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and ARAs II

NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of ACE inhibitors or ARAs II (angiotensin II receptor antagonists) and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Concomitant use of these agents should be performed 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 instructions for use").

Other antihypertensive agents (e.g., beta-blockers)

Concomitant use of meloxicam with these agents may result in reduced antihypertensive effect (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)

Concomitant use of meloxicam with these agents may increase nephrotoxicity (due to effects on renal prostaglandins). Careful monitoring of renal function is recommended when these agents are used concomitantly, especially in elderly patients.

Deferasirox

Concomitant use of meloxicam with deferasirox increases the risk of gastrointestinal adverse reactions. Concomitant use of these agents requires caution.

Pharmacokinetic interactions

Lithium

It has been reported that NSAIDs increase 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 instructions for use"). If use of this combination is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate

NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. Concomitant use of NSAIDs in patients taking high-dose methotrexate (over 15 mg/week) is not recommended (see section "Special instructions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered when patients are taking low-dose methotrexate, particularly in patients with impaired renal function. If use of this combination is necessary, blood parameters 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 use of meloxicam, hematological toxicity of methotrexate is considered to increase during NSAID treatment (see section "Adverse reactions").

Pemetrexed

Concomitant use with meloxicam may reduce pemetrexed elimination and increase the frequency of adverse reactions associated with pemetrexed. This combination (meloxicam 15 mg) should be used with caution in patients with normal renal function (creatinine clearance ≥80 mL/min). In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), meloxicam should be withheld for 5 days before, on the day of, and for 2 days after pemetrexed administration. If use of this combination 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).

Cholestyramine

Concomitant use with cholestyramine may accelerate meloxicam elimination (due to disruption of enterohepatic circulation by cholestyramine, meloxicam clearance increases by 50%, and elimination half-life decreases to 13±3 hours). This interaction is clinically significant.

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 pathway CYP 3A4) and one-third via other pathways, e.g., peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is used 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 antidiabetic agents (sulfonylureas, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients should be closely monitored for hypoglycemia during concomitant use of these agents.

No clinically significant pharmacokinetic interaction was observed with concomitant use of meloxicam and 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 inadequate, 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 the treatment of patients requiring relief of acute pain.

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

Meloxicam cannot substitute corticosteroids in the treatment of corticosteroid insufficiency.

Before initiating therapy, consider any history of esophagitis, gastritis, and/or peptic ulcer in the patient and ensure complete healing. Patients previously treated with meloxicam and those with such history should be monitored regularly for possible recurrence.

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

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

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

Gastrointestinal disorders

At any time during NSAID therapy, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur, with or without prior symptoms or serious gastrointestinal disease history.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. Consider prescribing combination therapy with protective agents (such as misoprostol or proton pump inhibitors) for these patients, as well as for 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 report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during initial treatment stages.

The drug should be used with caution in patients with gastrointestinal disorders in history (ulcerative colitis, Crohn's disease), as these conditions may worsen (see section "Adverse reactions").

The drug is not recommended for patients who are simultaneously taking medications 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, the drug should be discontinued.

Hepatic effects

During NSAID use (including meloxicam), up to 15% of patients may experience elevated levels of one or more liver tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (approximately 3 times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and liver failure, some with fatal outcomes, have been reported.

Patients who develop or are suspected of hepatic dysfunction or who have experienced liver test abnormalities during therapy should be evaluated for signs of more severe hepatic failure. If clinical signs and symptoms suggest hepatic disease development or if systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), the drug should be discontinued.

Cardiovascular disorders

Careful monitoring is recommended in patients with a history of arterial hypertension and/or mild to moderate congestive heart failure when using the drug, as fluid retention and edema have been observed during NSAID treatment.

At the beginning of treatment, clinical monitoring of blood pressure is recommended for patients with risk factors.

Study data and epidemiological evidence suggest that use of certain NSAIDs (especially at high doses and for prolonged periods) 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.

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

NSAIDs increase the risk of serious cardiovascular thrombotic complications, myocardial infarction, and stroke, which may be fatal. The risk increases with duration of use. Patients with cardiovascular diseases 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 during meloxicam use. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment.

Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. 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), the drug should be discontinued. It is crucial to diagnose promptly and discontinue any medication that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis. This is associated with a better prognosis in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis during meloxicam treatment, the drug must never be restarted in the future.

Cases of fixed drug eruption have been reported with meloxicam use. This drug should not be re-administered to patients with a history of 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 prior reaction to meloxicam. The drug should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have experienced rhinitis, with or without nasal polyps, or who have had severe, potentially fatal bronchospasm after acetylsalicylic acid or other NSAID use. In case of anaphylactoid reaction, emergency measures should be taken.

Effects on liver and kidney function parameters

As with most NSAIDs, isolated cases of increased plasma transaminase and bilirubin levels or other liver function parameters, increased plasma creatinine and blood urea nitrogen levels, and other laboratory parameter deviations have occurred during meloxicam treatment. These deviations were mostly minor and transient. If significant or persistent deviations occur, the drug should be discontinued and follow-up tests performed.

Renal effects

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal failure due to decreased glomerular filtration. This adverse effect is dose-dependent.

In isolated cases, NSAIDs may lead to interstitial nephritis, glomerulonephritis, renal papillary necrosis, or nephrotic syndromes.

Careful monitoring of diuresis and renal function is recommended at the beginning of drug use or after dose increase in patients with the following risk factors:

• advanced age;
• concomitant use of ACE inhibitors, ARBs, sartans, diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal failure;
• nephrotic syndrome;
• lupus nephropathy;
• severe hepatic dysfunction (serum albumin <25 g/L or ≥10 according to Child-Pugh classification).

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

Hyperkalemia risk

Hyperkalemia may develop during meloxicam use, which may be favored by diabetes or concomitant use of drugs increasing potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, regular monitoring of plasma potassium levels is required.

Effects on water-electrolyte balance

NSAIDs may enhance sodium, potassium, and water retention and affect the natriuretic effects of diuretics. Additionally, reduced antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). Consequently, edema, heart failure, or arterial hypertension may develop or worsen in susceptible patients. Clinical monitoring is recommended during drug use in patients with such risks (see sections "Contraindications" and "Dosage and administration").

Hematological reaction risk

Anemia may occur during NSAID use, particularly meloxicam. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit levels should be monitored during long-term use if symptoms and 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. Patients in whom adverse effects on platelet function are possible, particularly coagulation disorders, and patients receiving anticoagulants should be carefully monitored during drug use.

Combination with pemetrexed

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

Elderly patients and patients at increased risk of adverse reactions

Adverse reactions are often poorly tolerated in elderly, frail, or weakened patients, who require careful monitoring. As with other NSAIDs, the drug should be used cautiously in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions during NSAID use, especially gastrointestinal bleeding and perforations, which may be fatal (see section "Dosage and administration").

Use in patients with asthma

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid in 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, the drug should not be used in patients sensitive to acetylsalicylic acid and should be used cautiously in patients with existing asthma.

Effect on fertility

Meloxicam use may negatively affect reproductive function and is not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility evaluation, discontinuation of the drug should be considered (see section "Use during pregnancy or breastfeeding").

Sodium content

The medicinal product contains less than 1 mmol (23 mg) of sodium 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 defects 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 receiving a prostaglandin synthesis inhibitor during organogenesis, the frequency of various developmental abnormalities, including cardiovascular, increased.

From the 20th week of pregnancy, meloxicam use may cause oligohydramnios due to fetal renal dysfunction. Oligohydramnios may occur soon after starting treatment and is usually reversible after discontinuation. Therefore, the drug 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, dosage and duration of treatment should be minimized. Prenatal monitoring for oligohydramnios and arterial duct constriction is recommended after meloxicam exposure for several days starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, meloxicam use should be discontinued.

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

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

risks in late pregnancy for mother and newborn:

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

Therefore, the drug 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 drug is not recommended for breastfeeding women.

Fertility

Meloxicam, like other drugs inhibiting cyclooxygenase/prostaglandin synthesis, may negatively affect reproductive function and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Ability to affect reaction speed when driving or operating machinery

No specific studies on the effect of meloxicam on the ability to drive or operate machinery have been conducted. Given the pharmacodynamic profile and reported adverse reactions, the drug 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

Dosing

The medicinal product should be administered at a dose of 15 mg once daily (1 injection).

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 (i.e., when other routes of administration are not possible).

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.

Special Patient Populations

Elderly patients (see section "Pharmacokinetics"). The recommended dose of the medicinal product for elderly patients is 7.5 mg per day (half of a 1.5 ml ampoule) (also see subsection "Patients at increased risk of adverse reactions" below and section "Special Warnings and Precautions for Use").

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

Patients with renal impairment. The 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 on hemodialysis, 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).

Patients with hepatic impairment. The medicinal product is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Dose reduction is not required in patients with mild to moderate hepatic impairment.

Method of Administration

The medicinal product is intended for intramuscular use.

The injection solution should be administered slowly by deep intramuscular injection into the upper outer quadrant of the buttock, strictly adhering to aseptic technique. In case of repeated administration, it is recommended to alternate between left and right buttocks. Prior to injection, it is important to ensure that the needle tip has not entered a blood vessel.

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

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

For continuation of therapy, oral formulations of meloxicam should be used.

Children. The medicinal product 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 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 overdose.

Treatment. In case of NSAID overdose, symptomatic and supportive treatment is recommended. Studies have shown that meloxicam elimination is enhanced by administration of 4 oral doses of cholestyramine 4 g three times daily.

Adverse Reactions

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

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

Most of the adverse reactions observed with meloxicam 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 meloxicam, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported (see section "Special Warnings and Precautions for Use"). Gastritis occurs 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 adverse reactions listed below were observed in 27 clinical trials with treatment duration of at least 14 days. A total of 15,197 patients received oral meloxicam at daily doses of 7.5 mg or 15 mg for up to one year.

Also included are adverse reactions identified during post-marketing use.

Classification of frequency of adverse drug reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Uncommon — anemia; rare — blood test abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia.

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

Immune system disorders:

Uncommon — allergic reactions, excluding anaphylactic or anaphylactoid reactions; frequency not known — anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders:

Rare — mood alteration, 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 has been reported in association with NSAID use.

Vascular disorders:

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

Respiratory, thoracic and mediastinal disorders:

Rare — asthma in patients with aspirin or other NSAID allergy;

Frequency not known — upper respiratory tract infections, cough.

Gastrointestinal disorders:

Very common — gastrointestinal disorders: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea; uncommon — occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, eructation; rare — colitis, gastroduodenal ulcer, esophagitis; very rare — gastrointestinal perforation; frequency not known — pancreatitis.

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

Hepatobiliary disorders:

Uncommon — liver function test abnormalities (e.g., increased transaminase or bilirubin levels); very 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 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 serum creatinine and/or urea levels); very rare — acute renal failure, particularly in patients with risk factors (see section "Special Warnings and Precautions for Use"); frequency not known — urinary tract infections, disturbances in micturition frequency.

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 meloxicam but typical 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 suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report any 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 at temperatures not exceeding 25°C, in the original packaging, and in a place inaccessible to children.

Incompatibilities. Due to possible incompatibility, the medicinal product must not be mixed with other medicinal products in the same syringe.

Packaging. 1.5 ml in a vial; 3 vials in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Date of last review.