Loxidol

INSTRUCTIONS 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, glycofurol, poloxamer 188, glycine, sodium chloride, sodium hydroxide solution, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: yellowish-green transparent solution.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) from the oxicam group, with anti-inflammatory, analgesic, and antipyretic properties.

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. 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, maximum plasma concentration reaches approximately 1.6–1.8 μg/mL and is achieved 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 a coefficient of variation ranging from 11 to 32%.

Metabolism.

Meloxicam undergoes extensive hepatic metabolism. 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 CYP2C9 plays a significant role in the metabolic process, while CYP3A4 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.

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

Dose linearity.

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

Special patient groups.

Patients with hepatic/renal impairment.

Mild to moderate hepatic or renal impairment does not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment showed 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. The daily dose should not exceed 7.5 mg (see section "Dosage and administration").

Elderly patients.

In elderly male patients, mean pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers (see section "Dosage and administration").

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the active substance, to other components of the medicinal product, or to active substances with similar actions, such as NSAIDs, acetylsalicylic acid.

• History of hypersensitivity reactions (including asthma symptoms, nasal polyps, angioedema, urticaria) to acetylsalicylic acid or to NSAIDs.

• Recurrent peptic ulcer disease or bleeding in active form, or history of recurrence (two or more pronounced episodes of peptic ulcer or bleeding).

• Gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history.

• Gastrointestinal bleeding, cerebrovascular bleeding, or other coagulation disorders.

• Severe cardiac, hepatic, or renal insufficiency (without dialysis).

• Treatment of perioperative pain in coronary artery bypass grafting (CABG).

• Hemostasis disorders or concomitant use of anticoagulants (contraindications related to the route of administration).

• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

• Pediatric population under 18 years of age.

Interaction with other medicinal products and other forms of interactions.

Risks associated with hyperkalemia.

Certain 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 hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other NSAIDs and acetylsalicylic acid.

Possible enhancement of NSAID toxicity. Concomitant use with other NSAIDs (see section "Special precautions 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).

Possible increased risk of gastrointestinal bleeding or peptic ulcers. Concomitant use of these agents should be carried out with caution.

Anticoagulants or heparin.

Significantly increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may potentiate the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Concomitant use of NSAIDs and anticoagulants or heparin in geriatric practice or at therapeutic doses (see section "Special precautions for use") is not recommended. Due to intramuscular injection, meloxicam injection solution is contraindicated in patients undergoing anticoagulant therapy (see sections "Contraindications" and "Special precautions for use"). In other cases (e.g., prophylactic doses), heparin use requires caution due to increased bleeding risk.

Thrombolytics and antiplatelet agents.

Possible increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs).

Possible increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and ARBs (angiotensin receptor blockers II).

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 ARBs and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute kidney injury, which is usually reversible. Concomitant use of these medicinal products should be performed with caution. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., beta-blockers).

Possible reduction of antihypertensive effect (due to inhibition of vasodilatory prostaglandins).

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

Possible increased nephrotoxicity (due to mediation of renal prostaglandin effects). Careful monitoring of renal function is recommended when these medicinal products are used concomitantly, especially in elderly patients.

Deferasirox.

Possible increased risk of gastrointestinal adverse reactions. Concomitant use of these medicinal products should be performed with caution.

Pharmacokinetic interactions.

Lithium.

NSAIDs have been reported to 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 precautions for use"). If such combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning of treatment, during dose adjustment, and upon discontinuation.

Methotrexate.

NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. Concomitant use of NSAIDs in patients receiving high-dose methotrexate (over 15 mg/week) (see section "Special precautions for use") is not recommended. The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If such combination therapy is necessary, blood counts and renal function should be monitored. Caution is advised if NSAID and methotrexate administration continues 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 use, hematological toxicity of methotrexate may increase with NSAID treatment (see information above) (see section "Adverse reactions").

Pemetrexed.

Possible decreased elimination of pemetrexed and increased frequency of adverse reactions associated with pemetrexed. In patients with normal renal function (creatinine clearance ≥80 mL/min), concomitant use of this combination (meloxicam 15 mg) should be performed with caution. In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), meloxicam administration should be withheld for 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If such combination therapy 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).

Cholestyramine.

Possible accelerated elimination of meloxicam (due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13±3 hours). This interaction is clinically significant.

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, with minor contribution from CYP 3A4) and one-third via other pathways, such as peroxidative oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is used concomitantly with medicinal products that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when used in combination with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide). Since such interactions may lead to increased plasma levels of these agents and meloxicam, patients should be closely monitored for hypoglycemia when these are used concomitantly.

No clinically significant pharmacokinetic interaction of meloxicam 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 the disease (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose must not be exceeded. If there is insufficient therapeutic effect, additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefit. Concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should also be avoided.

Meloxicam should not be used for the treatment of patients requiring relief of acute pain.

If there is no improvement after several days, the clinical benefits of treatment should be re-evaluated.

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

Gastrointestinal effects.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or history of serious gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should be started on 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 that increase 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 the initial stages of treatment.

Use of meloxicam is not recommended in patients who are concomitantly taking medicinal products that may increase the risk of ulceration or bleeding, such as heparin as a 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.

If gastrointestinal bleeding or ulceration occurs, the drug 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").

Effects on the liver.

Elevations in one or more liver function tests may occur in up to 15% of patients taking NSAIDs (including meloxicam). These 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. Rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and hepatic failure, some with fatal outcomes, have also been reported.

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

Cardiovascular effects.

Careful monitoring is recommended in patients with hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been observed with NSAID use.

Patients with risk factors should be clinically monitored for blood pressure at the start of treatment, especially at the beginning of meloxicam therapy.

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

Therapy with meloxicam should be initiated only after careful consideration in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar evaluation is necessary before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking).

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.

Effects on the skin.

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment. Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. 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. Prompt diagnosis and discontinuation of any suspected causative agents for severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—is crucial, as early intervention improves prognosis. Meloxicam must never be re-administered in the future to patients who have experienced Stevens-Johnson syndrome or toxic epidermal necrolysis during its use.

Cases of fixed drug eruption have been reported with meloxicam.

The drug should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam.

Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known hypersensitivity to meloxicam. The drug 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 emergency measures should be taken if an anaphylactoid reaction occurs.

Effects on liver and kidney function parameters.

As with most NSAIDs, isolated cases of elevated transaminases and bilirubin levels in plasma, or other liver function parameters, as well as increased creatinine and blood urea nitrogen levels and other laboratory abnormalities, have been reported. In most cases, these abnormalities were mild and transient. If significant or persistent abnormalities are confirmed, 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. Careful monitoring of diuresis and renal function is recommended at the start of treatment or after dose increase in patients with risk factors such as: advanced age; concomitant use with ACE inhibitors, angiotensin II receptor antagonists (ARBs), sartans, or diuretics; hypovolemia (of any origin); congestive heart failure; renal impairment; nephrotic syndrome; lupus nephropathy; severe hepatic dysfunction (serum albumin <25 g/L or ≥10 g/L according to Child-Pugh classification).

In rare cases, NSAIDs may cause 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).

Effects on fluid and electrolyte balance.

NSAIDs may enhance sodium, potassium, and water retention and may interfere with the natriuretic effects of diuretics. In addition, the antihypertensive effect of antihypertensive drugs may be reduced. Consequently, edema, heart failure, or hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients with such risks (see sections "Contraindications" and "Dosage and administration").

Hyperkalemia.

Hyperkalemia may occur during meloxicam use, particularly in patients with diabetes or those receiving concomitant medications that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, plasma potassium levels should be monitored regularly.

Combination with pemetrexed.

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

Elderly patients and patients at increased risk of adverse reactions.

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

Masking symptoms of infectious diseases.

Meloxicam, like other NSAIDs, may mask symptoms of infectious diseases.

Injection site reactions.

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

Effects on fertility.

Meloxicam may negatively affect reproductive function and is therefore not recommended for women wishing to become pregnant. Women planning pregnancy or undergoing infertility evaluation should consider discontinuing the drug (see section "Use during pregnancy or breastfeeding").

Masking of inflammation and fever.

The pharmacological action of meloxicam in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Concomitant corticosteroid therapy.

Meloxicam cannot be considered a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological reactions.

Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, gastrointestinal bleeding of unknown origin (microscopic or macroscopic), or an incompletely described effect on erythropoiesis. Hemoglobin or hematocrit should be monitored during long-term treatment 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, transient, and reversible. Patients who may be at risk of adverse effects related to platelet function changes, including coagulation disorders, or those receiving anticoagulants, should be closely monitored during treatment.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid (aspirin) in such patients is associated with severe, potentially fatal bronchospasm. 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 with caution in patients with asthma.

Precautions related to excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. This risk is considered to increase with higher doses and longer duration of treatment.

From the 20th week of pregnancy, use of meloxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, most of which resolved after stopping treatment.

During the first and second trimesters of pregnancy, the drug should not be used except in cases of strong medical necessity. If a woman is trying to conceive or is using meloxicam during the first or second trimester, the dose and duration of treatment should be as low as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to meloxicam for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or 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);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above);

possible 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.

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

Fertility.

Meloxicam, like other drugs that inhibit 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 the drug should be considered.

Ability to influence 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. However, based on its pharmacodynamic profile and observed adverse reactions, meloxicam is unlikely to have any effect or may have a negligible effect on such activities. Nevertheless, 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

The medicinal product is intended for intramuscular use.

Dosing

Administer the medicinal product at a dose of 15 mg (1 injection) once daily.

Do not exceed the dose of 15 mg per day.

Treatment should be limited to 1 injection at the beginning, with a maximum duration of up to 2–3 days, only in justified exceptional cases (e.g., when oral or rectal administration routes 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.

Special Patient Populations

Elderly patients and patients at increased risk of adverse reactions

The recommended dose for elderly patients is 7.5 mg per day. For patients at increased risk of adverse reactions, treatment should be initiated at 7.5 mg per day (half of a 1.5 ml vial) (see section "Special Warnings and Precautions for Use").

Patients with Renal Impairment

For patients with severe renal impairment undergoing dialysis, the dose should not exceed 7.5 mg per day (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). For patients with severe renal impairment not undergoing dialysis, see section "Contraindications".

Patients with Hepatic Impairment

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

Method of Administration

The medicinal product should be administered slowly via deep intramuscular injection into the upper outer quadrant of the buttock, strictly following aseptic technique. When repeated injections are necessary, alternate between the left and right buttocks. Prior to injection, it is important to ensure that the needle tip has not entered 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 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

Symptoms of acute NSAID overdose are usually limited to drowsiness, lethargy, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Severe poisoning may lead to hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, seizures, cardiovascular collapse, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

Treatment

In case of overdose, symptomatic and supportive treatment should be initiated. Studies have shown that administration of 4 g of cholestyramine three times daily accelerates the elimination of meloxicam.

Adverse reactions.

Data from studies and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and during prolonged treatment) may be associated with a small increase in the risk of vascular thrombotic events, such as myocardial infarction or stroke (see section "Special precautions for use").

Edema, arterial hypertension, and heart failure have been observed during treatment with NSAIDs.

Most of the adverse reactions observed are of gastrointestinal origin. Peptic ulcer, perforation, or gastrointestinal hemorrhage, sometimes fatal, may occur, particularly in elderly patients (see section "Special precautions for use"). During treatment, 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 precautions for use"). Gastritis has been observed less frequently.

Serious skin reactions have been reported: Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special precautions for use").

Criteria for assessing the frequency of adverse 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 the available data).

Blood and lymphatic system disorders:

Uncommon – anemia; rare – blood test abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia; very rare – agranulocytosis (see "Specific serious and/or common adverse reactions").

Immune system disorders:

Uncommon – allergic reactions (excluding anaphylactic or anaphylactoid reactions); frequency not known – anaphylactic/anaphylactoid reactions, including shock.

Psychiatric disorders:

Rare – mood changes, nightmares; 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 has also been reported in association with the use of NSAIDs.

Vascular disorders:

Uncommon – increased blood pressure (see section "Special precautions for use"), hot flushes.

Respiratory, thoracic and mediastinal disorders:

Rare – asthma in patients with allergic reactions to acetylsalicylic acid or other NSAIDs; frequency not known – upper respiratory tract infections, cough.

Gastrointestinal disorders:

Very common – gastrointestinal disturbances such as 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.

Peptic ulcer, perforation, or gastrointestinal hemorrhage may be severe and potentially fatal, particularly in elderly patients (see section "Special precautions for use").

Hepatobiliary disorders:

Uncommon – liver function test abnormalities (e.g., increased levels of transaminases or bilirubin); 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 precautions for use").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"), renal function test abnormalities (increased plasma creatinine and/or urea levels); very rare – acute renal failure, particularly in patients at increased risk (see section "Special precautions for use"); frequency not known – urinary tract infections, changes in micturition frequency.

Reproductive system and breast disorders:

Frequency not known – female infertility, ovulation delay.

Musculoskeletal and connective tissue disorders:

Frequency not known – arthralgia, back pain, joint signs and symptoms.

General disorders and administration site conditions:

Common – injection site induration, injection site pain; uncommon – edema, including peripheral edema; frequency not known – influenza-like symptoms.

Specific serious and/or common adverse reactions.

Very rare cases of agranulocytosis have been reported in patients receiving meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Adverse reactions not previously observed with meloxicam but characteristic of other drugs in this pharmacotherapeutic group.

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 precautions for use").

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is very important. It allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C 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 solution in a glass ampoule; 3 ampoules in a blister pack; 1 blister pack in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

K.O. Rompharm Company S.R.L., Romania / S.C. Rompharm Company S.R.L., Romania.

Manufacturer's address and location of operations.

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov / Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.