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

Composition:

Active ingredient: meloxicam;

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

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

Pharmaceutical form. Injection solution.

Main physico-chemical properties: light yellow clear solution.

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 enolic acid class, exhibiting anti-inflammatory, analgesic, and antipyretic effects.

It 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 for 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 a coefficient of variation within 11–32%.

Metabolism

Meloxicam undergoes extensive biotransformation in the liver. Four different metabolites of meloxicam, pharmacodynamically inactive, have been identified in urine. The main metabolite, 5’-carboxymeloxicam (60% of the dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of the dose). In vitro studies suggest that CYP 2C9 plays a major role in the metabolism process, while CYP 3A4 isoenzymes play a minor role. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination

Elimination of meloxicam occurs primarily 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. 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 or renal impairment does 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. Such patients should not exceed a daily dose of 7.5 mg (see sections "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 when other routes of administration cannot be used. LOXIDOL, solution for injection, is indicated for treatment of adults.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
hypersensitivity to active substances with similar actions, 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 previous NSAID therapy in medical history;
active or recurrent peptic ulcer/gastrointestinal bleeding (two or more separate confirmed episodes of ulcer or bleeding) in medical history;
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;
treatment of perioperative pain in coronary artery bypass grafting (CABG);
third trimester of pregnancy (see section "Use in pregnancy or lactation");
patients under 18 years of age.

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

Pharmacodynamic interactions

Other NSAIDs and acetylsalicylic acid

Combination with other NSAIDs is not recommended (see section "Special precautions for use"), as well as with acetylsalicylic acid at doses ≥ 500 mg per 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 using heparin for prophylactic purposes), caution is required due to increased risk of bleeding.

Thrombolytics and antiplatelet agents

Increased risk of bleeding through inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and ARB 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 renal impairment), concomitant use of ACE inhibitors or ARB II and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section "Special precautions for use").

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

As with the use of the following listed medicinal products, a reduction in antihypertensive effect may occur (due to inhibition of vasodilatory prostaglandins).

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

The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs through mediation of renal prostaglandin effects. Renal function should be monitored during treatment. Careful monitoring of renal function is recommended, especially in elderly patients.

Deferasirox

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

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. If such combination therapy is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam therapy.

Methotrexate

NSAIDs may decrease 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 test 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 administration of meloxicam, hematological toxicity of methotrexate is considered to potentially increase during NSAID treatment (see information provided above) (see section "Adverse reactions").

Pemetrexed

Concomitant use with meloxicam may result in 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 should be withheld for 5 days before pemetrexed administration, on the day of administration, and for 2 days after administration. If such combination therapy 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 the elimination of meloxicam (due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13 ± 3 hours). This interaction is clinically significant.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome (CYP) P450 enzymes (mainly CYP 2C9 and secondary CYP 3A4) and one-third via other pathways, such as peroxidase 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 combined with medicinal products such as oral antidiabetic agents (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients should be closely monitored for the development of hypoglycemia when these medicinal products are used concomitantly.

No clinically significant pharmacokinetic interaction was observed with concomitant administration 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 the disease (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

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

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

If no improvement is observed after several days, the clinical benefit 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. Patients treated with meloxicam and those with such history should be monitored regularly for possible recurrence.

Gastrointestinal disorders

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or 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 (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, concomitant 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 initial stages of treatment.

The use of meloxicam is not recommended in patients who are concurrently using medicinal products that may increase the risk of ulceration or bleeding, such as heparin used as definitive therapy or in geriatric practice, 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, meloxicam 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

Up to 15% of patients receiving NSAIDs (including LOXIDOL) may experience elevated levels of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately 3 times or more above the upper normal limit) have been observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice, fulminant fatal hepatitis, liver necrosis, and liver failure, some with fatal outcomes, 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 signs of more severe hepatic failure during LOXIDOL therapy. If clinical signs and symptoms suggest hepatic disease or if systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), LOXIDOL should be discontinued.

Cardiovascular and cerebrovascular disorders

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

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

Data from studies and epidemiological evidence suggest that the use of certain NSAIDs, including meloxicam (particularly at high doses and with 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 a risk for meloxicam.

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

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment.

If a patient develops symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g., progressive skin rash, often with blisters or mucosal involvement), meloxicam treatment should be discontinued. It is important to diagnose promptly and discontinue any drugs that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis. This is associated with a better prognosis in severe skin reactions. Meloxicam must not be re-administered at any time in the future if a patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis during previous use.

Cases of fixed drug eruption have been reported with meloxicam use.

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

Potential cross-reactivity may occur with other oxicams.

Anaphylactoid reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known sensitivity to LOXIDOL. LOXIDOL 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 have experienced severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Immediate measures should be taken if anaphylactic reactions occur.

Liver parameters and renal function

As with most NSAIDs, isolated cases of elevated serum transaminases, serum bilirubin, or other liver function parameters, elevated serum creatinine and blood urea nitrogen, and other laboratory parameter deviations have been reported. In most cases, these deviations were mild and transient. If significant or persistent abnormalities are confirmed, meloxicam should be discontinued and follow-up tests performed.

Functional renal impairment

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

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

Careful monitoring of renal function, including urine output, 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, ARBs, sartans, or diuretics (see section "Interaction with other medicinal products and other forms of interaction");
hypovolemia (of any origin);
congestive heart failure;
renal impairment;
nephrotic syndrome;
lupus nephropathy;
severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

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 may affect the natriuretic effects of diuretics. In addition, a reduction in the antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure, or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended in patients at risk of sodium, potassium, and water retention (see sections "Contraindications", "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 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").

Other warnings and safety measures

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

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

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

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

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

Masking of inflammation and fever

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

Corticosteroid therapy

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

Hematological effects

Anemia may occur in patients receiving NSAIDs, including LOXIDOL. 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 in patients undergoing long-term NSAID treatment, including LOXIDOL, if symptoms or signs of anemia are present.

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

Use in patients with asthma

Patients with asthma may have aspirin-sensitive asthma. Administration of acetylsalicylic acid to patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, the medicinal product 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

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 believed to increase with higher doses and longer duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation losses and embryofetal mortality. Additionally, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been reported.

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

Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of essential need. If a woman trying to conceive or pregnant during the first or second trimester uses meloxicam, the dose and duration of treatment should be as low as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. 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 (premature constriction/closure of the arterial duct and pulmonary hypertension);
renal dysfunction (see above);

and possible risks to the mother and newborn near term:

potential for 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 for LOXIDOL are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended in women who are breastfeeding.

Fertility

Meloxicam, like other medicinal products that inhibit cyclooxygenase/prostaglandin synthesis, 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.

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 the pharmacodynamic profile and observed adverse reactions, meloxicam has no effect or a negligible effect on this ability. 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

Dosing

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

The dose must not exceed 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 only in justified exceptional cases (i.e., when other routes of administration are not feasible).

Adverse reactions may 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 vial) (also see section "Method of Administration and Dosage"—"Patients at Increased Risk of Adverse Reactions" and section "Special Warnings and Precautions for Use").

The patient's need for symptomatic relief and response to treatment should be periodically evaluated.

Patients at Increased Risk of Adverse Reactions (see section "Special Warnings and Precautions for Use")

For patients at increased risk of adverse reactions, e.g., those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg per day (half of a 1.5 ml vial).

Patients with Renal Impairment

The medicinal product is contraindicated in patients with severe renal impairment who are not undergoing hemodialysis (see section "Contraindications").

For patients with end-stage renal disease undergoing hemodialysis, 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 (patients with creatinine clearance above 25 ml/min).

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 via deep intramuscular injection into the upper outer quadrant of the buttock, strictly following 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.

The injection should be immediately discontinued if severe pain occurs during administration.

In the presence of a hip prosthesis, the injection should be administered into the opposite buttock.

For continuation of treatment, oral forms of meloxicam (tablets) should be used.

Children

The medicinal product LOXIDOL, injection solution 15 mg/1.5 ml, is contraindicated in children under 18 years of age (see section "Contraindications").

Overdose

Symptoms

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. 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 accelerated elimination of meloxicam with 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 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 treatment with NSAIDs.

Most of the adverse reactions observed are gastrointestinal in origin. Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease have been reported after administration (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently.

Serious skin reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special Warnings and Precautions for Use").

The frequency of the adverse reactions listed below is based on reported adverse events recorded in 27 clinical trials with treatment duration of at least 14 days. The information is derived from clinical studies involving 15,197 patients who received oral meloxicam at daily doses of 7.5 mg or 15 mg for up to one year.

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

Criteria for assessing the frequency of adverse drug reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <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 alterations, 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 associated with NSAID use has been reported.

Vascular disorders:

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

Respiratory, thoracic and mediastinal disorders:

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

Frequency not known – upper respiratory tract infections, cough.

Gastrointestinal disorders:

Very common – 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 potentially fatal, particularly in elderly patients (see section "Special Warnings and Precautions for Use").

Hepatobiliary disorders:

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

Skin and subcutaneous tissue disorders:

Uncommon – angioneurotic edema, pruritus, rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria; very rare – bullous dermatitis, erythema multiforme; frequency not known – photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders:

Uncommon – sodium and water retention, hyperkalemia (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), changes in renal function tests (increased serum creatinine and/or urea); very rare – acute renal failure, particularly in patients with risk factors (see section "Special Warnings and Precautions for Use"); frequency not known – urinary tract infections, disturbances in micturition frequency.

Reproductive system and breast disorders:

Frequency not known – female infertility, delayed ovulation.

General disorders and administration site conditions:

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

Musculoskeletal and connective tissue disorders:

Frequency not known – arthralgia, back pain, signs and symptoms related to joints.

Specific serious and/or common adverse reactions

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

Adverse reactions not associated with the use of this medicinal product but generally recognized as typical for other compounds of 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 of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. 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

5 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, this 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 cardboard box.

Prescription Status

Prescription only.

Manufacturer

PharmaVision San. ve Tic. A.S.

Manufacturer's Address and Place of Business

Davutpasa Cad. No:145 Zeytinburnu Istanbul, Turkey

Loxidol