Melosso: detailed information

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

Composition:

Active substance: meloxicam;

1.5 ml of injection solution contains 15 mg of meloxicam;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellow liquid or yellow with a greenish tint.

Pharmacotherapeutic group.

Anti-inflammatory and antirheumatic agents. Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. Meloxicam. ATC code M01A C06.

Pharmacological properties.

Pharmacodynamics.

MELOSSE is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, exhibiting anti-inflammatory, analgesic, and antipyretic effects.

Meloxicam demonstrates 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%). Meloxicam penetrates into synovial fluid, where its concentration is about half that in plasma. The volume of distribution is low, averaging 11 L after intramuscular or intravenous administration, with individual variations within 7–20%. The volume of distribution after multiple oral doses of meloxicam (7.5 to 15 mg) is 16 L, with a coefficient of variation ranging from 11 to 32%.

Biotransformation

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 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 major role in the metabolism 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 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 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 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, the area under the plasma concentration-time curve (AUC) is higher and the 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 other routes of administration cannot be used.

Contraindications.

Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");
Patient age under 18 years;
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 administered to patients who experience 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 ulcers or bleeding);
Severe hepatic impairment;
Severe renal impairment without dialysis;
Gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
Hemostasis disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
Severe heart failure;
Treatment of perioperative pain in coronary artery bypass grafting (CABG).

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 (ACE) inhibitors, angiotensin II receptor antagonists, NSAIDs, (low molecular weight or unfractionated) heparins, cyclosporine, tacrolimus, and trimethoprim.

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

Pharmacodynamic interactions

Other NSAIDs and acetylsalicylic acid at doses ≥ 3 g per day

Combination with other NSAIDs is not recommended (see section "Special precautions for use"), acetylsalicylic acid at doses ≥ 500 mg per single dose or ≥ 3 g total daily dose.

Corticosteroids (e.g., glucocorticoids)

Concomitant use with corticosteroids requires caution due to an 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., prophylactic doses), caution is required when using heparin due to an 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 angiotensin II antagonists

NSAIDs may reduce the efficacy of diuretics and other antihypertensive medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination therapy should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

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

As with the use of the medicinal products listed below, a reduction in the antihypertensive effect of beta-blockers 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 interaction: effect of meloxicam on the pharmacokinetics of other medicinal products

Lithium

Data exist for NSAIDs increasing plasma lithium concentrations (by reducing renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate

NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (over 15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, including those with impaired renal function. If combination therapy is required, blood test parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate administration continues for 3 consecutive days, as plasma methotrexate levels may rise and increase toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID therapy (see above) (see section "Adverse reactions").

Pemetrexed

When meloxicam is used concomitantly with pemetrexed in patients with creatinine clearance between 45 and 79 mL/min, meloxicam administration should be suspended 5 days before, on the day of, and 2 days after pemetrexed administration. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for signs of myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance below 45 mL/min).

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

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

Cholestyramine

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

No clinically significant pharmacokinetic interaction was observed with concomitant administration of antacids, cimetidine, or digoxin.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome (CYP) P450 enzymes (mainly CYP 2C9 and minor CYP 3A4 pathways) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected in combination with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide preparations should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interaction was observed with concomitant administration of meloxicam with 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 benefit. 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 is observed after several days, the clinical benefits of treatment should be re-evaluated.

Esophagitis, gastritis, and/or peptic ulcer in the patient's history should be taken into account to ensure complete treatment prior to initiating meloxicam therapy. Particular attention should be paid to possible recurrence in patients treated with meloxicam and in those with such history.

Gastrointestinal disorders

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or 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. 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 low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

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

Meloxicam is not recommended for patients who are concomitantly using drugs that may increase the risk of ulceration or bleeding, such as heparin, anticoagulants (e.g., warfarin), other NSAIDs, or acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose, especially in radical therapy or geriatric practice (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (e.g., 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 MELOSSO) may experience elevated levels in one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Significant elevations of ALT or AST (approximately three times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice, fulminant fatal hepatitis, liver necrosis, and liver failure, some with fatal outcomes, have been reported during NSAID clinical trials.

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 MELOSSO therapy. If clinical signs and symptoms suggest hepatic disease or if systemic manifestations (e.g., eosinophilia, rash, etc.) occur, MELOSSO should be discontinued.

Cardiovascular disorders

Careful monitoring is recommended for 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 therapy.

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

Clinical and epidemiological data suggest that the use of certain NSAIDs (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.

Meloxicam therapy should be initiated only after careful evaluation in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Such evaluation is also 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 disorders

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about the 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. Early diagnosis and immediate discontinuation of any drug that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are crucial for a better prognosis. Meloxicam must not be re-administered in the future if a patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis during its 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. Cross-reactivity with other oxicams is possible.

Anaphylactic reactions

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

Liver parameters and renal function

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

Functional renal failure

NSAIDs, due to inhibition of the vasodilatory effect of renal prostaglandins, may induce functional renal failure by reducing glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and renal function is recommended at the start of treatment or after dose increase in patients with the following risk factors:

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

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

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

Sodium, potassium, and water retention

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

Hyperkalemia

Hyperkalemia may be caused by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, potassium levels should be monitored regularly.

Combination with pemetrexed

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

Other warnings and safety precautions

Adverse reactions are often more severe in elderly, debilitated, or weakened patients, who require careful monitoring. As with other NSAIDs, caution is advised in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher incidence of NSAID-related adverse reactions, 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, this medicinal product 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 sodium (23 mg) per 1.5 mL vial, i.e., is essentially sodium-free.

Masking of inflammation and fever

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

Corticosteroid therapy

MELOSSO cannot be considered a substitute for corticosteroids in corticosteroid-deficient conditions.

Hematological effects

Anemia may occur in patients taking NSAIDs, including MELOSSO. This may be related to fluid retention, occult or macroscopic gastrointestinal bleeding, or incompletely described effects on erythropoiesis. Patients undergoing long-term NSAID therapy, including MELOSSO, should have hemoglobin or hematocrit monitored if symptoms or signs of anemia occur.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively smaller, short-term, and reversible. Patients receiving MELOSSO who are at risk of adverse reactions related to platelet function changes, such as coagulation disorders, or those on anticoagulant therapy, require careful monitoring.

Use in patients with asthma

Patients with asthma may have aspirin-induced asthma. Administration of acetylsalicylic acid to such patients is associated with severe, potentially fatal bronchospasm. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, MELOSSO should not be used in patients hypersensitive to acetylsalicylic acid and should be used with caution in patients with existing 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 defects 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 MELOSSO may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, which in most cases resolved after stopping treatment. Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except when strictly necessary. If meloxicam is used by a woman trying to conceive or during the first and second trimesters, the dose should be as low as possible and treatment duration as short as possible.

After exposure to MELOSSO for several days starting from the 20th gestational week, oligohydramnios and arterial duct constriction should be considered in prenatal monitoring. MELOSSO should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

Risks for the mother at the end of pregnancy and for the newborn:

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 (see section "Contraindications").

Breastfeeding period

Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended in 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 influence reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive a vehicle or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, meloxicam has no effect or 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.

Dosage

One injection of 15 mg once daily.

Do not exceed the dose of 15 mg per day.

Treatment should be limited to one injection at the beginning of therapy, with a maximum duration of up to 2–3 days in justified exceptional cases (e.g., when other routes of administration are not feasible). Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special instructions").

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

Special patient categories

Elderly patients (see section "Pharmacokinetics")

The recommended dose for elderly patients is 7.5 mg per day (half of a 1.5 ml vial) (also see sections "Special instructions" and "Method of administration and dosage" – "Patients at increased risk of adverse reactions").

Patients at increased risk of adverse reactions (see section "Special instructions")

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

Patients with renal impairment

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

For patients with end-stage renal disease on 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 (i.e., patients with creatinine clearance above 25 ml/min).

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 is intended for intramuscular use.

The drug should be administered by deep intramuscular injection into the upper outer quadrant of the buttock, observing strict 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 case of hip joint prosthesis, the injection should be administered into the opposite buttock.

For continuation of treatment, oral dosage forms of the drug (tablets) should be used.

Children.

The medicinal product MELOSSO 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 therapy. 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 measures are recommended for patients. Studies have shown accelerated elimination of meloxicam using 4 oral doses of cholestyramine given 3 times daily.

Adverse reactions.

Data from studies and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and with prolonged use) may be associated with a small increased 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 NSAID therapy.

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

Severe 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 of the medicinal product: 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 the 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 changes, night terrors; frequency not known – confusion, disorientation, insomnia.

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

Eye disorders:
Rare – visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders:
Uncommon – dizziness; rare – tinnitus.

Cardiac disorders:
Rare – palpitations. Cases of heart failure associated with NSAID use have been reported.

Vascular disorders:
Uncommon – increased blood pressure (see section "Special precautions for use"), flushing.

Respiratory, thoracic and mediastinal disorders:
Rare – asthma in patients with allergy to acetylsalicylic acid and other NSAIDs; frequency not known – upper respiratory tract infections, cough.

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

Hepatobiliary disorders:
Uncommon – abnormalities in liver function tests (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 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"), 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 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 – induration at injection site, pain at injection site; uncommon – edema, including edema of the lower limbs; frequency not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders:
Frequency not known – arthralgia, back pain, signs and symptoms related to joints.

Specific serious and/or common adverse reactions

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

Adverse reactions not associated with the use of the drug but generally recognized as characteristic of other compounds in the class

Organic kidney damage, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special precautions for use").

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

1.5 ml in ampoules, 5 ampoules in a blister, 1 blister in a cardboard pack.

Prescription status.

By prescription only.

Manufacturers.

LLC NPF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of business activity.

5 Budynstustriyi Street, Kyiv, 01013, Ukraine.

INSTRUCTION

for medical use of the medicinal product

MELOSSO

(MELOSSO)

Composition:

Active ingredient: meloxicam;

1.5 ml of injectable solution contains 15 mg of meloxicam;

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

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear yellow or yellowish-green transparent liquid.

Pharmacotherapeutic group.

Anti-inflammatory and antirheumatic agents. Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. Meloxicam. ATC code M01A C06.

Pharmacological properties.

Pharmacodynamics.

MELOS is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, exhibiting anti-inflammatory, analgesic, and antipyretic effects.

Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its precise mechanism of action remains unknown. However, there is a common mechanism of action shared by all NSAIDs (including meloxicam): inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption

Meloxicam is completely absorbed 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, the maximum plasma concentration reaches approximately 1.6–1.8 \µg/mL and is achieved within 1–6 hours.

Distribution

Biotransformation

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 the dose), is formed via oxidation of the intermediate metabolite 5'-hydroxymethylmeloxicam, which is excreted to a lesser extent (9% of the dose). In vitro studies suggest that CYP2C9 plays a major role in the metabolism 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, excreted equally 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 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 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 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

Clinical characteristics.

Indications.

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

Contraindications.

Third trimester of pregnancy (see section "Use in pregnancy or lactation");
patient age under 18 years;
hypersensitivity to the active substance or to other components of the medicinal product;
hypersensitivity to active substances with similar actions, such as NSAIDs, acetylsalicylic acid; meloxicam should not be administered to patients who experience symptoms of asthma, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
gastrointestinal bleeding or perforation associated with previous NSAID therapy in history;
active or recurrent peptic ulcer/bleeding in history (two or more separate confirmed episodes of ulcer or bleeding);
severe hepatic impairment;
severe renal impairment without dialysis;
gastrointestinal bleeding, cerebrovascular bleeding in history, or other coagulation disorders;
coagulation disorders or concomitant use of anticoagulants (contraindications related to the route of administration);
severe heart failure;
treatment of perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other types of interactions.

Risks associated with hyperkalemia

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 at doses ≥ 3 g per day

Combination with other NSAIDs is not recommended (see section "Special precautions for use"), as well as 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 an increased risk of gastrointestinal bleeding or ulceration.

Anticoagulants or heparin

In other cases (e.g., prophylactic doses), caution is required when using heparin due to an increased risk of bleeding.

Thrombolytic and antiplatelet medicinal products

Increased risk of gastrointestinal 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 angiotensin II antagonists

NSAIDs may reduce the efficacy of diuretics and other antihypertensive medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination therapy should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

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

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

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

Deferasirox

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

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

Lithium

Data on NSAIDs indicate increased plasma lithium concentrations (due to reduced renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate

NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients taking high-dose methotrexate (>15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients taking low-dose methotrexate, including those with impaired renal function. If combination therapy is required, blood counts and renal function should be monitored. Caution is advised when NSAID and methotrexate are taken for 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID therapy (see above) (see section "Adverse reactions").

Pemetrexed

When meloxicam is used concomitantly with pemetrexed in patients with creatinine clearance between 45 and 79 ml/min, meloxicam administration should be withheld for 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for signs of myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance <45 ml/min).

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

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

Cholestyramine

No clinically significant pharmacokinetic interaction was observed with concomitant use of antacids, cimetidine, or digoxin.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 (CYP) enzymes (mainly CYP 2C9 and minor pathway CYP 3A4) and one-third via other pathways, such as peroxidative oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered 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 in combination with medicinal products such as oral antidiabetic agents (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these medicinal products and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

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.

The recommended maximum daily dose should not be exceeded if the therapeutic effect is insufficient, 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 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 their complete treatment before starting meloxicam therapy. Close monitoring for possible recurrence is required in patients treated with meloxicam and in patients with such history.

Gastrointestinal disorders

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

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses in patients with a history of peptic ulcer, especially complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of meloxicam is not recommended in patients taking drugs that may increase the risk of ulceration or bleeding, such as heparin, anticoagulants such as warfarin or other NSAIDs, or acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g total daily dose, or as radical therapy or in geriatric practice (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

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

Hepatic disorders

Up to 15% of patients taking NSAIDs (including the medicinal product MELOSSE) may have elevated levels of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Significant increases in ALT or AST (approximately three times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis and liver failure, some of them fatal, have been reported during clinical trials with NSAIDs.

Patients with symptoms and/or signs of hepatic dysfunction or with abnormal liver function tests should be evaluated for the development of more severe hepatic failure during treatment with MELOSSE. If clinical signs and symptoms are consistent with the development of liver disease or if systemic manifestations of disease (e.g., eosinophilia, rash, etc.) are observed, treatment with MELOSSE should be discontinued.

Cardiovascular disorders

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

Clinical monitoring of blood pressure is recommended at the beginning of therapy, especially at the start of meloxicam treatment, in patients with risk factors.

Data from studies and epidemiological data suggest that the use of certain NSAIDs (especially 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 are insufficient data to exclude such a risk for meloxicam.

Meloxicam therapy should be initiated 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 an assessment is also necessary before starting 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 complications, myocardial infarction and stroke, which may be fatal. The risk increases with the duration of use. Patients with cardiovascular diseases or cardiovascular risk factors may have an increased risk of thrombotic complications.

Skin disorders

Life-threatening severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with meloxicam use. Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of developing 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. If a patient has developed Stevens-Johnson syndrome or toxic epidermal necrolysis while taking meloxicam, the drug must not be restarted at any time in the future.

Cases of fixed drug eruption have been reported with meloxicam use. Meloxicam should not be re-administered to patients who have had a history of fixed drug eruption associated with meloxicam use. Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions

As with other NSAIDs, anaphylactic reactions may occur in patients without known reaction to the medicinal product MELOSSE. The medicinal product should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have reported rhinitis with or without nasal polyps, or who have experienced severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Emergency measures should be taken if an anaphylactic reaction is detected.

Liver parameters and kidney function

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

Functional renal failure

NSAIDs, due to inhibition of the vasodilatory effect of renal prostaglandins, may induce functional renal failure by reducing glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and kidney function is recommended at the beginning of treatment or after dose increase in patients with the following risk factors:

advanced age;
concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, 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 nephritis;
severe hepatic dysfunction (serum albumin < 25 g/l or ≥ 10 g/l according to Child-Pugh classification).

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

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

Sodium, potassium and water retention

NSAIDs may enhance sodium, potassium and water retention and affect the natriuretic effects of diuretics. In addition, a 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 sensitive patients. Therefore, clinical monitoring is recommended in patients at risk of sodium, potassium and water retention (see sections "Contraindications" and "Dosage and administration").

Hyperkalemia

Combination with pemetrexed

In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be suspended 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 treatment with other NSAIDs, caution is required in elderly patients in whom a decline in kidney, liver and heart function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

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

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

Meloxicam may negatively affect fertility; therefore, this medicinal product is not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility investigations, 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. is essentially sodium-free.

Masking of inflammation and fever

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

Corticosteroid therapy

The medicinal product MELOSSE cannot be a likely substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects

Anemia may occur in patients taking NSAIDs, including the medicinal product MELOSSE. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or an incompletely described effect on erythropoiesis. Patients undergoing long-term treatment with NSAIDs, including MELOSSE, should have hemoglobin or hematocrit monitored if symptoms and signs of anemia are observed.

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 receiving MELOSSE who may have adverse reactions related to changes in platelet function, such as coagulation disorders, or patients receiving anticoagulants, require careful monitoring.

Use in patients with asthma

Patients with asthma may have aspirin-induced asthma. Administration of acetylsalicylic acid to patients with aspirin-induced 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 MELOSSE 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 development of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac defects increased from less than 1% to approximately 1.5%. This risk is considered to increase with increasing dose and duration of treatment.

From the 20th week of pregnancy, use of the medicinal product MELOSSE may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible after discontinuation of treatment. In addition, there have been reports of arterial duct constriction after treatment in the second trimester of pregnancy, which in most cases resolved after discontinuation of treatment. Therefore, meloxicam 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 become pregnant or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

During antenatal monitoring, oligohydramnios and arterial duct constriction should be considered if MELOSSE has been used for several days starting from the 20th gestational week. Use of MELOSSE should be discontinued if oligohydramnios or arterial duct constriction is detected.

When used in 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 kidney function, which may progress to renal failure with oligohydramnios (see above).

Risks to the mother at the end of pregnancy and to the newborn:

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

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

Lactation period

Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended 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 investigations, discontinuation of meloxicam should be considered.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

One injection of 15 mg once daily.

Do not exceed the dose of 15 mg per day.

Treatment should be limited to one injection at the beginning of therapy, with a maximum duration of up to 2–3 days in justified exceptional cases (e.g., when 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 Categories

Elderly Patients (see section "Pharmacokinetics")

The recommended dose for elderly patients is 7.5 mg per day (half of a 1.5 ml vial) (also see sections "Special Warnings and Precautions for Use" and "Method of Administration and Dosage" – "Patients at Increased Risk of Adverse Reactions").

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

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

Patients with Renal Impairment

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

For patients with end-stage renal disease undergoing hemodialysis, the dose should not exceed 7.5 mg per day (half of a 1.5 ml vial).

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

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 is intended for intramuscular use.

The drug should be administered by 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 dosage forms of the drug (tablets) should be used.

Children.

MELOSSO 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, liver 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 measures are recommended. Studies have shown accelerated elimination of meloxicam with 4 oral doses of cholestyramine administered 3 times daily.

Adverse Reactions

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

Edema, arterial hypertension, and heart failure have been observed during NSAID therapy.

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

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

Criteria for assessing the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); 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").

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

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

Eye disorders:
Rare – visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders:
Uncommon – dizziness; 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.

Gastrointestinal disorders:
Very common – gastrointestinal disturbances: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea; uncommon – occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, eructation; rare – colitis, gastroduodenal ulcer, esophagitis; very rare – gastrointestinal perforation; frequency not known – pancreatitis.
Gastrointestinal bleeding, ulcers, or perforation may be severe and potentially fatal, especially in elderly patients (see section "Special Warnings and Precautions for Use").

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

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

Renal and urinary disorders:
Uncommon – sodium and water retention, hyperkalemia (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), changes in renal function parameters (increased 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, changes 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 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").

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.

Packaging.

1.5 ml in ampoules, 5 ampoules in a blister, 1 blister in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL RESEARCH AND PRODUCTION LIMITED (production unit).

Manufacturer's address.

24-v Promyslova Street, Severodonetsk, Luhansk region, 93400, Ukraine.

Marketing Authorization Holder.

MICROCHEM PHARMACEUTICAL RESEARCH AND PRODUCTION LIMITED.

Address of the Marketing Authorization Holder.

5 Budindustriyi Street, Kyiv, 01013, Ukraine.

You can report an adverse event associated with this medicinal product at the phone number +38 (050) 309-83-54 (24/7).