ELIPRO

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELIPROB ELIPROB

Composition:

Active substance: meloxicam;

1.5 ml of solution contains 15 mg of meloxicam;

Excipients: meglumine, glycofural, poloxamer 188, glycine, sodium chloride, sodium hydroxide 1M solution, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear yellow solution with a greenish tint, practically free from particles.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Oxicams.

ATC code M01A C06.

Pharmacological Properties

Pharmacodynamics

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

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

Pharmacokinetics

Absorption. Meloxicam is completely absorbed after intramuscular injection. 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 of 15 mg, the 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%.

Biological Transformation. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam have been identified in urine, all of which are pharmacodynamically inactive. 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 metabolic process, while the isoenzyme CYP3A4 is involved to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, which account for 16% and 4% of the administered dose, respectively.

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

Dose Linearity. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg 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 (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, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers (see section "Dosage and Administration").

Clinical characteristics

Indications. ELEPROB, solution for injection, is indicated in adults for short-term symptomatic treatment of acute attacks of rheumatoid arthritis and ankylosing spondylitis when other routes of administration are not applicable.

Contraindications.

• Third trimester of pregnancy (see section "Use in pregnancy or lactation");
• patient age under 18 years;
• hypersensitivity to the active substance or to any of the excipients;
• hypersensitivity to active substances with similar actions, such as NSAIDs or aspirin. Meloxicam should not be administered to patients who experience asthma, nasal polyps, angioedema, or urticaria after taking aspirin or other NSAIDs;
• gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• active or recurrent peptic ulcer/bleeding in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• severe hepatic insufficiency;
• severe renal insufficiency 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.

Do not use for treatment of perioperative pain associated with coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other types of interactions

Risks associated with hyperkalemia

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

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

Pharmacodynamic interactions

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid ≥ 3 g/day. 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 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 of heparin use (e.g., prophylactic doses), caution is required due to an increased risk of bleeding.

Thrombolytic 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., in dehydrated patients or elderly patients), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combined therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., beta-blockers). Possible reduction in the antihypertensive effect of beta-blockers (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs via 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 increases 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 (via reduced renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Metotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (more than 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 parameters and renal function should be monitored. Caution is needed when NSAID and methotrexate administration occurs for three consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant treatment with meloxicam, hematological toxicity of methotrexate may increase during NSAID treatment (see above and 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), 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 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.

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

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 enzymes (mainly CYP 2C9 and minor pathway CYP 3A4) 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 clearly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected with medicinal products such as oral antidiabetic agents (sulfonylurea derivatives, nateglinide); such interactions may lead to increased plasma levels of both agents 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 administration of antacids, cimetidine, or digoxin.

Children

Interaction studies have been conducted only in adults.

Special precautions for use

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose should not be exceeded if 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 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 their complete treatment before initiating meloxicam therapy. Patients treated with meloxicam, as well as those with such history, should be regularly monitored for possible recurrence.

Gastrointestinal disorders

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment, regardless of the presence or absence of 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, concomitant therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered. This also applies to patients requiring concomitant use of low-dose aspirin 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, particularly elderly patients, should be informed about any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment.

The use of meloxicam is not recommended in patients who are simultaneously taking drugs that increase the risk of ulceration or bleeding, such as heparin, radical therapy or in geriatric practice, anticoagulants such as warfarin, other nonsteroidal anti-inflammatory drugs, acetylsalicylic acid at doses ≥ 500 mg per dose or ≥ 3 g per day (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

Elevated values of one or more liver tests may occur in up to 15% of patients taking NSAIDs. Such laboratory abnormalities may progress, remain unchanged, or resolve during continued treatment. Significant increases in alanine aminotransferase [ALT] or aspartate aminotransferase [AST] (approximately three times or more above the upper limit of normal) were observed in 1% of patients during clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis and liver failure, some of which were fatal, have been reported.

During therapy with the medicinal product ELIPROB, patients with symptoms/signs of hepatic dysfunction or abnormal liver test results should be evaluated for the development of more severe hepatic failure. If clinical symptoms are consistent with hepatic disease or if systemic manifestations of disease (e.g., eosinophilia, rash) occur, ELIPROB should be discontinued.

Cardiovascular disorders

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure should be carefully monitored, as fluid retention and edema have been observed during NSAID therapy.

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

Clinical trial data and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and with prolonged treatment) may slightly increase the risk of vascular thrombotic events (such as myocardial infarction or stroke). There are insufficient data to exclude such a risk with meloxicam.

Therapy with meloxicam 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. A similar assessment is required before initiating long-term treatment in patients with cardiovascular risk factors (arterial hypertension, hyperlipidemia, diabetes mellitus, smoking, etc.).

NSAIDs 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 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 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 must be discontinued. — —It is crucial to diagnose promptly and discontinue any drugs that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis — early discontinuation is associated with a better prognosis. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while taking meloxicam, the drug must never be restarted in the future.

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.

Potential cross-reactivity may occur with other oxicams.

Anaphylactoid reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients who have not previously reacted to meloxicam. ELIPROB should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who develop rhinitis, sometimes with nasal polyps, or experience severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Immediate measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and renal function

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

Functional renal impairment

NSAIDs, due to inhibition of the vasodilatory effect of renal prostaglandins, may induce functional renal impairment by decreasing glomerular filtration. This adverse effect is dose-dependent. 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, 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 impairment;
• nephrotic syndrome;
• lupus nephritis;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

In isolated cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndromes.

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

Sodium, potassium and water retention

NSAIDs may enhance sodium, potassium and water retention and affect the natriuretic effects of diuretics. Additionally, 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 develop or worsen in susceptible patients. Therefore, clinical monitoring is recommended for patients at risk of sodium, potassium and water retention (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia

Hyperkalemia may be promoted 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 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 precautions

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

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

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

Meloxicam may adversely affect fertility and is not recommended for women who are trying to conceive. Therefore, 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., essentially sodium-free.

Masking of inflammation and fever

The pharmacological action of ELIPROB, aimed at reducing fever and inflammation, may reduce the diagnostic value of data regarding suspected non-infectious painful conditions.

Treatment with corticosteroids

ELIPROB cannot replace corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects

Anemia may occur in patients receiving NSAIDs, including ELIPROB. This may be related to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic bleeding, or incompletely described effects on erythropoiesis. Hemoglobin or hematocrit levels should be monitored in patients undergoing long-term treatment with NSAIDs, including ELIPROB, if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, transient, and reversible. Careful monitoring is required in patients receiving ELIPROB who may have adverse effects on platelet function, such as coagulation disorders, or patients receiving anticoagulants.

Use in patients with asthma

Patients with asthma may have aspirin-induced asthma. Administration of aspirin to patients with aspirin-induced asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, ELIPROB should not be used in patients hypersensitive to aspirin 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 congenital heart defects increased from less than 1% to about 1.5%. This risk is believed to increase with higher doses and longer duration of treatment.

In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation losses and embryofetal mortality. Furthermore, in animals receiving a prostaglandin synthesis inhibitor during organogenesis, the frequency of various developmental abnormalities, including cardiovascular, was increased.

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

Therefore, meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of urgent need. For women trying to conceive or during the first and second trimesters of pregnancy, the dosage and duration of meloxicam treatment should be as low as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after meloxicam exposure for several days starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, meloxicam should be discontinued.

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

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

and risks to the mother and newborn at term:

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

Therefore, meloxicam is contraindicated during the third trimester of pregnancy.

Breastfeeding. Although specific data on ELIPROB are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended for breastfeeding women.

Fertility. Meloxicam, like other medicinal products that inhibit cyclooxygenase/prostaglandin synthesis, may negatively affect reproductive function and is not recommended for women who are trying to conceive. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

One injection of 15 mg once daily.

DO NOT EXCEED THE DOSE OF 15 MG/DAY.

Treatment should be limited to one injection at the beginning of therapy, with a maximum duration of up to 2–3 days in justified exceptional cases (i.e., 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 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 for elderly patients is 7.5 mg per day (half of a 1.5 ml vial) (also see "Patients at increased risk of adverse reactions" below and section "Special Warnings and Precautions for Use").

Patients at increased risk of adverse reactions (see section "Special Warnings and Precautions for Use")

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).

Renal impairment

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

For patients with end-stage renal disease on haemodialysis, 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).

Hepatic impairment

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

Method of Administration

For intramuscular use.

The 15 mg/1.5 ml injection solution 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.

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

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

Children. ELIPROB 15 mg/1.5 ml injection solution 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 care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in overdose.

Treatment. Symptomatic and supportive measures are recommended for NSAID overdose. Studies have shown that meloxicam elimination is accelerated by administration of oral 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 prolonged treatment) may slightly increase the risk of vascular thrombotic events (such as myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

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

Most adverse effects observed with NSAIDs? meloxicam? are gastrointestinal in origin. Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease have been reported following administration of NSAIDs? meloxicam? (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").

The following are adverse reactions associated with meloxicam identified during 27 clinical trials involving 15,197 patients who received oral meloxicam at daily doses of 7.5 mg or 15 mg for durations ranging from 14 days to one year, as well as during post-marketing use.

Criteria for assessing frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from 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" below).

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, 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, 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., elevated transaminase or bilirubin levels);
Very rare — hepatitis;
Frequency not known — jaundice, hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon — angioedema, pruritus, rash;
Rare — Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria;
Very rare — bullous dermatitis, erythema multiforme;
Frequency not known — photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders:

Uncommon — sodium and water retention, hyperkalemia (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), changes in renal function parameters (elevated 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, micturition frequency disturbances.

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 typical of other compounds in the class

Renal parenchymal damage that 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 after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 4 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 a vial, 3 or 5 vials in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. C.T. Rompharm Company S.R.L. / S.C. Rompharm Company S.R.L.

Manufacturer's address and location of operations
Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.

Marketing Authorization Holder. LLC "BFC "SALUTARIS".

Address of Marketing Authorization Holder. 9, Druzhby Narodiv Boulevard, Kyiv, 01042, Ukraine.