Milisole

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİLIXOL (Milixol)

Composition:

Active substance: meloxicam;

1.5 ml of solution contains 15 mg of meloxicam;

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

Pharmaceutical form. Solution for injection.

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

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A C06.

Pharmacological Properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, exerting 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, a common mechanism of action for all NSAIDs (including meloxicam) is inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption. Meloxicam is completely absorbed following intramuscular injection. 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 (Cmax) reaches approximately 1.6–1.8 µg/mL and is attained 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 mg 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, which are pharmacodynamically inactive, have been identified in urine. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed by 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, whereas 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 mainly 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 a single oral dose, intravenous, or rectal administration.

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

Special patient groups

Patients with hepatic/renal impairment. Mild to moderate hepatic and renal impairment do not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment had significantly higher total clearance. Reduced plasma protein binding 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. Daily dose should not exceed 7.5 mg (see sections «Contraindications» and «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 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 meloxicam or any of the excipients of the medicinal product, or to active substances with similar actions, such as NSAIDs, acetylsalicylic acid (meloxicam should not be administered to patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs);
• gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• active or recurrent peptic ulcer/gastrointestinal bleeding in medical history (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.

Interaction with other medicinal products and other forms of interaction.

Risks associated with hyperkalemia

Some medicinal products or therapeutic groups may cause hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim.

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

Pharmacodynamic interactions

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

Corticosteroids (e.g., glucocorticoids). Concomitant use with corticosteroids requires caution due to increased risk of bleeding or gastrointestinal 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 (see section "Special precautions for use"). 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 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 cyclooxygenase-inhibiting medicinal products may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., beta-blockers). As with the use of the medicinal products listed below, a possible 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 interactions

Effect of meloxicam on the pharmacokinetics of other medicinal products

Lithium. Data exist for NSAIDs increasing plasma lithium concentrations (by reducing renal lithium excretion), 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 parameters and renal function should be monitored. Caution should be exercised if 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 with NSAID treatment (see above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance from 45 ml/min to 79 ml/min), meloxicam administration should be suspended 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 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).

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 secondarily 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 in combination with medicinal products such as oral antidiabetics (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these medicinal products and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide preparations should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interaction of the medicinal product was observed when administered concomitantly 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 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 relief of acute pain.

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

Patients with a history of esophagitis, gastritis, and/or peptic ulcer should be treated prior to starting meloxicam therapy. Patients previously treated with meloxicam and those with such history should be monitored regularly for possible recurrence.

Gastrointestinal disorders

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

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, 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").

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

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

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

NSAIDs should be used cautiously 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 receiving NSAIDs (including Miliksol) may have elevated values 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. Additionally, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and liver failure, some with fatal outcomes, have been reported during clinical trials with NSAIDs.

Patients with symptoms and/or signs of hepatic dysfunction or those who have shown abnormalities in liver function tests should be evaluated for the development of more severe hepatic failure during Miliksol therapy. If clinical signs and symptoms consistent with hepatic disease development are observed or if systemic manifestations of disease occur (e.g., eosinophilia, rash), Miliksol should be discontinued.

Cardiovascular disorders

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

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

Data from studies and epidemiological data suggest that use of certain NSAIDs (particularly at high doses and with prolonged treatment) may be associated with a small increased risk of vascular thrombotic events (such as myocardial infarction or stroke). There are insufficient data to exclude such 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 assessment is also necessary before initiating long-term treatment in patients with cardiovascular risk factors (e.g., patients with arterial hypertension, hyperlipidemia, diabetes mellitus, and 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 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. Prompt diagnosis and discontinuation of any drugs that may cause severe skin reactions—Stevens-Johnson syndrome or toxic epidermal necrolysis—are crucial, as this is associated with a better prognosis in severe skin reactions. 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 use. Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to Miliksol. Miliksol 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. Emergency measures should be taken if an anaphylactic reaction occurs.

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, and other laboratory parameter abnormalities have been reported. In most cases, these abnormalities were mild and transient. If significant or persistent abnormalities are confirmed, meloxicam use 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 reducing glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of kidney 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 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 level > 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 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, regular monitoring of potassium levels is required.

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 advised in elderly patients, in whom reduced 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 and is therefore not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

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

Masking of inflammation and fever

The pharmacological action of Miliksol aimed at reducing fever and inflammation may lead to misleading results in assessing complications related to suspected non-infectious painful conditions.

Glucocorticoid therapy

Miliksol cannot be considered a substitute for glucocorticoids in the treatment of glucocorticoid deficiency.

Hematological effects

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

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike acetylsalicylic acid, their effect on platelet function is quantitatively smaller, short-term, and reversible. Careful monitoring is required for patients receiving Miliksol who may have adverse effects related to changes in platelet function, such as coagulation disorders, or patients receiving anticoagulants.

Use in patients with asthma

Patients with asthma may have aspirin-sensitive asthma. Use of acetylsalicylic acid in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs, Miliksol should not be used in patients sensitive to acetylsalicylic acid and should be used cautiously in patients with existing asthma.

Combination with pemetrexed

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

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 heart 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, meloxicam use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible after discontinuation. Additionally, there have been reports of arterial duct constriction after second-trimester treatment, most of which resolved after treatment discontinuation. Meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of urgent need. If a woman trying to conceive or pregnant during the first and second trimesters uses meloxicam, the dose and duration of treatment should be minimized. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. Meloxicam use should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

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

Potential risks in late pregnancy for mother and newborn:

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

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

Lactation

Although specific data on Miliksol are lacking, NSAIDs are known to pass into breast milk. Therefore, use of this medicinal product is not recommended for breastfeeding women.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosing

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 oral or rectal administration is not possible). Adverse reactions may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

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

Special Patient Populations

Elderly Patients (see section "Pharmacokinetics")

The recommended dose for elderly patients is 7.5 mg per day (half of a 1.5 ml ampoule) (also see section "Method of Administration and Dosage" ("Patients at Increased Risk of Adverse Reactions") 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, e.g., those with a history of gastrointestinal disorders or risk factors for cardiovascular disease, treatment should be initiated at a dose of 7.5 mg per day (half of a 1.5 ml ampoule).

Renal Impairment

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

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

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

Method of Administration

The medicinal product should be administered by deep intramuscular injection into the upper outer quadrant of the buttock, strictly observing aseptic technique. In case of repeated administration, the injection site should be alternated between the left and right buttocks. Prior to injection, it is important to ensure that the needle tip is not within a blood vessel.

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

In patients with a hip prosthesis, the injection should be administered into the opposite buttock.

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

Children

Milixol 15 mg/1.5 ml solution for injection 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 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 enhanced by administration of 4 oral doses of cholestyramine given 3 times daily.

Adverse Reactions

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

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

Most of the adverse effects observed are gastrointestinal in origin. Peptic ulcer, perforation, or gastrointestinal hemorrhage, 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 exacerbation of colitis and Crohn's disease have been reported after administration (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently.

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

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

Immune system disorders:

Uncommon – allergic reactions other than anaphylactic or anaphylactoid;
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 – 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"), hot flushes.

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., 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 system:

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

Specific serious and/or common adverse reactions

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

Adverse reactions not associated with the use of the drug 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.

5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

1.5 ml in ampoules, 5 ampoules per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

HELP S.A.

Manufacturer's address.

Pedini Ioanninon, Ioannina, 45500, Greece.

Marketing Authorisation Holder.

UAB "Farmlyga" / JSC "Farmliga".

Address of Marketing Authorisation Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.