Movalis^® (Tablets, Solution) Instructions for Use

ATC Code

M01AC06 (Meloxicam)

Active Substance

Meloxicam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic drugs; non-steroidal anti-inflammatory and antirheumatic drugs; oxicams

Pharmacological Action

A non-steroidal anti-inflammatory drug (NSAID), belongs to the enolic acid derivatives and has anti-inflammatory, analgesic, and antipyretic effects. The pronounced anti-inflammatory effect of meloxicam has been established in all standard models of inflammation.

The mechanism of action of meloxicam consists in its ability to inhibit the synthesis of prostaglandins, known mediators of inflammation.

Meloxicam in vivo inhibits the synthesis of prostaglandins at the site of inflammation to a greater extent than in the gastric mucosa or kidneys. These differences are associated with more selective inhibition of COX-2 compared to COX-1. It is believed that inhibition of COX-2 provides the therapeutic actions of NSAIDs, whereas inhibition of the constantly present COX-1 isoenzyme may be the cause of side effects from the stomach and kidneys.

The selectivity of meloxicam for COX-2 has been confirmed in various test systems, both in vitro and in vivo. The selective ability of meloxicam to inhibit COX-2 was demonstrated using human whole blood in vitro as a test system. It was found that Meloxicam (at doses of 7.5 mg and 15 mg) more actively inhibited COX-2, exerting a greater inhibitory effect on lipopolysaccharide-stimulated prostaglandin E₂ production (a reaction controlled by COX-2) than on thromboxane production involved in blood clotting (a reaction controlled by COX-1). These effects were dose-dependent. Ex vivo studies have shown that Meloxicam (at doses of 7.5 mg and 15 mg) does not affect platelet aggregation and bleeding time.

In clinical studies, gastrointestinal side effects overall occurred less frequently with meloxicam 7.5 mg and 15 mg than with other NSAIDs used for comparison. This difference in the frequency of gastrointestinal side effects is mainly due to the fact that phenomena such as dyspepsia, vomiting, nausea, and abdominal pain were observed less frequently with meloxicam. The frequency of perforations in the upper gastrointestinal tract, ulcers, and bleeding associated with the use of meloxicam was low and depended on the dose of the drug.

Pharmacokinetics

Absorption

Meloxicam is well absorbed from the gastrointestinal tract, as evidenced by its high absolute bioavailability (90%) after oral administration. After a single use of meloxicam, C_max in plasma is reached within 5-6 hours. Concurrent intake of food and inorganic antacids does not alter absorption. When the drug is taken orally (in doses of 7.5 and 15 mg), its concentrations are proportional to the doses. Steady-state pharmacokinetics are achieved within 3-5 days. The range of differences between C_max and C_min of the drug after its administration once a day is relatively small and is 0.4-1.0 µg/ml when using a dose of 7.5 mg, and when using a dose of 15 mg – 0.8-2.0 µg/ml (the values of C_min and C_max at steady state are given, respectively), although values outside this range have also been noted. C_max in plasma at steady state is reached 5-6 hours after oral administration.

Distribution

Meloxicam binds very well to plasma proteins, mainly albumin (99%). It penetrates into the synovial fluid, the concentration in the synovial fluid is approximately 50% of the plasma concentration. V_d after multiple oral administration of meloxicam (in doses from 7.5 mg to 15 mg) is about 16 L, with a coefficient of variation from 11 to 32%.

Metabolism

Meloxicam is almost completely metabolized in the liver to form 4 pharmacologically inactive derivatives. The main metabolite, 5′-carboxymeloxicam (60% of the dose), is formed by oxidation of an intermediate metabolite, 5′-hydroxymethylmeloxicam, which is also excreted, but to a lesser extent (9% of the dose). In vitro studies have shown that the isoenzyme CYP2C9 plays an important role in this metabolic transformation, with the isoenzyme CYP3A4 having additional significance. Peroxidase, whose activity probably varies individually, is involved in the formation of two other metabolites (constituting 16% and 4% of the drug dose, respectively).

Excretion

It is excreted equally through the intestine and kidneys, mainly in the form of metabolites. Less than 5% of the daily dose is excreted unchanged in the feces; in the urine, the drug is found only in trace amounts unchanged. The average T_1/2 of meloxicam varies from 13 to 25 hours. Plasma clearance averages 7-12 ml/min after a single dose of meloxicam.

Pharmacokinetics in special clinical cases

Hepatic insufficiency, as well as mild renal insufficiency, do not have a significant effect on the pharmacokinetics of meloxicam. The rate of elimination of meloxicam from the body is significantly higher in patients with moderate renal insufficiency. Meloxicam binds less well to plasma proteins in patients with end-stage renal failure. In end-stage renal failure, an increase in V_d may lead to higher concentrations of free meloxicam, so in these patients the daily dose should not exceed 7.5 mg.

Elderly patients

Elderly patients have similar pharmacokinetic parameters compared to young patients. In elderly patients, the average plasma clearance at steady state is slightly lower than in young patients. Elderly women have higher AUC values and a longer T_1/2 compared to young patients of both sexes.

Indications

Symptomatic treatment

• Osteoarthritis (arthrosis, degenerative joint diseases), incl. with a pain component;
• Rheumatoid arthritis;
• Ankylosing spondylitis;
• Other inflammatory and degenerative diseases of the musculoskeletal system, such as arthropathies, dorsopathies (for example, sciatica, low back pain, shoulder periarthritis), accompanied by pain.

ICD codes

Dosage Regimen

Solution

The drug is administered by deep intramuscular injection. The drug must not be administered intravenously.

Intramuscular administration of the drug is indicated only during the first few days of therapy. Subsequently, treatment is continued using oral dosage forms.

The recommended dose is 7.5 mg or 15 mg once a day, depending on the intensity of pain and the severity of the inflammatory process.

Osteoarthritis with pain syndrome 7.5 mg/day. If necessary, the dose can be increased to 15 mg/day.

Rheumatoid arthritis 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day.

Ankylosing spondylitis: 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day.

In patients with an increased risk of adverse reactions (history of gastrointestinal diseases, presence of risk factors for cardiovascular diseases), it is recommended to start treatment with a dose of 7.5 mg/day.

Since the potential risk of adverse reactions depends on the dose and duration of treatment, the lowest possible doses and duration of use should be used.

The maximum recommended daily dose is 15 mg.

In patients with severe renal insufficiency on hemodialysis, the dose should not exceed 7.5 mg/day.

Combined use

The drug should not be used simultaneously with other NSAIDs.

The total daily dose of Movalis^® used in different dosage forms should not exceed 15 mg.

Given the possible incompatibility, Movalis^® solution for intramuscular injection should not be mixed in the same syringe with other medicines.

Tablets

Osteoarthritis with pain syndrome 7.5 mg/day. If necessary, the dose can be increased to 15 mg/day.

Rheumatoid arthritis: 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day.

Ankylosing spondylitis 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7.5 mg/day.

In patients with an increased risk of adverse reactions (history of gastrointestinal diseases, presence of risk factors for cardiovascular diseases), it is recommended to start treatment with a dose of 7.5 mg/day.

In patients with severe renal insufficiency on hemodialysis, the dose should not exceed 7.5 mg/day.

General recommendations

Since the potential risk of adverse reactions depends on the dose and duration of treatment, the lowest possible doses and duration of use should be used.

The maximum recommended daily dose is 15 mg.

Combined use

The drug should not be used simultaneously with other NSAIDs.

The total dose of Movalis^® used in different dosage forms should not exceed 15 mg/day.

Adolescents

The maximum dose in adolescents aged 12-18 years is 0.25 mg/kg and should not exceed 15 mg.

Use of tablets

The use of the drug is contraindicated in children under 12 years of age, due to the inability to select an appropriate dose for this age group.

The total daily dose should be taken in one dose, with meals, with water or another liquid.

Adverse Reactions

The following describes side effects for which the relationship with the use of Movalis^® was considered possible.

Side effects registered during post-marketing use, for which the relationship with the drug was considered possible, are marked with an *.

Within system-organ classes, the following categories are used for the frequency of side effects: 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.

Blood and lymphatic system disorders uncommon – anemia; rare – changes in blood cell count, including changes in the leukocyte formula, leukopenia, thrombocytopenia.

Immune system disorders uncommon – other immediate hypersensitivity reactions*; frequency not known – anaphylactic shock*, anaphylactoid reactions*.

Nervous system disorders common – headache; uncommon – dizziness, somnolence.

Psychiatric disorders common – mood changes*; frequency not known – confusion*, disorientation*.

Eye and ear disorders uncommon – vertigo; rare – conjunctivitis*, visual disturbances, including blurred vision*, tinnitus.

Gastrointestinal disorders common – abdominal pain, dyspepsia, diarrhea, nausea, vomiting; uncommon – occult or overt gastrointestinal bleeding, gastritis*, stomatitis, constipation, flatulence, eructation; rare – gastroduodenal ulcers, colitis, esophagitis; very rare – gastrointestinal perforation.

Hepatobiliary disorders uncommon – transient changes in liver function parameters (e.g., increased transaminase activity or bilirubin concentration); very rare – hepatitis*.

Skin and subcutaneous tissue disorders uncommon – angioedema*, pruritus, skin rash; rare – toxic epidermal necrolysis*, Stevens-Johnson syndrome*, urticaria; very rare – bullous dermatitis*, erythema multiforme*; frequency not known – photosensitivity.

Respiratory, thoracic and mediastinal disorders rare – bronchial asthma in patients allergic to acetylsalicylic acid or other NSAIDs.

Cardiac and vascular disorders uncommon – increased blood pressure, feeling of facial flushing; rare – palpitations.

Renal and urinary disorders uncommon – changes in renal function parameters (increased serum creatinine and/or urea levels), urinary disorders, including acute urinary retention*; very rare – acute renal failure*.

Reproductive system and breast disorders uncommon – delayed ovulation*; frequency not known – female infertility*.

Concomitant use with drugs that inhibit bone marrow hematopoiesis (e.g., methotrexate) may provoke cytopenia.

Gastrointestinal bleeding, ulcer, or perforation can be fatal.

As with other NSAIDs, the occurrence of interstitial nephritis, glomerulonephritis, renal medullary necrosis, and nephrotic syndrome cannot be ruled out.

Contraindications

• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, angioedema or urticaria caused by intolerance to acetylsalicylic acid or other NSAIDs (including in history) due to the existing probability of cross-sensitivity;
• Erosive and ulcerative lesions of the stomach and duodenum in the acute stage or recently suffered;
• Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis in the acute stage);
• Severe hepatic failure;
• Severe renal failure (if hemodialysis is not performed, CrCl <30 ml/min, as well as with confirmed hyperkalemia);
• Progressive kidney disease;
• Active gastrointestinal bleeding, recent cerebrovascular bleeding or established diagnosis of blood clotting disorders;
• Severe uncontrolled heart failure;
• Therapy of perioperative pain during coronary artery bypass grafting;
• Pregnancy;
• Period of lactation (breastfeeding);
• Children under 12 years of age;
• Rare hereditary galactose intolerance (the maximum daily dose of the drug with meloxicam dosage of 7.5 mg and 15 mg contains 47 mg and 20 mg of lactose, respectively);
• Hypersensitivity to the active substance or auxiliary components of the drug.

With caution history of gastrointestinal diseases (peptic ulcer of the stomach and duodenum, liver diseases); congestive heart failure; renal failure (CrCl 30-60 ml/min); coronary artery disease; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; concomitant therapy with the following drugs: oral corticosteroids, anticoagulants (including warfarin), antiplatelet agents, selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); peripheral arterial diseases; elderly age; long-term use of NSAIDs; smoking; frequent alcohol consumption.

Use in Pregnancy and Lactation

The use of Movalis^® is contraindicated during pregnancy.

It is known that NSAIDs are excreted in breast milk, so the use of Movalis^® during breastfeeding is contraindicated.

As a drug that inhibits COX/prostaglandin synthesis, Movalis^® may affect fertility, and therefore is not recommended for women planning pregnancy. Meloxicam may lead to delayed ovulation. In this regard, in women who have problems with conception and are undergoing examination for such problems, it is recommended to discontinue the use of Movalis^®.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic failure.

In patients with cirrhosis of the liver (compensated), dose adjustment is not required.

Use in Renal Impairment

The drug is contraindicated in severe renal failure (if hemodialysis is not performed, CrCl <30 ml/min, as well as with confirmed hyperkalemia), progressive kidney disease.

The drug should be prescribed with caution in renal failure (CrCl 30-60 ml/min).

In patients with severe renal insufficiency on hemodialysis, the dose should not exceed 7.5 mg/day.

In patients with mild to moderate renal insufficiency (CrCl >25 ml/min), dose adjustment is not required.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Patients with gastrointestinal diseases should be regularly monitored. If ulcerative gastrointestinal lesions or gastrointestinal bleeding occur, Movalis^® should be discontinued.

Gastrointestinal ulcers, perforation, or bleeding can occur at any time during the use of NSAIDs, both in the presence of warning symptoms or a history of serious gastrointestinal complications, and in the absence of these signs. The consequences of these complications are generally more serious in the elderly.

Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis may develop with the use of Movalis^®. Therefore, special attention should be paid to patients reporting the development of adverse events from the skin and mucous membranes, as well as hypersensitivity reactions to the drug, especially if such reactions were observed during previous courses of treatment. The development of such reactions is usually observed within the first month of treatment. If the first signs of a skin rash, changes in the mucous membranes, or other signs of hypersensitivity appear, the issue of discontinuing the use of Movalis^® should be considered.

Cases of increased risk of serious cardiovascular thrombosis, myocardial infarction, and angina attack, possibly fatal, have been described with the use of NSAIDs. This risk increases with long-term use of the drug, as well as in patients with a history of the aforementioned diseases and those predisposed to such diseases.

NSAIDs inhibit the synthesis of prostaglandins in the kidneys, which are involved in maintaining renal perfusion. The use of NSAIDs in patients with reduced renal blood flow or reduced circulating blood volume may lead to decompensation of latent renal failure. After discontinuation of NSAIDs, renal function usually returns to the baseline level. Patients at the highest risk for this reaction are the elderly, patients with dehydration, congestive heart failure, liver cirrhosis, nephrotic syndrome, or acute renal dysfunction, patients concurrently taking diuretics, ACE inhibitors, angiotensin II receptor antagonists, as well as patients who have undergone major surgical interventions leading to hypovolemia. In such patients, diuresis and renal function should be carefully monitored at the beginning of therapy.

Concomitant use of NSAIDs with diuretics may lead to sodium, potassium, and water retention, as well as a reduction in the natriuretic effect of diuretics. As a result, in predisposed patients, signs of heart failure or arterial hypertension may worsen. Therefore, careful monitoring of such patients’ condition and maintenance of adequate hydration are necessary. Renal function should be investigated before starting treatment.

In case of combination therapy, renal function should also be monitored.

With the use of the drug Movalis^® (as well as most other NSAIDs), occasional increases in transaminase activity or other serum liver function parameters have been reported. In most cases, this increase was slight and transient. If the detected changes are significant or do not decrease over time, Movalis^® should be discontinued and the identified laboratory changes should be monitored.

Weakened or debilitated patients may tolerate adverse events less well; therefore, such patients require careful observation.

Like other NSAIDs, Movalis^® may mask the symptoms of an infectious disease.

As a drug that inhibits COX/prostaglandin synthesis, Movalis^® may affect fertility, and therefore it is not recommended for women having difficulties conceiving. For women undergoing examination for this reason, discontinuation of Movalis^® is recommended.

In patients with mild to moderate renal insufficiency (creatinine clearance >25 ml/min), dose adjustment is not required.

In patients with (compensated) liver cirrhosis, dose adjustment is not required.

Effect on ability to drive vehicles and operate machinery

No specific clinical studies on the effect of the drug on the ability to drive a car and operate machinery have been conducted. However, when driving a car and working with machinery, the possibility of developing dizziness, drowsiness, visual disturbances, or other CNS disorders should be taken into account. Patients should exercise caution when driving a car and operating machinery.

Overdose

Insufficient data have been accumulated on cases related to drug overdose. Symptoms characteristic of NSAID overdose are likely to be present, in severe cases: drowsiness, impaired consciousness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, acute renal failure, changes in blood pressure, respiratory arrest, asystole.

Treatment no specific antidote is known; in case of drug overdose, gastric evacuation and general supportive therapy should be performed. Cholestyramine accelerates the elimination of meloxicam.

Drug Interactions

Other inhibitors of prostaglandin synthesis, including glucocorticoids and salicylates – concurrent administration with meloxicam increases the risk of GI ulcers and gastrointestinal bleeding (due to synergistic action). Concurrent administration with other NSAIDs is not recommended.

Oral anticoagulants, systemically administered heparin, thrombolytic agents – concurrent administration with meloxicam increases the risk of bleeding. In case of concurrent use, careful monitoring of the blood coagulation system is necessary.

Antiplatelet agents, serotonin reuptake inhibitors – concurrent administration with meloxicam increases the risk of bleeding due to inhibition of platelet function. In case of concurrent use, careful monitoring of the coagulation system is necessary.

Lithium preparations – NSAIDs increase plasma lithium levels by reducing its renal excretion. Concurrent use of meloxicam with lithium preparations is not recommended. If concurrent use is necessary, careful monitoring of plasma lithium concentration is recommended throughout the course of lithium medication use.

Methotrexate – NSAIDs reduce the renal secretion of methotrexate, thereby increasing its plasma concentration. Concurrent use of meloxicam and methotrexate (at a dose of more than 15 mg per week) is not recommended. In case of concurrent use, careful monitoring of renal function and blood count is necessary. Meloxicam may enhance the hematological toxicity of methotrexate, especially in patients with impaired renal function. When meloxicam and methotrexate are used together for 3 days, the risk of increased toxicity of the latter increases.

Contraception – there is evidence that NSAIDs may reduce the effectiveness of intrauterine contraceptive devices, but this has not been proven.

Diuretics – the use of NSAIDs while taking diuretics in the case of patient dehydration is associated with the risk of developing acute renal failure.

Antihypertensive agents (beta-blockers, ACE inhibitors, vasodilators, diuretics). NSAIDs reduce the effect of antihypertensive agents due to inhibition of prostaglandins that have vasodilating properties.

Angiotensin II receptor antagonists, as well as ACE inhibitors, when used concomitantly with NSAIDs, enhance the reduction in glomerular filtration, which may thereby lead to the development of acute renal failure, especially in patients with impaired renal function.

Cholestyramine, by binding Meloxicam in the gastrointestinal tract, leads to its faster elimination.

NSAIDs, by affecting renal prostaglandins, may enhance the nephrotoxicity of cyclosporine.

Pemetrexed – with the concurrent use of meloxicam and pemetrexed in patients with a creatinine clearance from 45 to 79 ml/min, meloxicam should be discontinued 5 days before starting pemetrexed and may be resumed 2 days after finishing the drug. If there is a need for the combined use of meloxicam and pemetrexed, patients should be under careful monitoring, especially regarding myelosuppression and the occurrence of gastrointestinal adverse events. In patients with creatinine clearance <45 ml/min, the use of meloxicam together with pemetrexed is not recommended.

When used concomitantly with meloxicam and drugs that have a known ability to inhibit CYP2C9 and/or CYP3A4 (or are metabolized by these enzymes), such as sulfonylurea derivatives or probenecid, the possibility of pharmacokinetic interaction should be taken into account.

When used concomitantly with oral hypoglycemic agents (e.g., sulfonylurea derivatives, nateglinide), an interaction mediated by CYP2C9 is possible, which may lead to an increase in the blood concentration of both the hypoglycemic agents and meloxicam. Patients concurrently taking Meloxicam with sulfonylurea drugs or nateglinide should carefully monitor blood glucose levels due to the possibility of hypoglycemia.

No significant pharmacokinetic interaction was identified with the simultaneous use of meloxicam with antacids, cimetidine, digoxin, and furosemide.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.