Meloxicam Canon (Gel, Suppositories) Instructions for Use

ATC Code

M01AC06 (Meloxicam)

Active Substance

Meloxicam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID, an enolic acid derivative, has anti-inflammatory, analgesic, and antipyretic effects.

The anti-inflammatory effect is associated with the inhibition of the enzymatic activity of COX-2, which is involved in the biosynthesis of prostaglandins in the area of inflammation. Meloxicam has a lesser effect on COX-1, which is involved in the synthesis of prostaglandin that protects the gastrointestinal mucosa and participates in the regulation of renal blood flow.

It suppresses the synthesis of prostaglandins in the area of inflammation to a greater extent than in the gastric mucosa or kidneys, which is associated with relatively selective inhibition of COX-2.

Pharmacokinetics

After rectal administration, the C_max of meloxicam in plasma at steady state is reached in approximately 5 hours. Meloxicam is highly bound to plasma proteins, mainly albumin (99%). It penetrates into the synovial fluid, where its concentration is approximately 50% of the plasma concentration. The V_d is low, averaging 11 L. Individual variations are 30-40%.

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 (accounting for 16% and 4% of the dose, respectively).

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

Indications

Symptomatic treatment: osteoarthritis (arthrosis, degenerative joint diseases), including with a pain component; rheumatoid arthritis; ankylosing spondylitis; other inflammatory and degenerative diseases of the musculoskeletal system, such as arthropathies, dorsopathies (e.g., sciatica, low back pain, shoulder periarthritis), accompanied by pain.

ICD codes

Dosage Regimen

For the gel, apply externally only. Use a thin layer on intact skin over the affected area. Apply and gently rub in twice daily. Wash hands thoroughly after each application. Avoid contact with eyes, mucous membranes, and open wounds. Do not apply under occlusive dressings. The maximum recommended duration of treatment is four weeks.

For suppositories, administer rectally. The standard adult dose is 7.5 mg to 15 mg once per day. Use the lowest effective dose for the shortest duration necessary to control symptoms. For osteoarthritis, the recommended dose is 7.5 mg once daily. For rheumatoid arthritis and ankylosing spondylitis, the recommended dose is 15 mg once daily.

The maximum daily dose is 15 mg. Do not exceed this dose. In elderly patients, initiate therapy at the lower end of the dosage range. Monitor patients for signs of gastrointestinal bleeding and other adverse events. For patients with an increased risk of adverse reactions, use the lowest effective dose. Regularly reassess the need for continued treatment. Discontinue if no therapeutic benefit is achieved.

Adverse Reactions

From the hematopoietic system uncommon – anemia; rare – leukopenia, thrombocytopenia, changes in blood cell counts, including changes in the leukocyte formula.

From the immune system uncommon – immediate hypersensitivity reactions; frequency not known – anaphylactic shock, anaphylactoid reactions.

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

From the nervous system common – headache; uncommon – dizziness, drowsiness.

From the sensory organs uncommon – vertigo; rare – conjunctivitis, visual disturbances, including blurred vision, tinnitus.

From the cardiovascular system uncommon – increased blood pressure, feeling of “flushing”; rare – palpitations.

From the respiratory system rare – bronchial asthma in patients allergic to acetylsalicylic acid and other NSAIDs.

From the digestive system common – abdominal pain, dyspepsia, diarrhea, nausea, vomiting; uncommon – occult or overt gastrointestinal bleeding, gastritis, stomatitis, constipation, flatulence, belching; rare – gastroduodenal ulcers, colitis, esophagitis; very rare – gastrointestinal perforation.

From the liver and biliary tract uncommon – transient changes in liver function parameters (e.g., increased transaminase activity or bilirubin concentration); very rare – hepatitis.

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

From the urinary system uncommon – changes in renal function parameters (increased serum creatinine and/or urea concentration), urination disorders, including acute urinary retention; very rare – acute renal failure.

From the reproductive system uncommon – delayed ovulation; frequency not known – infertility in women.

Other: uncommon – edema.

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

Gastrointestinal bleeding, ulcer, or perforation can be fatal.

As with other NSAIDs, the possibility of interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome cannot be excluded.

Contraindications

Hypersensitivity to meloxicam; hypersensitivity (including to other NSAIDs); complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose or paranasal sinuses, angioedema or urticaria caused by intolerance to acetylsalicylic acid or other NSAIDs due to the existing probability of cross-sensitivity (including in history); 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 and heart failure; severe renal failure (if hemodialysis is not performed, CrCl <30 ml/min, as well as with confirmed hyperkalemia); active liver disease; active gastrointestinal bleeding, recently suffered cerebrovascular bleeding or established diagnosis of blood clotting disorders; concomitant therapy with anticoagulants, because of the risk of intramuscular hematoma formation; therapy of perioperative pain during coronary artery bypass grafting; pregnancy; lactation (breastfeeding); inflammatory diseases of the rectum or anus; recent bleeding from the rectum or anus; children and adolescents under 15 years of age.

With caution

History of gastrointestinal diseases (presence of Helicobacter pylori infection); 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: anticoagulants, oral corticosteroids, antiplatelet agents, selective serotonin reuptake inhibitors; peripheral arterial diseases; elderly age; long-term use of NSAIDs; smoking; frequent alcohol consumption.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in severe hepatic failure, active liver disease.

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

Use in Renal Impairment

Contraindicated for use in severe renal failure (if hemodialysis is not performed, CrCl <30 ml/min, as well as with confirmed hyperkalemia).

Use with caution in renal failure (CrCl 30-60 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 15 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Patients with gastrointestinal diseases require regular monitoring. If ulcerative gastrointestinal lesions or gastrointestinal bleeding occur, Meloxicam should be discontinued.

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

Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis may develop during the use of meloxicam. 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 question of discontinuing the use of meloxicam should be considered.

Cases of increased risk of serious cardiovascular thrombosis, myocardial infarction, angina attack, possibly fatal, have been described when taking NSAIDs. This risk increases with long-term use of the drug, as well as in patients with a history of the above-mentioned 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, kidney function usually returns to the initial level. Patients at the highest risk of developing this reaction are the elderly, patients with dehydration, congestive heart failure, liver cirrhosis, nephrotic syndrome or acute renal dysfunction, patients simultaneously taking diuretics, ACE inhibitors, angiotensin II receptor antagonists, as well as patients who have undergone major surgical interventions leading to hypovolemia. In such patients, at the beginning of therapy, diuresis and renal function should be carefully monitored.

The use of NSAIDs together with diuretics can lead to retention of sodium, potassium and water, as well as to a decrease in the natriuretic effect of diuretics. As a result, in predisposed patients, signs of heart failure or arterial hypertension may increase. Therefore, careful monitoring of the condition of such patients is necessary, as well as maintaining adequate hydration.

Before starting treatment, renal function should be examined. In case of combination therapy, renal function should also be monitored.

When using meloxicam (as well as most other NSAIDs), episodic increases in serum transaminase activity or other liver function parameters are possible. In most cases, this increase was small and transient. If the detected changes are significant or do not decrease over time, Meloxicam should be discontinued and the identified laboratory changes should be monitored.

Weakened or debilitated patients may tolerate adverse events worse, so such patients should be carefully observed.

Like other NSAIDs, Meloxicam may mask the symptoms of an underlying infectious disease.

As an agent that inhibits COX/prostaglandin synthesis, Meloxicam may affect fertility, and therefore is not recommended for women having difficulty conceiving. In women undergoing examination for this reason, discontinuation of meloxicam is recommended.

In patients with mild to moderate renal impairment (CrCl >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 mechanisms

The use of meloxicam may cause undesirable effects such as headache, dizziness, and drowsiness. One should refrain from driving vehicles and mechanisms.

Drug Interactions

Other inhibitors of prostaglandin synthesis, including glucocorticoids and salicylates – simultaneous administration with meloxicam increases the risk of gastrointestinal ulcers and gastrointestinal bleeding (due to synergy of action). Simultaneous use with other NSAIDs is not recommended.

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

Anti-platelet drugs, serotonin reuptake inhibitors – simultaneous administration with meloxicam increases the risk of bleeding due to inhibition of platelet function. In case of simultaneous use, careful monitoring of the blood coagulation system is necessary.

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

Methotrexate – NSAIDs reduce the renal secretion of methotrexate, thereby increasing its plasma concentration. Simultaneous use of meloxicam and methotrexate (at a dose of more than 15 mg per week) is not recommended. In case of simultaneous 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.

Diuretics – the use of NSAIDs against the background of diuretic intake in case of patient dehydration is accompanied by the risk of 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 decrease 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 excretion.

Pemetrexed – when meloxicam and pemetrexed are used concomitantly in patients with CrCl from 45 to 79 ml/min, meloxicam should be discontinued 5 days before starting pemetrexed and can be resumed 2 days after the end of pemetrexed intake. If there is a need for concomitant use of meloxicam and pemetrexed, patients should be carefully monitored, especially with regard to myelosuppression and the occurrence of gastrointestinal side effects. In patients with CrCl <45 ml/min, the use of meloxicam together with pemetrexed is not recommended.

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

When used concomitantly with meloxicam with drugs that have a known ability to inhibit CYP2C9 and/or CYP3A4 (or are metabolized with the participation of 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 concentration of both hypoglycemic agents and meloxicam in the blood. Patients simultaneously taking Meloxicam with sulfonylurea drugs or nateglinide should carefully monitor blood glucose levels due to the possibility of hypoglycemia.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.