Meloflex Rompharm (Solution) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

ATC Code

M01AC06 (Meloxicam)

Active Substance

Meloxicam (Rec.INN registered by WHO)

Dosage Form

Meloflex Rompharm

Solution for intramuscular injection 10 mg/1 ml: amp. 1.5 ml 3 or 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intramuscular injection yellow with a greenish tint, transparent.

Excipients: meglumine – 6.25 mg, glycofurol – 100 mg, poloxamer 188 – 50 mg, glycine – 5 mg, sodium chloride – 3.5 mg, sodium hydroxide solution 1M to pH 8.6-9.0, water for injection – up to 1 ml.

1.5 ml – ampoules of colorless glass with a capacity of 2 ml (3) – contour cell packs (1) – cardboard boxes.
1.5 ml – ampoules of colorless glass with a capacity of 2 ml (5) – contour cell packs (1) – cardboard boxes.

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID

Pharmacological Action

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

The mechanism of the anti-inflammatory 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 related to more selective inhibition of COX-2 compared to COX-1. It is believed that inhibition of COX-2 provides the therapeutic effects of NSAIDs, whereas inhibition of the constantly present isoenzyme COX-1 may be responsible for gastric and renal side effects. 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 (in 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 the blood clotting process (a reaction controlled by COX-1). These effects were dose-dependent.

Ex vivo studies have shown that Meloxicam (in 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 at doses of 7.5 and 15 mg than with other NSAIDs with which it was compared. 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 dose-dependent.

Pharmacokinetics

Meloxicam is completely absorbed after intramuscular administration. The relative bioavailability compared to oral bioavailability is almost 100%. Therefore, when switching from injectable to oral forms, dose adjustment is not required. After administration of a 15 mg intramuscular dose, the C_max in plasma, which is about 1.6-1.8 µg/ml, is reached within approximately 60-96 minutes.

Meloxicam is highly bound 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.

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 dose, respectively).

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 urine, Meloxicam 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 application.

Meloxicam demonstrates linear pharmacokinetics at doses of 7.5-15 mg with intramuscular administration.

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 (for example, sciatica, low back pain, shoulder periarthritis), accompanied by pain.

Parenterally used as initial therapy and for short-term symptomatic treatment.

ICD codes

Dosage Regimen

Administer the solution by deep intramuscular injection only.

The recommended adult dose is 7.5 mg (0.75 ml) or 15 mg (1.5 ml) once daily.

Use the lowest effective dose for the shortest duration necessary to control symptoms.

Do not exceed the maximum daily dose of 15 mg.

For initial therapy, administer the injection; transition to an oral form for continued treatment as clinically appropriate.

The duration of intramuscular use should be as short as possible, typically not exceeding 2-3 days.

In patients with severe renal impairment (creatinine clearance less than 30 ml/min) who are not on dialysis, do not use this medication.

No dosage adjustment is required for patients with mild to moderate renal impairment (creatinine clearance greater than 30 ml/min) or for patients with compensated liver cirrhosis.

Use with caution in elderly patients; initiate therapy at the lower end of the dosing range.

Monitor patients for signs of gastrointestinal bleeding, cardiovascular events, and renal or hepatic impairment, especially with long-term use.

Adverse Reactions

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

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

Psychiatric disorders rare – mood changes; frequency not established – 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 established – 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 established – infertility in women.

Other: common – pain and swelling at the injection site; 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, creatinine clearance <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 there is a risk of intramuscular hematoma formation; therapy of perioperative pain during coronary artery bypass surgery; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age.

With caution

History of gastrointestinal diseases (presence of Helicobacter pylori infection); congestive heart failure; renal failure (creatinine clearance 30-60 ml/min); coronary artery disease; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; concomitant therapy with the following drugs: anticoagulants, oral glucocorticosteroids, 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 insufficiency, 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, creatinine clearance <30 ml/min, as well as with confirmed hyperkalemia).

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

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Patients with gastrointestinal diseases require regular monitoring. If gastrointestinal ulceration or gastrointestinal bleeding occurs, Meloxicam 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 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 with the use of meloxicam. Therefore, special attention should be paid to patients reporting the development of adverse events related to 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 generally observed within the first month of treatment. If the first signs of skin rash, changes in 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 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 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 baseline. Patients at greatest risk for this reaction are the elderly, patients who are dehydrated, have congestive heart failure, liver cirrhosis, nephrotic syndrome, or acute renal dysfunction, patients concurrently taking diuretics, ACE inhibitors, angiotensin II receptor antagonists, and patients who have undergone major surgical procedures leading to hypovolemia. In such patients, diuresis and renal function should be carefully monitored at the beginning of therapy.

The use of NSAIDs together with diuretics may lead to retention of sodium, potassium and water, as well as a decrease 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 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 less well, so such patients should be carefully monitored.

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 (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

When driving a car and working with machinery, the possibility of developing dizziness, drowsiness, visual disturbances or other disorders of the central nervous system should be taken into account. During the treatment period, patients must exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

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.

Antiplatelet 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 the plasma level of lithium 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 use 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 the inhibition of prostaglandins, which 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 GI tract, leads to its more rapid elimination.

Pemetrexed – with the concomitant use of meloxicam and pemetrexed in patients with a CrCl from 45 to 79 ml/min, the use of meloxicam should be discontinued 5 days before the start of pemetrexed administration and can be resumed 2 days after the completion of its administration. If there is a need for the concomitant use of meloxicam and pemetrexed, patients should be carefully monitored, especially with regard to myelosuppression and the occurrence of GI side effects. In patients with CrCl <45 ml/min, the use of meloxicam concomitantly with pemetrexed is not recommended.

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

With the concomitant use of meloxicam and medicinal products 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 a pharmacokinetic interaction should be taken into account.

With the concomitant use 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 concomitantly taking Meloxicam with sulfonylurea preparations 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.