Exen-sanovel (Tablets) Instructions for Use

Marketing Authorization Holder

Sanovel Pharmaceutical Products Ind., Inc. (Turkey)

ATC Code

M01AC06 (Meloxicam)

Active Substance

Meloxicam (Rec.INN registered by WHO)

Dosage Forms

	Exen-sanovel	Tablets 7.5 mg: 30 pcs.
		Tablets 15 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets light yellow with a greenish tint, round, biconvex, with a score on one side.

Excipients: lactose monohydrate – 25 mg, sodium citrate dihydrate – 18 mg, microcrystalline cellulose – 115.5 mg, povidone – 11 mg, colloidal silicon dioxide – 4 mg, crospovidone – 17 mg, magnesium stearate – 2 mg.

10 pcs. – blisters (3) – cardboard packs.

Tablets light yellow with a greenish tint, oval, biconvex, with a score on both sides.

Excipients: lactose monohydrate – 37.5 mg, sodium citrate dihydrate – 27 mg, microcrystalline cellulose – 170 mg, povidone – 16.5 mg, colloidal silicon dioxide – 6 mg, crospovidone – 25 mg, magnesium stearate – 3 mg.

10 pcs. – blisters (3) – cardboard packs.

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 associated with 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 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 (in doses of 7.5 mg and 15 mg) more actively inhibited COX-2, exerting a greater inhibitory effect on the production of prostaglandin E₂ stimulated by lipopolysaccharide (a reaction controlled by COX-2) than on the production of thromboxane 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 well absorbed from the gastrointestinal tract, as evidenced by 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 taken orally (in doses of 7.5 and 15 mg), the concentration of meloxicam is proportional to the dose. Steady-state pharmacokinetics are achieved within 3-5 days. The range of differences between C_max and C_min of meloxicam 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 (values of C_min and C_max during the steady-state pharmacokinetic period are given, respectively), although values outside this range have also been noted. C_max in plasma during the steady-state pharmacokinetic period is reached 5-6 hours after oral administration.

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. V_d after repeated 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%. Interindividual differences range from 7-20%.

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 detected 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.

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

Determine the dosage individually based on pain intensity and severity of inflammation.

Administer the drug orally once daily with food.

For osteoarthritis, the recommended initial and maintenance dose is 7.5 mg once daily.

If insufficient, the dose may be increased to a maximum of 15 mg once daily.

For rheumatoid arthritis and ankylosing spondylitis, the recommended dose is 15 mg once daily.

Based on therapeutic response, the dose may be reduced to 7.5 mg once daily.

The maximum daily dose is 15 mg; do not exceed this limit.

For long-term therapy, use the lowest effective dose for the shortest possible duration.

In patients with an increased risk of adverse reactions, initiate therapy with 7.5 mg daily.

For patients with severe renal impairment requiring dialysis, do not exceed 7.5 mg daily.

Use with caution in patients with mild to moderate renal impairment (CrCl 30-60 ml/min); no initial dose adjustment is necessary.

No dose adjustment is required for patients with compensated liver cirrhosis.

Monitor elderly patients closely; consider using the lower end of the dosing range.

Swallow tablets whole with a sufficient amount of liquid.

The 15 mg tablet is scored and can be divided into equal halves.

Adverse Reactions

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

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

Mental disorders rarely – mood changes; frequency not established – confusion, disorientation.

From the nervous system often – headache; infrequently – dizziness, drowsiness.

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

From the cardiovascular system infrequently – increased blood pressure, feeling of “flushing” of the face; rarely – palpitations.

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

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

From the liver and biliary tract infrequently – transient changes in liver function parameters (e.g., increased activity of transaminases or bilirubin concentration); very rarely – hepatitis.

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

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

From the reproductive system infrequently – delayed ovulation; frequency not established – infertility in women.

Other: infrequently – 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, and nephrotic syndrome cannot be ruled out.

Contraindications

Hypersensitivity to meloxicam; hypersensitivity (incl. to other NSAIDs); complete or incomplete combination of bronchial asthma, recurrent nasal or sinus polyposis, angioedema or urticaria caused by intolerance to acetylsalicylic acid or other NSAIDs due to the existing probability of cross-sensitivity (incl. 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 there is a risk of intramuscular hematoma formation; therapy of perioperative pain during coronary artery bypass surgery; pregnancy; lactation period (breastfeeding); children under 12 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 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 cirrhosis of the liver (compensated), 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 under 12 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 during the use of NSAIDs at any time, 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, and toxic epidermal necrolysis may develop with 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 issue of discontinuing the use of meloxicam should be considered.

Cases of increased risk of serious cardiovascular thrombosis, myocardial infarction, and 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 baseline. Patients at greatest 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, diuresis and renal function should be carefully monitored at the beginning of therapy.

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 worsen. Therefore, careful monitoring of the condition of such patients is necessary, as well as maintaining adequate hydration.

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

When using meloxicam (as well as most other NSAIDs), episodic increases in the activity of transaminases in the blood serum 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, and therefore 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 it 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 cirrhosis of the liver (compensated), 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 from 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 level of lithium in the plasma by reducing its renal excretion. Simultaneous use of meloxicam with lithium preparations is not recommended. If simultaneous use is necessary, careful monitoring of the plasma lithium concentration throughout the course of lithium therapy is recommended.

Methotrexate – NSAIDs reduce the renal secretion of methotrexate, thereby increasing its plasma concentration. Simultaneous use of meloxicam and methotrexate (in 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 while taking diuretics in the case of patient dehydration is associated with a 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, 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 gastrointestinal tract, leads to its more rapid elimination.

Pemetrexed – with simultaneous 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 can be resumed 2 days after the end of its administration. If there is a need for concomitant use of meloxicam and pemetrexed, patients should be carefully monitored, especially for 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.

NSAIDs, by acting on 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 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 (for example, 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 simultaneously taking Meloxicam with sulfonylurea drugs or nateglinide should carefully monitor blood glucose levels due to the possibility of developing 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.