Meloxicam-Vertex, tablets 7.5 mg 20 pcs

Pharmgroup:

NSAIDs.

Pharmacology

The mechanism of action

Meloxicam is a NSAID that shows anti-inflammatory, analgesic and antipyretic effects in animal models. The mechanism of action of meloxicam, like other NSAIDs, is associated with COX inhibition.

Like other NSAIDs, meloxicam competitively inhibits both COX isoenzymes, COX-1 and COX-2, by blocking arachidonate metabolism, resulting in analgesic, antipyretic and anti-inflammatory pharmacological effects. NSAIDs do not affect the peroxidase response and do not inhibit the synthesis of leukotrienes by lipoxygenase pathways. Meloxicam has a predominant effect on COX-2.

Gastrointestinal side effects of meloxicam are mainly related to COX-1 inhibition, but the potential role of COX-2 inhibition in the GI tract is not fully understood.

In the kidneys, PGs produced by both COX-1 and COX-2 are important regulators of sodium and water metabolism as well as renal function and hemodynamics. In conditions where the renal blood flow depends on the synthesis of COX, taking NSAIDs can lead to a significant decrease in renal blood flow, which can cause acute renal failure. In addition, changes in sodium and water reabsorption can worsen the condition of patients with elevated BP.

Pharmacokinetics

Intake

The absolute bioavailability of meloxicam capsules was 89% after a single oral dose of 30 mg compared to a bolus IV injection at the same dose. Dose-dependent pharmacokinetics were observed in the dose range from 5 to 60 mg after a single IV injection. After multiple oral doses, the pharmacokinetics of meloxicam in capsules was dose-dependent over a dose range of 7.5 to 15 mg. Mean Cmax was reached within 4-5 h after ingestion of meloxicam 7.5 mg tablet on an empty stomach, indicating prolonged absorption of the drug. With multiple dosing, stable concentrations were achieved by day 5. A second peak in meloxicam concentrations was observed approximately 12-14 h after administration of the dose, indicating intrahepatic recirculation.

Table 1

Pharmacokinetic parameters of single dose and equilibrium states with oral administration of meloxicam at doses of 7.5 and 15 mg (mean value and coefficient of variation, %)

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1 The parameter values in the table are taken from various studies.

Ingestion of food and antacids. Administration of meloxicam capsules after a high-fat breakfast (75 g fat) resulted in an increase in Cmax of approximately 22%, while AUC was unchanged. Tmax was 5 to 6 h. No FCV was detected with concomitant administration of antacids. Based on these data, meloxicam tablets can be administered regardless of the time of eating or concomitant use of antacids.

Distribution

The average Vss of meloxicam is approximately 10L. Meloxicam is approximately 99.4% bound to plasma proteins (primarily to albumin ) in the therapeutic dose range. The proportion of binding to proteins does not depend on the concentration of meloxicam in the clinically relevant range, but decreases to about 99% in patients with renal insufficiency. Meloxicam penetration into human erythrocytes after oral administration is less than 10%. After administration of a radioactively labeled dose, more than 90% of the radioactivity detected in plasma was present as unchanged meloxicam.

The concentration of meloxicam in synovial fluid after a single oral administration is 40 to 50% of the plasma concentration. The free fraction in synovial fluid is 2.5 times higher than in plasma due to the lower albumin content in synovial fluid compared to plasma. The significance of this phenomenon is unknown.

Metabolism

Meloxicam is almost completely metabolized to four pharmacologically inactive metabolites. The main metabolite, 5′-carboxymeloxicam (60% of the dose), is formed by oxidation of the intermediate metabolite 5′-hydroxymethylmeloxicam, which is excreted at 9% of the dose. In vitro studies show that CYP2C9 plays an important role in this metabolic pathway with a minor contribution of CYP3A4 isoenzyme. Peroxidase activity is probably responsible for the other two metabolites, which account for 16 and 4% of the administered dose, respectively.

The excretion of meloxicam occurs predominantly as metabolites and equally in the urine and feces. Only traces of the unchanged parent compound are excreted with urine (0.2%) and feces (1.6%). Urinary excretion was confirmed for unchanged multiple doses of 7.5 mg – 0.5%, 6% and 13% were detected in the urine as meloxicam, 5′-hydroxymethyl- and 5′-carboxymetabolites, respectively. Significant biliary and/or enteric secretion of meloxicam has been observed.

This has been demonstrated when oral administration of colestyramine after a single IV injection of meloxicam reduced its AUC by 50%. The average T1/2 is 15 to 20 h. T1/2 is unchanged at different dose levels, indicating a linear metabolism over a range of therapeutic doses. Plasma clearance is 7 to 9 ml/min.

Particular patient groups

Elderly age. In elderly men (≥65 years), plasma concentrations of meloxicam and equilibrium pharmacokinetics were similar to those observed in younger patients. In older women (≥65 years), after weight normalization, AUCss by 47% and Cmax, ss by 32% were higher than in younger women (≤55 years). Despite this increase, the adverse event profile was comparable for both patient groups. A lower free fraction was found in older female patients compared with older male patients.

Gender. Young women have slightly lower plasma concentrations than young men. After a single dose of 7.5 mg of meloxicam, the mean T1/2 was 19.5 h for women compared with 23.4 h for men. In the equilibrium state, the data were similar (17.9 versus 21.4 h). This difference by sex is probably of little clinical significance. Linearity in pharmacokinetics was observed and there were no appreciable differences in Cmax or Tmax values for men and women.

Hepatic impairment. After a single dose of meloxicam 15 mg, there were no observable differences in plasma concentrations in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment compared to healthy volunteers. Hepatic insufficiency did not affect the binding of meloxicam to plasma proteins. No dose adjustment is required in mild to moderate hepatic impairment. Sufficient studies with the participation of patients with severe hepatic impairment (class C according to Child-Pugh classification) have not been conducted.

Renal insufficiency. Pharmacokinetics of meloxicam has been studied in patients with renal insufficiency of various degrees. Total plasma concentration of the drug decreased according to the severity of renal failure, while the AUC value of the free fraction was similar. Total clearance of meloxicam was increased in patients with renal failure, probably due to an increase in the free fraction, which resulted in accelerated metabolic clearance.

In patients with mild to moderate renal impairment (creatinine Cl >15 ml/min), no dose adjustment is required. Patients with severe renal impairment have not been studied sufficiently. The use of meloxicam in patients with severe renal failure is not recommended.

Hemodialysis. After a single dose of meloxicam, the Cmax of free fraction in plasma was higher in patients with renal failure who were on permanent hemodialysis (free fraction 1%) compared to healthy volunteers (0.3%). Hemodialysis did not decrease the total plasma concentration of meloxicam. Thus, no additional doses are required after hemodialysis. Meloxicam is not amenable to dialysis.

Clinical studies

Osteoarthritis and rheumatoid arthritis. The use of meloxicam for the treatment of signs and symptoms of osteoarthritis of the knee and hip joints was evaluated in a 12-week double-blind controlled study. Meloxicam (3.75, 7.5, and 15 mg/d) was compared with placebo. The four primary endpoints were the investigator’s total score, the patient’s total score, the patient’s pain score, and the total WOMAC score (a self-administered questionnaire concerning pain, function, and stiffness). Patients receiving meloxicam at doses of 7.5 and 15 mg/day showed significant improvement in each of these endpoints compared to placebo.

The use of meloxicam to treat signs and symptoms of osteoarthritis has been evaluated in six double-blind, actively controlled studies outside the United States that ranged in duration from 4 weeks to 6 months. In these studies, the efficacy of meloxicam at doses of 7.5 and 15 mg/day was comparable to that of piroxicam at 20 mg/day and diclofenac in a prolonged dose of 100 mg/day and comparable to that observed in the US study.

The use of meloxicam to treat signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational study. Meloxicam (7.5, 15, and 22.5 mg/d) was compared with placebo. The primary endpoint in this study was the degree of ACR20 response, a composite measure of clinical, laboratory, and functional measures of rheumatoid arthritis response. Patients who received meloxicam at doses of 7.5 and 15 mg daily showed a significant improvement in the primary endpoint compared to placebo.

No additional improvement was observed at the 22.5 mg dose compared with the 15 mg dose. Higher doses of meloxicam (22.5 mg or more) have been associated with an increased risk of serious GI adverse reactions, so the daily dose of meloxicam tablets should not exceed 15 mg.

Carcinogenesis, mutagenesis, impaired fertility

No carcinogenic effects of meloxicam were observed in rats given orally up to 0.8 mg/kg/day (approximately 0.4 dose for a 50 kg adult at 15 mg/day and recalculated per unit body surface area) for 104 weeks, or in mice given orally up to 8 mg/kg/day (approximately 2.2 higher doses for humans, as indicated) for 99 weeks.

Meloxicam showed no mutagenicity in the Ames test or clastogenicity in the human lymphocyte chromosomal abnormality assay and the in vivo micronucleus test in mouse bone marrow.

Meloxicam had no effect on fertility in male and female rats at oral doses of up to 9 and 5 mg/kg/day, respectively (4.9 and 2.5 times higher than for humans, as noted above). However, an increased incidence of embryonic death at oral doses of ≥1 mg/kg/day (0.5 dose for humans, as noted above) was observed in rats when females received meloxicam 2 weeks before mating and during early embryonic development.

Indications

• Osteoarthritis
• rheumatoid arthritis
• ankylosing spondylitis (Behterev’s disease).
• inflammatory and degenerative joint diseases accompanied by painful syndrome

Active ingredient

Meloxicam

Composition

1 tablet contains:

The active ingredient:

meloxicam – 7.5 mg;

excipients:

Lactose monohydrate – 88.0 mg;

Microcrystalline cellulose – 62.4 mg;

sodium citrate dihydrate – 7.5 mg;

Sodium carboxymethyl starch – 7.2 mg;

povidone K-30 – 3.6 mg;

colloidal silica – 2.0 mg;

calcium stearate – 1.8 mg.

How to take, the dosage

Overly, with meals, once a day.

Rheumatoid arthritis: 15 mg daily. If positive therapeutic effect is achieved, the dose can be reduced to 7.5 mg per day.

Osteoarthritis: 7.5 mg daily. If necessary, the dose can be increased to 15 mg per day.

Ankylosing spondylitis: 15 mg daily. Depending on the therapeutic effect, the dose may be reduced to 7.5 mg per day.

The maximum daily dose of meloxicam is 15 mg. In patients at increased risk of side effects, as well as in patients with severe renal impairment who are on hemodialysis, the maximum daily dose is 7.5 mg. The maximum dose for adolescents is 0.25 mg/kg.

In moderately severe renal and hepatic insufficiency and in clinically stable cirrhosis, no dose adjustment is required.

Interaction

Concomitant use with acetylsalicylic acid and other NSAIDs increases the risk of erosive ulcerative lesions and bleeding from the gastrointestinal tract.

Concomitant use with hypotensive drugs may decrease the effectiveness of the latter.

Simultaneous use with lithium preparations may lead to cumulation of lithium and increase its toxic effects (we recommend monitoring the lithium concentration in the blood).

Concomitant use with methotrexate helps to increase the side effect of the latter on the hematopoietic system (there is a risk of anemia and leukopenia.

Periodic control of total blood count is necessary). Concomitant use with diuretics and cyclosporine leads to an increased risk of renal failure.

The simultaneous use with intrauterine contraceptives may decrease the effectiveness of the latter.

In concomitant use with anticoagulants (heparin, ticlopidine, warfarin), as well as with thrombolytic drugs (streptokinase, fibrinolysin) the risk of bleeding increases (periodic monitoring of blood clotting).

Concomitant use with colestiramine increases excretion of meloxicam through the gastrointestinal tract (as a result of binding meloxicam). No pharmacokinetic interaction was found in concomitant use of meloxicam with antacids.

Special Instructions

The potential risk of side effects depends on the dose and duration of treatment, so the lowest effective dose of the drug Meloxicam should be used.

The duration of treatment is determined individually depending on the course of the disease and the effectiveness of the therapy.
Patients with a history of gastric or duodenal ulcer disease, as well as patients on anticoagulant therapy should undergo regular medical examination, since these patients are at increased risk of gastrointestinal erosive ulcers.

In case of peptic ulcers or gastrointestinal bleeding or in case of side effects of skin and mucous membranes the drug should be discontinued.

In patients with cardiovascular disease or with risk factors for such diseases, NSAIDs may increase the risk of serious cardiovascular thrombosis, myocardial infarction, angina attack, which may be fatal. This risk may increase with longer duration of treatment.

NSAIDs inhibit the renal synthesis of prostaglandins that are involved in maintaining renal perfusion. 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 recovers to baseline levels. Elderly patients, patients with dehydration, congestive heart failure, cirrhosis, nephrotic syndrome or acute renal dysfunction, patients simultaneously taking diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and patients who have undergone serious surgical interventions that lead to hypovolemia, are at highest risk for this reaction. Diuresis and renal function should be carefully monitored in such patients at the beginning of therapy.
The use of NSAIDs in conjunction with diuretics may lead to retention of sodium, potassium and water, as well as reducing the natriuretic action of diuretics. As a result, in predisposed patients there may be increased signs of heart failure or hypertension. Therefore, close monitoring of such patients is necessary, and they should be kept adequately hydrated. Prior to the start of treatment, renal function should be studied.

In patients with mild to moderate renal insufficiency (CKR over 30 ml/min) the dose adjustment is not required.

In patients with terminal renal failure who are on hemodialysis the dose of Meloxicam should not exceed 7.5 mg per day.

When using Meloxicam (as well as most other NSAIDs), an occasional increase in serum transaminase activity or other liver function indicators may have been noted. In most cases, these increases were small and transient. If the changes detected are significant or do not decrease over time, the drug Meloxicam should be discontinued and the identified laboratory changes should be monitored.

No dose adjustment is required in patients with (compensated) cirrhosis.

Weakened or emaciated patients may have a worse tolerance to adverse events and therefore these patients should be closely monitored.

Like other NSAIDs, meloxicam may mask the symptoms of an underlying infectious disease.
The drug Meloxicam, which inhibits cyclooxygenase/prostaglandin synthesis, may affect fertility and is therefore not recommended for women who have difficulty conceiving. Therefore, in women undergoing evaluation for this reason, it is recommended to discontinue the drug Meloxicam.

In very rare cases serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been observed when using NSAIDs. A high risk of such reactions was observed at the beginning of treatment, and in most cases such reactions appeared within the first month of treatment. The first appearance of skin rashes, lesions of mucous membranes or other signs of hypersensitivity should stop using the drug Meloxicam.

Influence on the ability to drive vehicles and mechanisms
The use of the drug Meloxicam may cause adverse reactions in the form of headache, dizziness and drowsiness. During the treatment it is necessary to be cautious while driving motor transport and engaging in other potentially dangerous activities that require high concentration and quick psychomotor reactions.

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Features

Meloxicam is intended for symptomatic therapy, it should not be taken for the prevention of exacerbation of diseases. Caution should be exercised when treating patients with a history of gastrointestinal diseases and in patients receiving anticoagulants.

Patients with gastrointestinal symptoms should be monitored regularly. Periodic monitoring of blood clotting parameters is necessary.
If gastrointestinal ulceration or gastrointestinal bleeding occurs, meloxicam should be discontinued. If allergic reactions occurred during treatment (itching, urticaria, skin rash, photosensitization), it is necessary to consult a physician to address the issue of stopping the drug.
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 recovers to the baseline level.
Patients at greatest risk of developing this reaction are elderly patients; patients with dehydration; patients with congestive heart failure, cirrhosis, nephrotic syndrome or renal disease; patients receiving diuretics, ACE inhibitors, angiotensin II receptor antagonists; and patients who have undergone serious surgical interventions leading to hypovolemia.

In these patients at the beginning of therapy urine output and renal function should be carefully monitored.
Increase of transaminases is usually transient and insignificant. If there is a significant and persistent increase in transaminase activity, meloxicam should be discontinued and liver function should be monitored. Weakened or emaciated patients may have worse tolerance to adverse events, so such patients should be closely monitored.

Caution should be exercised when treating elderly patients who are more likely to have renal, hepatic and cardiac dysfunction.
Use of NSAIDs in conjunction with diuretics may lead to retention of sodium, potassium and water, and affect the natriuretic effect of diuretics. As a result, in predisposed patients may increase signs of heart failure or hypertension.
Meloxicam, as well as other NSAIDs, may mask the symptoms of infectious disease. The use of meloxicam, as well as other drugs that block the synthesis of prostaglandins, may affect fertility, so the drug is not recommended for women who want to get pregnant.
Influence on the ability to drive vehicles and operate machinery
No special studies on the effect of the drug on the ability to drive vehicles and operate machinery have been conducted.
Caution should be exercised while driving motor transport and engaging in other potentially dangerous activities that require high speed psychomotor reactions due to possible CNS adverse reactions such as visual disturbances, drowsiness and dizziness.

Contraindications

• Hypersensitivity to meloxicam and/or to any of the drug components, the combination of bronchial asthma and recurrent polyposis of the nose and sinuses, intolerance to acetylsalicylic acid and pyrazolone products;

• Gastric and duodenal ulcer in the acute phase, active gastrointestinal bleeding, other bleeding; severe hepatic insufficiency and active liver disease; severe renal insufficiency (unless hemodialysis is performed and creatinine clearance is less than 30 ml/min),

• progressive renal disease, hyperkalemia; severe heart failure, condition after aortocoronary bypass surgery; pregnancy, lactation (breastfeeding); children under 12 years of age, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome.

With caution

• Age over 65 years, coronary heart disease, chronic heart failure, cerebrovascular disease, dyslipidemia, hyperlipidemia, diabetes mellitus, diseases

• peripheral arterial disease, smoking, creatinine clearance less than 60 ml/min, history of gastrointestinal ulcers, history of infection with Helicobacter рylori, long-term use of NSAIDs, alcoholism, severe medical conditions.

• diseases, concomitant use of oral glucocorticosteroids (anticoagulants (including warfarin).anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors. citalopram, fluoxetine, paroxetine, sertraline), angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists.

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Side effects

Digestive system: dyspepsia, including nausea, vomiting, abdominal pain, diarrhea, constipation, flatulence, belching; gastrointestinal erosive and ulcerative lesions, stomach or intestinal perforation, gastrointestinal bleeding (hidden or evident); transient increase in liver transaminases activity, hyperbilirubinemia, hepatitis, esophagitis, stomatitis, gastritis, colitis, dry mouth.

Cardiovascular system: peripheral edema, tachycardia, increased or decreased blood pressure, hot flashes, vasculitis.

Blood organs: anemia, leukopenia, thrombocytopenia.

Respiratory system: bronchospasm, bronchial asthma with intolerance to aspirin (unstable bronchial asthma).

Central nervous system: dizziness, headache, tinnitus, sleep disorders (drowsiness/insomnia), disorientation, emotional lability, confusion, anxiety, depression.

Urinary system disorders: hematuria, albuminuria, increased creatinine level, acute renal failure.

Allergic reactions: anaphylactoid and anaphylactic reactions, pruritus, skin rash, urticaria, erythema multiforme, Stephen-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome), photosensitization.

Other: taste disorders, conjunctivitis, visual disturbances (blurring), weakness, fever.

If any of the side effects specified in the instructions worsen, or if you notice any other side effects not specified in the instructions, inform your doctor.

If you notice manifestations of allergic reactions of any drug, such as rash, itching, difficulty in swallowing and breathing, swelling of the throat and tongue, immediately stop taking the drug and consult a doctor.

Overdose

Symptoms: intensification of side effects.

Treatment: gastric lavage, taking activated charcoal (within the next hour), symptomatic therapy.

Colestyramine accelerates excretion of the drug from the body. Forced diuresis, urine alkalinization, hemodialysis are ineffective due to the high binding of meloxicam with blood proteins. No specific antidotes and antagonists were found.

Pregnancy use

Meloxicam is contraindicated in children under 15 years of age, pregnancy and lactation.

Similarities

Movalis, Meloxicam, Amelotex, Movasin, Arthrosan, Meloxicam-Teva, Meloxicam DS, Meloxicam Stada, Petcam Tabs, Meloxidil, Elox-SOLofar