Meloxicam

Instructions for use of the drug

Structure

Active ingredient: meloxicam;

1.5 ml of the drug contains 15 mg of meloxicam;

1 ml of the drug contains 10 mg of meloxicam;

Excipients: meglumine, glycofurol, poloxamer 188, sodium chloride, glycine, sodium hydroxide, water for injection.

Dosage form.

Injection.

Basic physical and chemical properties: transparent, yellow solution with a green tint.

Pharmacological group.

Nonsteroidal anti-inflammatory and antirheumatic drugs.

Automatic telephone exchange code M01A C06.

Pharmacological properties.

Pharmacodynamics

Algezicam^® - This is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, has anti-inflammatory, analgesic and antipyretic effects.

Meloxicam showed high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, there is a common developmental mechanism for all NSAIDs (including meloxicam): inhibition of the biosynthesis of prostaglandins, which are mediators of inflammation.

Pharmacokinetics

Absorption. Meloxicam is completely absorbed after intramuscular injection. Relative bioavailability compared with oral administration is almost 100%. Therefore, there is no need to adjust the dose when switching from IM to the oral route of administration. After the intramuscular injection of 15 mg, the maximum plasma concentration is about 1.6-1.8 μg / ml and is reached in 1-6 hours.

Distribution. Meloxicam binds very well to plasma proteins, mainly with albumin (99%). Meloxicam penetrates into the synovial fluid, the concentration of which is 2 times less than in blood plasma. The volume of distribution is low, on average 11 l after i / m or iv injection, individual deviations within 7-20% are noted. The volume of distribution after repeated use of oral doses of meloxicam (7.5-15 mg) is 16 l with a deviation coefficient in the range of 11-32%.

Biotransformation. Meloxicam undergoes extensive biotransformation in the liver.

In urine, four different meloxicam metabolites are identified that are pharmacodynamically inactive. The main metabolite of 5′-carboxymeloxicam (60% of the dose) is formed by oxidation of the intermediate metabolite of 5′-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of the dose). In vitro studies suggest that CYP 2C9 plays an important role in the metabolic process, while CYP 3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients is probably responsible for the other two metabolites that make up

16% and 4% of the dose taken, respectively.

Elimination. The elimination of meloxicam occurs mainly in the form of metabolites in equal parts with urine and feces. Less than 5% of the daily dose is excreted unchanged with feces, a small amount is excreted in the urine. The elimination half-life varies from 13 to 25 hours depending on the method of application (oral administration, intramuscular or intravenous). Plasma clearance is about 7-12 ml / min after a single oral dose, iv or rectal administration.

The linearity of the dose. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose of 7.5 to 15 mg after oral and / m administration.

Special groups of patients.

Patients with hepatic / renal failure. Mild and moderate hepatic and renal failure does not significantly affect the pharmacokinetics of meloxicam. In patients with a moderate degree of renal failure, a significantly higher overall clearance was noted. Decreased plasma protein binding was detected in patients with end-stage renal failure.In terminal renal failure, an increase in the volume of distribution can lead to an increase in the concentration of free meloxicam. The daily dose of 7.5 mg should not be exceeded (see the section "Dosage and Administration").

Elderly patients. In elderly male patients, the average pharmacokinetic parameters are similar in young male volunteers. In elderly female patients, the area under the concentration-time pharmacokinetic curve (AUC) is higher and the elimination half-life is longer compared to those in young volunteers of both sexes. The average clearance from the blood plasma in equilibrium in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of an acute attack of rheumatoid arthritis and ankylosing spondylitis, when the oral and rectal routes of administration cannot be applied.

Contraindications

• Iii trimester of pregnancy (see section "use during pregnancy and lactation"); patient age up to 18 years; hypersensitivity to the active substance or other components of the drug; hypersensitivity to active substances with a similar effect as NSAIDs, acetylsalicylic acid. meloxicam should not be prescribed to patients who have asthma symptoms, nasal polyps, angioedema or urticaria after taking acetylsalicylic acid or other NSAIDs; gastrointestinal bleeding or perforation associated with previous history of NSAID therapy; history of active or recurring ulcer / bleeding (2 or more separate confirmed cases of ulcer or bleeding); severe liver failure; severe renal failure without dialysis; gastrointestinal bleeding, a history of cerebrovascular bleeding, or other bleeding disorders; hemostatic disorders or the simultaneous use of anticoagulants (contraindications associated with the route of use) severe heart failure; not used to treat perioperative pain with coronary artery bypass grafting.

Interactions with other drugs and other types of interactions.

Interaction studies were conducted only with adults.

Risks associated with hyperkalemia.

Some drugs or therapeutic groups can contribute to hyperkalemia: potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, low molecular weight or unfractionated heparins, cyclosporin, tacrolimus and trimethoprim.

The onset of hyperkalemia may depend on whether there are factors associated with it. The risk of developing hyperkalemia increases with the simultaneous use of the above drugs and meloxicam.

Pharmacodynamic interactions.

Other NSAIDs and acetylsalicylic acid ≥ 3 g / day.

A combination with other NSAIDs is not recommended (see section "Peculiarities of Use"), including acetylsalicylic acid in anti-inflammatory doses (≥ 500 mg single dose or ≥ 3 g total daily dose).

Corticosteroids (e.g. glucocorticoids).

Concomitant use with corticosteroids requires caution because of the risk of bleeding or ulcers in the digestive tract.

Anticoagulants or heparin.

Significantly increases the risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Features of use"). The simultaneous use of NSAIDs and anticoagulants or heparin in geriatric practice or in therapeutic doses is not recommended (see section "Features of use").A solution of meloxicam for intramuscular administration is contraindicated in patients who are treated with anticoagulants (see sections "Contraindications" and "Features of use").

In other cases (for example, when using preventive doses), the use of heparin requires caution because of the increased risk of bleeding.

Thrombolytic and antiplatelet drugs.

Increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective Serotonin Reuptake Inhibitors (SSRIs).

Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors and angiotensin II antagonists.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (patients with dehydration or elderly patients with impaired renal function), the simultaneous use of ACE inhibitors or angiotensin II antagonists and drugs that inhibit COX can lead to further deterioration of kidney function, including possible acute renal failure, which usually reversible. Therefore, the combination should be used with caution, especially in elderly patients. Patients need to receive an adequate amount of fluid, and kidney function should be monitored after the start of combination therapy and periodically in the future (see section "Features of use").

Other antihypertensive drugs (e.g., β-adrenergic blockers).

As with the drugs listed below, it is possible to reduce the antihypertensive effect of β-adrenoreceptor blockers (due to inhibition of prostaglandins with a vasodilating effect).

Calcineurin inhibitors (e.g. cyclosporine, tacrolimus).

Nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs due to mediation of the effects of renal prostaglandins. During treatment, renal function should be monitored. Close monitoring of renal function is recommended, especially in elderly patients.

Deferasirox.

The simultaneous use of meloxicam and Deferasirox may increase the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these medicines.

Pharmacokinetic interactions The effect of meloxicam on the pharmacokinetics of other drugs.

Lithium.

There is evidence of NSAIDs that increase the level of lithium concentration in blood plasma (due to a decrease in renal excretion of lithium), which can reach toxic values. The simultaneous use of lithium and NSAIDs is not recommended (see section "Features of use"). If combination therapy is necessary, it is necessary to carefully monitor the level of lithium in the blood plasma at the beginning of treatment, when selecting a dose and when ceasing treatment with meloxicam.

Methotrexate.

NSAIDs can reduce tubular secretion of methotrexate, thereby increasing plasma concentrations. For this reason, the concomitant use of NSAIDs in patients taking a high dose of methotrexate (15 mg / week) is not recommended (see section "Features of use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients taking a low dose of methotrexate, in particular with impaired renal function. If combination treatment is required, blood counts and kidney function should be monitored. Caution should be exercised if NSAIDs and methotrexate are taken for 3 consecutive days, since plasma levels of methotrexate may increase and increase toxicity. Although the pharmacokinetics of methotrexate (15 mg / week) does not change with concomitant treatment with meloxicam, it should be borne in mind that the hematological toxicity of methotrexate may increase in the treatment of NSAIDs (see the section “Adverse Reactions”).

Pemetrexed.

With the simultaneous use of meloxicam with pemetrexed in patients with mild to moderate renal failure (creatinine clearance 45 - 79 ml / min), meloxicam should be stopped for 5 days before pemetrexed administration, on the day of administration and 2 days after administration. If a combination of meloxicam with pemetrexed is necessary, patients should be carefully monitored, especially regarding the occurrence of myelosuppression and gastrointestinal adverse reactions. For patients with severe renal failure (creatinine clearance below 45 ml / min), the simultaneous use of meloxicam with pemetrexed is not recommended.

For patients with normal renal function (creatinine clearance ≥ 80 ml / min), doses of 15 mg of meloxicam can reduce the elimination of pemetrexed, therefore, increase the incidence of adverse reactions associated with pemetrexed. Therefore, caution should be exercised when prescribing 15 mg of meloxicam concurrently with pemetrexed for patients with normal renal function (creatinine clearance ≥ 80 ml / min).

Pharmacokinetic interactions: the effect of other drugs on the pharmacokinetics of meloxicam.

Colestyramine accelerates the elimination of meloxicam due to impaired intrahepatic circulation, therefore, the clearance of meloxicam increases by 50% and the half-life decreases to 13 ± 3:00. This interaction is clinically significant.

There were no clinically significant pharmacokinetic interactions of meloxicam with concomitant use with antacids, cimetidine and digoxin.

Features of the application.

Adverse reactions can be minimized by applying the minimum effective dose for the short duration of treatment needed to control the symptoms (see section “dosage and administration” and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, and NSAIDs should not be used additionally, as this can increase toxicity, while therapeutic benefits have not been proven. The simultaneous use of meloxicam with NSAIDs, including selective COX-2 inhibitors, should be avoided.

ALGEZICAM® is not suitable for the treatment of patients who need to reduce the severity of acute pain.

In the absence of improvement after several days of use of the drug, it is necessary to re-evaluate the clinical benefits of treatment.

Attention should be given to a history of esophagitis, gastritis and / or peptic ulcer in order to ensure their complete cure before starting meloxicam therapy. It should be regularly monitored regarding the possible manifestation of relapse in patients taking meloxicam, and patients with a history of such cases.

Violations of the digestive tract.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulcers, or perforations can occur at any time during treatment with or without previous symptoms or serious gastrointestinal illnesses.

The risk of gastrointestinal bleeding, ulcers or perforation is increased with increasing doses of NSAIDs in patients with a history of an ulcer, especially complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should begin treatment with the minimum effective dose. For such patients, combination therapy with protective drugs (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring a low dose of acetylsalicylic acid or other drugs that increase gastrointestinal risks (seeinformation below and the section “Interactions with other drugs and other types of interactions”).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be advised of all unusual abdominal symptoms (especially gastrointestinal bleeding), mainly in the initial stages of treatment.

For patients who are simultaneously taking medicines that may increase the risk of ulcers or bleeding, in particular heparin, as a radical therapy or in geriatric practice, anticoagulants such as warfarin or other NSAIDs, including acetylsalicylic acid in a dose of ≥ 500 mg single dose, or ≥ 3 g total daily intake, the use of meloxicam is not recommended (see section "Interaction with other drugs and other types of interactions").

If gastrointestinal bleeding or ulcers occur in patients using meloxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), since these conditions may worsen (see the section “Adverse Reactions”).

Violations of the liver.

Up to 15% of patients taking NSAIDs (including meloxicam) may report an increase in the level of one or more liver tests. Such laboratory abnormalities may progress, remain unchanged, or be temporary with continued treatment. A significant increase in AlAT or AsAT (about 3 or more times higher than normal) was recorded in 1% of patients during clinical trials with NSAIDs. In addition, rare cases of hepatic reaction, including jaundice and fulminant lethal hepatitis, liver necrosis and liver failure, some of them fatal, were recorded during clinical trials with NSAIDs.

Patients with symptoms and / or suspicion of hepatic dysfunction or for whom abnormal liver tests were detected should be evaluated for the development of symptoms of more severe liver failure during meloxicam therapy. If clinical signs and symptoms are correlated with the development of liver diseases or if systemic manifestations of the disease are observed (for example, eosinophilia, rash), the use of the drug ALGEZICAM® should be discontinued.

Cardiovascular disorders.

Patients with mild to moderate arterial hypertension and / or congestive heart failure should have a close observation in history, since fluid retention and edema were observed during NSAID therapy.

Patients with risk factors are recommended clinical observation of blood pressure at the beginning of therapy, especially at the beginning of the course of treatment with meloxicam.

Studies and epidemiological data suggest that the use of certain NSAIDs (especially in high doses and with long-term treatment) may be associated with a slight increase in the risk of vascular thrombotic events (such as myocardial infarction or stroke). There is insufficient data to exclude such a risk for meloxicam.

Patients with uncontrolled arterial hypertension, congestive heart failure, established coronary heart disease, peripheral arterial disease and / or cerebrovascular disease should be treated with meloxicam only after a thorough examination. Such an examination is necessary before the start of long-term treatment of patients with risk factors for cardiovascular diseases (for example, arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

NSAIDs may increase the risk of serious cardiovascular thrombotic complications, myocardial infarction, and stroke, sometimes fatal. Increased risk is associated with the duration of use.Patients with cardiovascular disease or cardiovascular risk factors may have an increased risk of thrombotic complications.

Violations of the skin.

Life-threatening severe skin lesions have been reported: Stevens-Johnson syndrome and toxic epidermal necrolysis with meloxicam. Patients should be informed of the signs and symptoms of severe lesions and closely monitor skin reactions. The greatest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis exists during the first weeks of treatment. If the patient has symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (for example, a skin rash that often progresses with vesicles or mucosal lesions), treatment with meloxicam should be discontinued. It is important to diagnose and stop using any drugs that can cause severe skin lesions as soon as possible: Stevens-Johnson syndrome or toxic epidermal necrolysis. A better prognosis for severe skin lesions is associated with this. If the patient has Stevens-Johnson syndrome or toxic epidermal necrolysis with meloxicam, the drug should not be used at any time in the future.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions can occur in patients without a known reaction to meloxicam. ALGEZICAM® should not be used in patients with the aspirin triad. This symptomatic complex is detected in patients with bronchial asthma,