Instructions for Revmoxicam tablets 15 mg blister No. 20
Composition
active ingredient: meloxicam;
1 tablet contains meloxicam 7.5 mg or 15 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, sodium citrate, povidone, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: yellow tablets, with a flat surface, a bevel and a score. Marbling is allowed on the surface of the tablets.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. ATC code M01A C06.
Pharmacological properties
Pharmacodynamics
Revmoxicam® is a nonsteroidal anti-inflammatory drug (NSAID) of the enoleic acid class that has anti-inflammatory, analgesic, and antipyretic effects.
Meloxicam has shown 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 mechanism of development for all NSAIDs (including meloxicam): inhibition of the biosynthesis of prostaglandins, which are mediators of inflammation.
Pharmacokinetics
Absorption. Meloxicam is well absorbed from the gastrointestinal tract after oral administration, the absolute bioavailability of the drug is 90%. After a single dose of meloxicam, the maximum concentration in the blood plasma is reached within 5-6 hours.
With multiple dosing, steady-state concentrations are reached on the 3rd to 5th day. Once-daily dosing results in mean plasma concentrations with relatively small peak fluctuations: within 0.4-1 μg/ml for 7.5 mg and 0.8-2 μg/ml for 15 mg, respectively (Cmin and Cmax at steady state, respectively). Mean plasma concentrations of meloxicam at steady state are reached within 5-6 hours.
Simultaneous food intake or the use of inorganic antacids does not affect the absorption of the drug.
Distribution. Meloxicam is bound to plasma proteins, mainly albumin (99%). Meloxicam penetrates into the synovial fluid, where the concentration is half that in plasma. The volume of distribution is low, averaging 11 l after intramuscular or intravenous administration, and shows individual variations in the range of 7-20%. The volume of distribution after multiple oral doses of meloxicam (7.5 to 15 mg) is 16 l with a coefficient of variation in the range of 11% to 32%.
Biotransformation: Meloxicam undergoes extensive biotransformation in the liver.
Four different metabolites of meloxicam have been identified in urine, which are pharmacodynamically inactive. The main metabolite 5'-carboxymeloxicam (60% of the dose) is formed by oxidation of the intermediate metabolite 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 metabolism process, while CYP 3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients is probably responsible for the other two metabolites, which account for 16% and 4% of the administered dose, respectively.
Elimination. Meloxicam is excreted mainly as metabolites in equal parts with urine and feces. Less than 5% of the daily dose is excreted unchanged in the feces, a small amount is excreted in the urine. The half-life varies from 13 to 25 hours after oral, intramuscular and intravenous administration. Plasma clearance is about 7-12 ml/min after a single oral dose, intravenous or rectal administration.
Dose linearity: Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg after oral and intramuscular administration.
Special groups of patients.
Patients with hepatic/renal insufficiency. Mild to moderate hepatic and renal insufficiency do not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal insufficiency had a significantly higher total clearance. Reduced binding to plasma proteins was observed in patients with end-stage renal failure. In end-stage renal failure, an increase in the volume of distribution may lead to an increase in the concentration of free meloxicam. The daily dose of 7.5 mg should not be exceeded (see section "Method of administration and dosage").
Elderly patients. In elderly male patients, mean pharmacokinetic parameters were similar to those in young male volunteers. In elderly female patients, AUC values were higher and half-life was longer compared to those in young volunteers of both sexes. Mean steady-state plasma clearance in elderly patients was slightly lower than in young volunteers.
Indication
Short-term symptomatic treatment of exacerbations of osteoarthritis.
Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis.
Contraindication
– gastrointestinal bleeding or perforation associated with previous NSAID therapy in history;
– history of active or recurrent peptic ulcer/bleeding (two or more separate confirmed episodes of ulceration or bleeding);
– severe liver failure;
– severe renal failure without dialysis;
– gastrointestinal bleeding, history of cerebrovascular bleeding or other blood clotting disorders;
– severe heart failure;
– perioperative pain during coronary artery bypass grafting (CABG).
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions.
Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid ≥ 3 g/dose.
Combination with other NSAIDs is not recommended (see section "Special warnings and precautions for use"), including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g single dose or ≥ 3 g total daily dose).
Corticosteroids (e.g. glucocorticoids): Concomitant use with corticosteroids requires caution due to increased risk of gastrointestinal bleeding or ulceration.
Anticoagulants or heparin used in geriatric practice or at therapeutic doses. The risk of bleeding is significantly increased due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special instructions"). The concomitant use of NSAIDs and anticoagulants or heparin in geriatric practice or at therapeutic doses is not recommended (see section "Special instructions").
In other cases, heparin should be used with caution due to the increased risk of bleeding. Careful monitoring of the INR (international normalized ratio) is necessary if the combination is proven to be unavoidable.
Thrombolytic and antiplatelet agents: 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 (e.g. dehydrated patients or elderly patients with impaired renal function), the concomitant use of ACE inhibitors or angiotensin II antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section 4.4).
Other antihypertensive drugs (e.g. beta-blockers). Possible reduction of the antihypertensive effect of beta-blockers (due to inhibition of prostaglandins with vasodilating effect).
Calcineurin inhibitors (e.g. cyclosporine, tacrolimus). Nephrotoxicity of calcineurin inhibitors may be potentiated by NSAIDs due to mediation of renal prostaglandin effects. Renal function should be monitored during treatment. Close monitoring of renal function is recommended, especially in elderly patients.
Intrauterine contraceptives. NSAIDs reduce the effectiveness of intrauterine contraceptives. It has been previously reported that the effectiveness of intrauterine contraceptives is reduced by NSAIDs, but this requires further confirmation.
Pharmacokinetic interaction: the effect of meloxicam on the pharmacokinetics of other drugs.
Lithium.
NSAIDs have been shown to increase plasma lithium concentrations (due to decreased renal lithium excretion), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section 4.4). If combination therapy is necessary, careful monitoring of plasma lithium levels is recommended at the start of treatment, during dose adjustment and upon discontinuation of meloxicam.
Methotrexate.
NSAIDs may reduce the tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high doses of methotrexate (more than 15 mg/week) (see section 4.4). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low doses of methotrexate, in particular
Pharmacokinetic interaction: the effect of other drugs on the pharmacokinetics of meloxicam.
Cholestyramine: Cholestyramine accelerates the elimination of meloxicam due to impaired intrahepatic circulation, so the clearance of meloxicam increases by 50% and the half-life decreases to 13±3 hours. This interaction is clinically significant.
No clinically significant pharmacokinetic interaction was found when co-administered with antacids, cimetidine, and digoxin.
Application features
Adverse reactions can be minimised by using the lowest effective dose for the shortest duration necessary to control 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, nor should additional NSAIDs be used, as this may increase toxicity while the therapeutic benefit has not been proven. The concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.
Meloxicam is not suitable for the treatment of patients requiring relief of acute pain.
If there is no improvement after a few days, the clinical benefit of treatment should be reassessed.
Attention should be paid to a history of esophagitis, gastritis and/or peptic ulcer in order to ensure that they are completely cured before starting therapy with meloxicam. Patients treated with meloxicam and patients with a history of such cases should be regularly monitored for possible recurrence.
Gastrointestinal disorders.
As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration or perforation may occur at any time during treatment with or without previous symptoms or a history of serious gastrointestinal disease.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses in patients with a history of ulcer, particularly complicated by bleeding or perforation (see section 4.3), and in the elderly. In such patients, treatment should be initiated at the lowest effective dose. Combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered for such patients, as well as for patients who require concomitant use of low-dose aspirin or other agents that increase gastrointestinal risks (see information below and section 4.5).
Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed of any unusual abdominal symptoms (especially gastrointestinal bleeding), especially during the initial stages of treatment.
Caution should be exercised in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, including heparin as a radical therapy or in geriatric practice, anticoagulants such as warfarin, or other non-steroidal anti-inflammatory drugs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g single dose or ≥ 3 g total daily dose) (see section “Interaction with other medicinal products and other forms of interaction”).
If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment with the drug should be discontinued.
NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section "Adverse reactions").
Liver disorders.
Up to 15% of patients taking NSAIDs (including Revmoxicam®) may have elevations in one or more liver function tests. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued treatment. Marked elevations in ALT or AST (approximately three times or more above normal) have been observed in 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which were fatal, have been reported.
Patients with symptoms or suspected liver dysfunction or who have had abnormal liver tests should be evaluated for the development of symptoms of more severe liver failure during therapy with Revmoxicam®. If clinical signs and symptoms are consistent with the development of liver disease or if systemic manifestations of the disease (e.g. eosinophilia, rash, etc.) are observed, then the use of Revmoxicam® should be discontinued.
Cardiovascular disorders.
Close monitoring is recommended in patients with hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAID therapy.
The use of some NSAIDs (especially at high doses and in long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g. myocardial infarction or stroke). There are insufficient data to exclude such a risk for meloxicam.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with meloxicam only after careful consideration. Such consideration is necessary before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).
NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which may be fatal. The increased risk is related to the duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.
Skin disorders.
Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (see section 4.8). The highest risk of such reactions was observed at the beginning of treatment, with the majority of such reactions occurring within the first month of treatment. Meloxicam should be discontinued at the first appearance of skin rash, mucosal lesions or other signs of hypersensitivity.
Anaphylactic reactions.
As with other NSAIDs, anaphylactic reactions may occur in patients with no known reaction to Revmoxicam®. Revmoxicam® should not be used in patients with the aspirin triad. This symptom complex occurs in patients with asthma who have reported rhinitis with or without nasal polyps or who have experienced severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. If an anaphylactoid reaction occurs, emergency medical care should be sought.
Liver parameters and kidney function.
As with most NSAIDs, isolated cases of increased transaminases, serum bilirubin or other liver function parameters, possibly increased serum creatinine and blood urea nitrogen and other laboratory abnormalities have been reported. In most cases, these abnormalities were minor and transient. If significant or persistent abnormalities occur, meloxicam should be discontinued and follow-up tests performed.
Functional renal failure.
NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, can induce functional renal failure due to a decrease in glomerular filtration. This side effect is dose-dependent. Monitoring of diuresis and renal function is recommended at the beginning of treatment or after increasing the dose in patients with the following risk factors:
- old age;
- concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section "Interaction with other medicinal products and other types of interactions");
- hypovolemia (of any origin);
- congestive heart failure;
- renal failure;
- nephrotic syndrome;
- lupus nephropathy;
- severe hepatic dysfunction (serum albumin < 25 g/l or ≥ 10 according to the Child-Pugh classification).
In rare cases, NSAIDs can lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndrome.
The dose of meloxicam for patients with end-stage renal disease on dialysis should not exceed 7.5 mg. In patients with mild to moderate renal impairment, the dose may not be reduced (creatinine clearance greater than 25 ml/min).
Sodium, potassium and water retention.
NSAIDs may increase sodium, potassium and water retention and may interfere with the natriuretic effects of diuretics. In addition, the antihypertensive effect of antihypertensive drugs may be reduced (see section 4.5). As a result, edema, heart failure or hypertension may be precipitated or aggravated in susceptible patients. Clinical monitoring is therefore recommended in patients at risk (see sections 4.2 and 4.3).
Hyperkalemia.
Hyperkalemia may be caused by diabetes mellitus or concomitant use of medicinal products that increase potassium levels (see section 4.5). In such cases, potassium levels should be monitored regularly.
Other warnings and precautions.
Meloxicam, like any other NSAID, may mask the symptoms of infectious diseases.
Meloxicam may impair reproductive function and is not recommended in women attempting to conceive. Therefore, in women attempting to conceive or undergoing investigation of infertility, discontinuation of meloxicam should be considered (see section 4.6).
Revmoxicam® 7.5 mg and 15 mg tablets contain lactose, therefore this drug is not recommended for patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Masking inflammation and fever.
The pharmacological action of Revmoxicam® to reduce fever and inflammation may complicate the diagnosis of suspected non-infectious pain conditions.
Corticosteroid treatment.
Revmoxicam® cannot be a likely substitute for corticosteroids in the treatment of corticosteroid insufficiency.
Hematological effects.
Anemia may occur in patients receiving NSAIDs, including Revmoxicam®. This may be due to fluid retention, gastrointestinal bleeding of unknown origin or macroscopic, or incompletely described effects on erythropoiesis. Patients on long-term treatment with NSAIDs, including Revmoxicam®, should have their hemoglobin or hematocrit monitored if they develop symptoms and signs of anemia.
NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively smaller, short-lived, and reversible. Patients taking Revmoxicam® who may have adverse effects related to changes in platelet function, including coagulation disorders, or patients receiving anticoagulants should be carefully monitored.
Use in patients with asthma.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which may be fatal. Because of cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, Revmoxicam® should not be used in patients sensitive to aspirin and should be prescribed with caution in patients with asthma.
Use during pregnancy or breastfeeding
Revmoxicam® is contraindicated during pregnancy.
Fertility: Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may have an adverse effect on reproductive function and is not recommended in women attempting to conceive. Therefore, in women planning pregnancy or undergoing investigation of infertility, discontinuation of meloxicam should be considered.
Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-foetal development. Epidemiological data suggest an increased risk of miscarriage and of cardiac malformations and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations has increased from less than 1% to approximately 1.5%. This risk is thought to increase with increasing dose and duration of treatment.
During the first and second trimesters of pregnancy, meloxicam should not be used unless clearly necessary. If a woman is trying to conceive or is using meloxicam during the first and second trimesters of pregnancy, the dosage and duration of treatment should be kept to a minimum.
In the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose a risk to the fetus:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
- impaired renal function, which may develop into renal failure with oligohydramnios;
possible risks in the last stages of pregnancy for the mother and newborn:
- possibility of prolongation of bleeding time, anti-aggregation effect even at very low doses;
- suppression of uterine contractions, leading to delayed or prolonged labor.
Therefore, meloxicam is contraindicated in the third trimester of pregnancy.
Breastfeeding: Although there are no specific data for meloxicam, NSAIDs are known to pass into breast milk. Therefore, its use is not recommended in women who are breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are no specific studies on the effects of meloxicam on the ability to drive or use machines. However, based on the pharmacodynamic profile and the adverse reactions observed, it can be assumed that meloxicam is likely to have no or negligible influence on these activities. However, patients who experience visual disturbances, including blurred vision, dizziness, drowsiness, vertigo or other central nervous system disorders, are advised to refrain from driving or using machines.
Method of administration and doses
Administer orally.
Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special warnings and precautions for use").
The patient's need for symptomatic relief and response to treatment should be assessed periodically.
Exacerbation of osteoarthritis: 7.5 mg/day. If necessary, the dose may be increased to 15 mg/day.
Rheumatoid arthritis, ankylosing spondylitis: 15 mg/day.
See also the section “Special patient categories” below.
According to the therapeutic effect, the dose can be reduced to 7.5 mg/day.
DO NOT EXCEED THE DOSE OF 15 mg/day.
Special categories of patients.
Elderly patients and patients at increased risk of developing adverse reactions.
The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg/day.
Patients at increased risk of adverse reactions should start treatment with a dose of 7.5 mg/day (see section "Special warnings and precautions for use").
Kidney failure.
In patients with severe renal insufficiency who are on dialysis, the dose should not exceed 7.5 mg/day.
No dose reduction is required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min) (for patients with severe renal impairment without dialysis, see section "Contraindications").
Liver failure.
No dose reduction is required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section "Contraindications").
Children.
Revmoxicam®, 7.5 mg and 15 mg tablets, is contraindicated in children under 16 years of age.
Overdose
Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic use of NSAIDs, which may also occur with overdose.
In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that the elimination of meloxicam is accelerated by the administration of four oral doses of cholestyramine 3 times a day.
Adverse reactions
The use of some NSAIDs (especially at high doses and with long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g. myocardial infarction or stroke) (see section "Special warnings and precautions for use").
Edema, hypertension, and heart failure have been observed with NSAID treatment.
From the blood and lymphatic system: anemia; deviation of blood test parameters from the norm (including changes in the number of leukocytes), leukopenia, thrombocytopenia.
Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic drugs (see section "Interaction with other medicinal products and other forms of interaction").
Immune system disorders: allergic reactions, anaphylactic and/or anaphylactoid reactions, including shock.
Mental disorders: mood swings, nightmares, confusion, disorientation, insomnia.
From the nervous system: headache, dizziness, drowsiness.
On the part of the organs of vision: visual function disorders, including blurred vision, conjunctivitis.
From the side of the organs of hearing and vestibular apparatus: dizziness, ringing in the ears.
Cardiac disorders: Palpitations. Heart failure has been reported in association with NSAID treatment.
Vascular disorders: increased blood pressure, hot flashes.
Respiratory, thoracic and mediastinal disorders: asthma in patients allergic to aspirin and other NSAIDs, upper respiratory tract infections, cough.
On the part of the digestive tract: dyspepsia, nausea, vomiting, including hematemesis, abdominal pain, constipation, flatulence, diarrhea, occult or macroscopic gastrointestinal bleeding, stomatitis, including ulcerative stomatitis, gastritis, belching, colitis, gastroduodenal ulcer, esophagitis, gastrointestinal perforation, melena, exacerbation of colitis and Crohn's disease.
Gastrointestinal bleeding, ulceration or perforation may be severe and potentially fatal, especially in the elderly (see section 4.4).
Hepatobiliary system: abnormal liver function tests (e.g. increased transaminases or bilirubin), hepatitis, jaundice, liver failure.
On the part of the urinary system: sodium and water retention, hyperkalemia (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions"), changes in kidney function (increased creatinine and/or serum urea), acute renal failure, particularly in patients with risk factors (see section "Special instructions"), urinary tract infections, urinary frequency disorders.
General disorders and administration site conditions: edema, including edema of the lower extremities, influenza-like symptoms.
Musculoskeletal: arthralgia, back pain, joint-related signs and symptoms.
Adverse reactions that have not been observed during use of the drug, but which are generally considered to be characteristic of other compounds of the class.
Organic renal damage, possibly leading to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome and papillary necrosis have been reported (see section "Special warnings and precautions for use").
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister. 1 or 2 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Frunze St., 63.
