Meloxicam bufus, 10 mg/ml 1.5 ml 5 pcs

Pharmacodynamics

Meloxicam is a non-steroidal anti-inflammatory drug with analgesic, anti-inflammatory and antipyretic effects. It belongs to the class of oxycams, derivatives of enolic acid. Anti-inflammatory effect is associated with inhibition of enzymatic activity of cyclooxygenase-2, which is involved in the biosynthesis of prostaglandins in the area of inflammation. To a lesser extent, meloxicam acts on cyclooxygenase-1, which is involved in the synthesis of prostaglandin that protects the mucosa of the gastrointestinal tract (GIT) and is involved in the regulation of blood flow in the kidneys.

Pharmacokinetics

Absorption

The relative bioavailability is about 100%. After intramuscular administration of the drug at a dose of 15 mg, the maximum plasma concentration of the drug (C_max) is 1.62 µg/mL and is reached within approximately 60 minutes.

Distribution

Meloxicam binds well to plasma proteins, especially to albumin (99%). It penetrates the synovial fluid, the concentration in synovial fluid being approximately 50% of the plasma concentration of the drug. The volume of distribution is low, approximately 11 liters. Interindividual variation is 30-40%.

Metabolism

Meloxicam is almost completely metabolized in the liver to form four pharmacologically inactive metabolites. The main metabolite, 5′-carboxymeloxicam (60% of the dose value), is formed by oxidation of the intermediate metabolite 5′-hydroxymethylmeloxicam, which is also excreted, but to a lesser extent (9% of the dose value).

In vitro studies have shown that CYP2C9 isoenzyme plays an important role in this metabolic transformation, CYP3A4 isoenzyme has additional importance. Peroxidase, the activity of which probably varies individually, is involved in the formation of the other two metabolites (which constitute, respectively, 16% and 4% of the drug dose).

Extracted equally in the feces and urine, mainly as metabolites. Less than 5% of daily dose is excreted unchanged in feces, in urine the drug is excreted unchanged only in trace amounts. The average half-life of meloxicam is 20 hours. Plasma clearance averages 8 ml/min.

Hepatic and/or renal insufficiency

Hepatic insufficiency and mild to moderate renal insufficiency have no significant effect on the pharmacokinetics of meloxicam. In terminal renal insufficiency, increased volume of distribution may lead to higher concentrations of free meloxicam; therefore, in patients with hepatic and/or renal insufficiency, the daily dose should not exceed 7.5 mg.

Elderly patients

The average plasma clearance during equilibrium pharmacokinetics is slightly lower in elderly patients than in younger patients.

Indications

Active ingredient

Composition

Active ingredient:

Meloxicam – 10,000 mg

Excipients:

Glycofurole (tetraglycol) – 100,000 mg

Poloxamer 188 – 50,000 mg

Meglumine – 6,250 mg

glycine – 5,000 mg

sodium chloride – 3,000 mg

sodium hydroxide – 0.152 mg

How to take, the dosage

The drug is given by deep intramuscular injection.

The drug should not be given intravenously.

Osteoarthritis with pain syndrome: 7.5 mg daily. If necessary, this dose can be increased to 15 mg per day.

Rheumatoid arthritis: 15 mg per day. Depending on the therapeutic effect, this dose may be reduced to 7.5 mg per day.

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

In patients with an increased risk of adverse reactions (history of GI disease, presence of cardiovascular risk factors), it is recommended to start treatment with a dose of 7.5 mg per day.

In patients with significant renal impairment who are on hemodialysis, the dose should not exceed 7.5 mg daily.

General recommendations

Because the potential risk of adverse reactions depends on the dose and duration of treatment, the lowest possible dose and duration of use should be used.

The maximum recommended daily dose is 15 mg.

Combined use

The drug should not be used concomitantly with other NSAIDs.

The total daily dose of Meloxicam used in different dosage forms should not exceed 15 mg.

Intramuscular administration of the drug is indicated only during the first few days of therapy. Thereafter, treatment is continued with the use of oral dosage forms. The recommended dose is 7.5 mg or 15 mg once a day, depending on the intensity of the pain and the severity of the inflammatory process.

Interaction

Other inhibitors of prostaglandin synthesis, including glucocorticoids and salicylates. Concomitant use with meloxicam increases the risk of gastrointestinal ulcers and gastrointestinal bleeding (due to synergistic action). Simultaneous use with other NSAIDs is not recommended.

Anticoagulants for oral administration, heparin for systemic use, thrombolytics. Concomitant use with meloxicam increases the risk of bleeding. In case of concomitant use it is necessary to monitor closely the blood clotting system.

Antiplatelet agents, serotonin reuptake inhibitors. Concomitant use with meloxicam increases the risk of bleeding due to inhibition of platelet function. In case of concomitant use, close monitoring of the clotting system is necessary.

Lithium preparations. NSAIDs increase the level of lithium in plasma, by reducing its excretion by the kidneys. Concomitant use of meloxicam with lithium preparations is not recommended. If concomitant use is necessary, it is recommended to carefully monitor the concentration of lithium in plasma throughout the course of use of lithium drugs.

Methotrexate. NSAIDs decrease renal secretion of methotrexate, thereby increasing its plasma concentrations. Simultaneous use of meloxicam and methotrexate (in dose more than 15 mg per week) is not recommended. In case of concomitant use, careful monitoring of renal function and blood counts is required. Meloxicam may increase hematological toxicity of methotrexate, especially in patients with impaired renal function.

Contraception. There is evidence that NSAIDs may reduce the effectiveness of intrauterine contraceptive devices, but this has not been proven. Mifepristone: Because of the theoretical risk of prostaglandin inhibitors altering mifepristone’s effectiveness, NSAIDs should not be used until 8-12 days after withdrawal of mifepristone.

Diuretics. Use of NSAIDs increases the risk of acute renal failure in patients with dehydration.

Antihypertensive agents (beta-adrenoblockers, angiotensin-converting enzyme inhibitors, vasodilators, diuretics). NSAIDs reduce the effect of antihypertensive drugs, due to inhibition of prostaglandins that have vasodilatory properties.

Angiotensin-II receptor antagonists. Co-administration with NSAIDs increases decrease of glomerular filtration, which may lead to development of acute renal failure, especially in patients with impaired renal function.

Colestyramine, by binding meloxicam in the gastrointestinal tract, leads to its faster excretion.

Pemetrexed. When concomitant use of meloxicam and pemetrexed in patients with creatinine clearance from 45 to 79 ml/min, meloxicam administration should be stopped 5 days before starting pemetrexed and may be resumed 2 days after the end of administration. If there is a need to use meloxicam and pemetrexed together, patients should be closely monitored, especially with regard to myelosuppression and the occurrence of gastrointestinal side effects.

In patients with a creatinine clearance of less than 45 mL/min, the use of meloxicam with pemetrexed is not recommended.

NSAIDs, by acting on renal prostaglandins, may increase the nephrotoxicity of cyclosporine.

When using with meloxicam the medicinal products with known ability to inhibit CYP2C9 and/or CYP3A4 (or metabolized with the participation of these enzymes), such as sulfonylurea derivatives or probenecid, the possibility of pharmacokinetic interaction should be taken into account.

When co-administered with oral antidiabetic agents (e.g., sulfonylurea derivatives, nateglinide), CYP2C9-mediated interactions are possible, which may lead to increased blood concentrations of both these drugs and meloxicam. Patients concomitantly taking meloxicam with sulfonylureas or nateglinide should carefully monitor blood sugar levels because of the possibility of hypoglycemia.

Special Instructions

Patients with gastrointestinal diseases should be monitored regularly. If gastrointestinal ulceration or gastrointestinal bleeding occurs, the drug should be discontinued.

Gastrointestinal ulcers, perforations, or bleeding may occur during use of NSAIDs at any time, with or without a history of alarming symptoms or serious gastrointestinal complications. The consequences of these complications are generally more serious in the elderly.

Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis may develop when using the drug. Therefore, special attention should be paid to patients who report the development of adverse reactions of the skin and mucous membranes, as well as hypersensitivity reactions to the drug, especially if such reactions were observed during the previous courses of treatment. The development of such reactions is usually observed during the first month of treatment. If the first signs of skin rash, mucous membrane changes or other signs of hypersensitivity appear, the discontinuation of the drug should be considered.

In cases of increased risk of serious cardiovascular thrombosis, myocardial infarction, angina attack, possibly with fatal outcome, are described when taking NSAIDs. This risk increases with long-term use of the drug, as well as in patients with the above-mentioned diseases in the history and predisposition to such diseases.

NSAIDs inhibit the renal synthesis of prostaglandins, which are involved in maintaining renal perfusion. Use of NSAIDs in patients with decreased renal blood flow or reduced circulating blood volume may lead to decompensation of latent renal insufficiency. After discontinuation of NSAIDs, renal function usually recovers to baseline levels. Elderly patients; patients with dehydration, chronic heart failure, cirrhosis, nephrotic syndrome or acute renal dysfunction; patients taking diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists simultaneously; and patients undergoing serious surgical interventions that lead to hypovolemia
are at highest risk for this reaction. In such patients, diuresis and renal function should be carefully monitored at the beginning of therapy. Application of NSAIDs together with diuretics may lead to retention of sodium, potassium and water, as well as to reduction of natriuretic action of diuretics.

As a result, predisposed patients may have increased signs of heart failure or hypertension. Therefore, close monitoring of such patients is necessary and adequate hydration should be maintained. Before initiating treatment it is necessary to study renal function.

In case of combined therapy, renal function should also be monitored.

When using meloxicam (as well as most other NSAIDs) there may be occasional increases in serum transaminase activity or other indicators of liver function. In most cases, these increases were small and transient. If the changes detected are significant or do not diminish over time, the drug should be discontinued and the laboratory changes detected should be monitored.

Weakened or debilitated patients may have a worse tolerance to adverse events, so these patients should be closely monitored.

Like other NSAIDs, meloxicam may mask symptoms of an underlying infectious disease.

The use of meloxicam, like other drugs that block cyclooxygenase and prostaglandin synthesis, may affect fertility, so it is not recommended for women who want to get pregnant. If women have impaired ability to conceive or are being evaluated for infertility, meloxicam should be considered for withdrawal.

In patients with mild to moderate renal impairment (creatinine clearance greater than 25 ml/min), no dose adjustment is required.

In patients with cirrhosis (compensated) no dose adjustment is required.

Impact on the ability to drive vehicles, mechanisms

Contraindications

– Hypersensitivity to the active substance or excipients of the drug, to acetylsalicylic acid and other NSAIDs;

– Complete or incomplete combination of bronchial asthma, recurrent nasal and paranasal sinus polyposis, angioedema, or urticaria caused by intolerance to acetylsalicylic acid or other NSAIDs due to a history of possible cross-sensitivity;

– erosive and ulcerative changes of the mucosa of the stomach and duodenum in the acute stage or recently suffered;

– inflammatory bowel disease – Crohn’s disease or ulcerative colitis in the acute stage;

– active gastrointestinal bleeding, recent history of cerebrovascular bleeding, or established diagnosis of blood clotting disorders;

– severe hepatic insufficiency or active liver disease;

– severe renal failure (unless hemodialysis, creatinine clearance less than 30 mL/min), advanced renal disease, including confirmed hyperkalemia;

– significant uncontrolled heart failure;

– therapy for perioperative pain during coronary artery bypass grafting;

– concomitant therapy with anticoagulants because of the risk of intramuscular hematomas;

– pregnancy;

– period of breastfeeding;

– age under 18 years.

With caution

– Diseases of the gastrointestinal tract (GIT) in the history (presence of Helicobacter pylori infection);

– Chronic heart failure;

– Coronary heart disease;

– renal insufficiency (creatinine clearance 30-60 ml/min);

– cerebrovascular disease;

– dyslipidemia/hyperlipidemia;

– diabetes mellitus;

– concomitant therapy with the following drugs: anticoagulants, oral glucocorticosteroids, antiaggregants, selective serotonin reuptake inhibitors;

– bronchial asthma, tuberculosis, severe osteoporosis;

– peripheral arterial disease;

– older age;

– long-term use of NSAIDs;

– smoking;

– frequent use of alcohol.

To reduce the risk of gastrointestinal (GI) adverse events, the lowest effective dose should be used for the shortest possible course.

Side effects

The incidence of side effects is classified according to the recommendations of the World Health Organization, characterized as: very frequently (≥ 1/10), frequently (≥ 1/100, < 1/10), infrequently (≥ 1/1000, < 1/100), rarely (≥ 1/10000, < 1/1000), very rarely (< 1/10000), not established.

Blood and lymphatic system disorders: infrequent – anemia; rare – leukopenia, thrombocytopenia, changes in blood cell count, including changes in the leukocytic formula.

Disorders of the immune system: infrequent – other reactions of immediate hypersensitivity; not established – anaphylactic shock, anaphylactoid reactions.

Mental disorders: rare – mood changes; not established – confusion, disorientation.

Nervous system disorders: frequent – headache; infrequent – dizziness, somnolence.

Sight, hearing, and labyrinth disorders: infrequent – vertigo; rare – conjunctivitis, visual disturbances, including blurred vision, tinnitus.

Cardiovascular disorders: infrequent – increase of blood pressure, feeling of “rush” of blood to the face; rare – feeling of palpitation.

Respiratory system disorders: rare – bronchial asthma in patients with an allergy to acetylsalicylic acid and other NSAIDs.

Gastrointestinal disorders: Frequent – abdominal pain, dyspepsia, diarrhea, nausea, vomiting; infrequent – latent and overt gastrointestinal bleeding, gastritis, stomatitis, constipation, abdominal bloating, belching; rare – gastroduodenal ulcers, colitis, esophagitis; very rare – gastrointestinal tract perforation.

Hepatic and biliary tract disorders: infrequent – transient changes in liver function parameters (e.g., increased transaminase or bilirubin activity); very rare – hepatitis.

Skin and subcutaneous tissue disorders: infrequent – angioedema, pruritus, skin rash; rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria; very rare – bullous dermatitis, erythema multiforme; not established – photosensitization.

Renal and urinary tract disorders: infrequent – changes of renal function parameters (increased serum creatinine and/or urea levels), urinary disorders, including acute urinary retention; very rare – acute renal failure.

Gender and mammary gland disorders: infrequent – late ovulation; not established – infertility in women.

General disorders and disorders at the site of administration: often – pain and swelling at the site of administration; infrequent – edema.

The concomitant use with drugs that suppress bone marrow (e.g., methotrexate) may provoke cytopenia.

Gastrointestinal bleeding, ulceration or perforation can be fatal.

As with other NSAIDs, the possibility of interstitial nephritis, glomerulonephritis, renal medullary necrosis, and nephrotic syndrome is not excluded.

Overdose

Symptoms: nausea, vomiting, epigastric pain, gastrointestinal bleeding, acute renal failure, liver failure, respiratory arrest, asystole, lethargy, somnolence, blood pressure changes, coma, seizures, cardiovascular collapse, cardiac arrest, anaphylactoid reaction.

Pregnancy use

The drug is contraindicated during pregnancy. The safety of using this drug during pregnancy has not been proven. The effect of inhibition of prostaglandin synthesis on embryogenesis during the first two trimesters of pregnancy is not clear. In the last trimester of pregnancy the mechanism of action of meloxicam is characterized by inhibition of labor activity, premature closure of Ductus arteriosus Botalli in the fetus, increased susceptibility to bleeding in the mother and child and increased risk of edema in the mother.

It is known that NSAIDs penetrate into breast milk, so meloxicam is not recommended during breastfeeding.

Similarities