NSAIDs, a derivative of enolic acid, have anti-inflammatory, analgesic and antipyretic effects.
The mechanism of the anti-inflammatory effect of meloxicam consists in its ability to inhibit the synthesis of prostaglandins - known mediators of inflammation.
In vivo meloxicam 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, while inhibition of the constantly present COX-1 isoenzyme may be responsible for side effects from the stomach and kidneys.
The selectivity of meloxicam in relation to COX-2 is confirmed in various test systems, both in vitro and in vivo. The selective ability of meloxicam to inhibit COX-2 is shown when using in vitro human whole blood as a test system. It was found that meloxicam (at 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, which is involved in blood coagulation ( reaction controlled by COX-1). These effects were dose dependent.
Ex vivo studies have shown that meloxicam (at doses of 7.5 mg and 15 mg) does not affect platelet aggregation and bleeding time.
In clinical studies, side effects from the gastrointestinal tract as a whole occurred less frequently when taking meloxicam at doses of 7.5 and 15 mg than when taking other NSAIDs with which comparison was made. This difference in the frequency of side effects from the gastrointestinal tract is mainly due to the fact that when taking meloxicam, less often observed phenomena such as dyspepsia, vomiting, nausea, abdominal pain. The frequency of perforations in the upper gastrointestinal tract, ulcers and bleeding associated with the use of meloxicam was low and dose-dependent.
Meloxicam is well absorbed from the digestive tract, as evidenced by the high absolute bioavailability (90%) after oral administration. After a single use of meloxicam Cmax in plasma is achieved within 5-6 hours. The simultaneous intake of food and inorganic antacids does not alter absorption. When administered orally (at doses of 7.5 and 15 mg), the concentration of meloxicam is proportional to the dose. A steady state of pharmacokinetics is achieved within 3-5 days.
The difference between Cmax and Cmin of the drug after taking it 1 time / 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 (Cmin values are given, respectively and Cmax during the period of steady state pharmacokinetics), although values outside the specified range were also noted. Cmax in plasma during the period of steady state pharmacokinetics is achieved 5-6 hours after ingestion.
After rectal administration of Cmax, meloxicam in plasma in equilibrium is reached after approximately 5 hours. Meloxicam is completely absorbed after i / m administration. Relative bioavailability compared with oral bioavailability is almost 100%. Therefore, when switching from injection to oral forms of dose selection is not required. After administration at a dose of 15 mg / m Cmax in plasma, a component of about 1.6-1.8 μg / ml, is achieved within approximately 60-96 minutes.
Meloxicam is highly bound to plasma proteins, mainly with albumin (99%). Penetrates into the synovial fluid, the concentration in the synovial fluid is approximately 50% of the plasma concentration. Vd 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 make up 7-20%.
Meloxicam is almost completely metabolized in the liver with the formation of 4 pharmacologically inactive derivatives. The main metabolite, 5'-carboxymeloxicam (60% of the dose), is formed by oxidation of the intermediate metabolite, 5'-hydroxymethylmeloxicam, which is also excreted, but to a lesser extent (9% of the dose). In vitro studies have shown that the CYP2C9 isoenzyme plays an important role in this metabolic transformation, and the CYP3A4 isoenzyme plays an additional role. In the formation of two other metabolites (constituting, respectively, 16% and 4% of the dose), peroxidase is involved, the activity of which is likely to individually vary. It is excreted equally through the intestines and kidneys, mainly in the form of metabolites. In an unchanged form, less than 5% of the daily dose is excreted with feces, in the urine in an unchanged form, the drug is found only in trace amounts. The average T1 / 2 of meloxicam varies from 13 to 25 hours. Plasma clearance is on average 7-12 ml / min after a single application. Meloxicam demonstrates linear pharmacokinetics in doses of 7.5-15 mg with i / m administration.
Hypersensitivity to meloxicam; hypersensitivity (including to other NSAIDs), a complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose or paranasal sinuses, angioedema or urticaria caused by intolerance to acetylsalicylic acid or other NSAIDs due to the existing likelihood of cross-sensitivity (in t. hours in the anamnesis); erosive and ulcerative lesions of the stomach and duodenum in the acute stage or recently transferred; inflammatory bowel disease (Crohn's disease or ulcerative colitis in the acute stage); severe liver and heart failure; severe renal failure (if hemodialysis is not performed, CC <30 ml / min, as well as with confirmed hyperkalemia); active liver disease; active gastrointestinal bleeding, recent cerebrovascular bleeding or an established diagnosis of coagulation diseases; concomitant anticoagulant therapy, as there is a risk of intramuscular hematomas;therapy of perioperative pain during coronary artery bypass grafting; pregnancy; lactation (breastfeeding); age up to 12 years (for oral administration), age up to 18 years (for i / m administration); inflammatory diseases of the rectum or anus; recent bleeding from the rectum or anus, age up to 15 years (for rectal use).
History of gastrointestinal tract diseases (presence of Helicobacter pylori infection); congestive heart failure; renal failure (CC 30-60 ml / min); Ischemic heart disease; cerebrovascular disease; dyslipidemia / hyperlipidemia; diabetes; concomitant therapy with the following drugs: anticoagulants, oral GCS, antiplatelet agents, selective serotonin reuptake inhibitors; peripheral artery disease; elderly age; prolonged use of NSAIDs; smoking; frequent drinking.
Pregnancy and lactation
Use during pregnancy and during breastfeeding is contraindicated.
From the hemopoietic system: infrequently - anemia; rarely - leukopenia, thrombocytopenia, a change in the number of blood cells, including changes in the leukocyte formula.
On the part of the immune system: infrequently - other immediate hypersensitivity reactions; not established - anaphylactic shock, anaphylactoid reactions.
Mental disorders: rarely - mood changes; not established - confusion, disorientation.
From the side of the nervous system: often - headache; infrequently - dizziness, drowsiness.
From the sensory organs: infrequently - vertigo; rarely conjunctivitis, visual impairment, including blurred vision, tinnitus.
From the side of the cardiovascular system: infrequently - increased blood pressure, a feeling of ""rush"" of blood to the face; rarely - palpitations.
From the side of the respiratory system: rarely - bronchial asthma in patients with allergies to acetylsalicylic acid and other NSAIDs.
From the digestive system: often - abdominal pain, dyspepsia, diarrhea, nausea, vomiting; infrequently - latent or obvious gastrointestinal bleeding, gastritis, stomatitis, constipation, bloating, belching; rarely - gastroduodenal ulcers, colitis, esophagitis; very rarely - perforation of the gastrointestinal tract.
On the part of the liver and biliary tract: infrequently - transient changes in liver function indices (for example, an increase in transaminase activity or bilirubin concentration); very rarely - hepatitis.
From the side of the skin and subcutaneous tissues: infrequently - angioedema, itching, 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 indicators of renal function (increased concentration of creatinine and / or urea in the blood serum), impaired urination, including acute urinary retention; very rarely - acute renal failure.
From the genitals and mammary gland: infrequently - late ovulation; not established - infertility in women.
General disorders and disorders at the injection site: often - pain and swelling at the injection site; infrequently - swelling.
Co-administration with drugs that inhibit bone marrow (e.g. methotrexate) can trigger cytopenia.
Gastrointestinal bleeding, ulcer, or perforation can be fatal.
As for other NSAIDs, the possibility of the appearance of interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome is not ruled out.
Other inhibitors of prostaglandin synthesis, including glucocorticoids and salicylates - concomitant use with meloxicam increases the risk of ulceration in the gastrointestinal tract and gastrointestinal bleeding (due to synergism of action). Concomitant use with other NSAIDs is not recommended.
Anticoagulants for oral administration, heparin for systemic use, 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 - concomitant use 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 plasma by reducing its excretion by the kidneys. The simultaneous use of meloxicam with lithium preparations is not recommended. If necessary, the simultaneous use of recommended careful monitoring of the concentration of lithium in the plasma throughout the course of lithium preparations.
Methotrexate - NSAIDs reduce the secretion of methotrexate by the kidneys, thereby increasing its plasma concentration. The simultaneous use of meloxicam and methotrexate (at 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 increase hematologic toxicity of methotrexate, especially in patients with impaired renal function.
Diuretics - the use of NSAIDs while taking diuretics in case of dehydration of patients is accompanied by a risk of acute renal failure.
Antihypertensive agents (beta-blockers, ACE inhibitors, vasodilators, diuretics). NSAIDs reduce the effect of antihypertensive drugs due to inhibition of prostaglandins with vasodilating properties.
Angiotensin II receptor antagonists, as well as ACE inhibitors, when used together with NSAIDs, increase the decrease in glomerular filtration, which, therefore, can lead to the development of acute renal failure, especially in patients with impaired renal function.
Colestyramine, binding to meloxicam in the gastrointestinal tract, leads to its faster elimination.
Pemetrexed - with the simultaneous use of meloxicam and pemetrexed in patients with CC from 45 to 79 ml / min, meloxicam should be discontinued 5 days before taking pemetrexed and possibly resumed 2 days after the end of the dose. If there is a need for the combined use of meloxicam and pemetrexed, then patients should be carefully monitored, especially with regard to myelosuppression and the occurrence of side effects from the gastrointestinal tract. In patients with CC <45 ml / min, the use of meloxicam together with pemetrexed is not recommended.
NSAIDs, acting on renal prostaglandins, may enhance cyclosporin nephrotoxicity.
When meloxicam is used simultaneously with drugs that have a known ability to inhibit CYP2C9 and / or CYP3A4 (or are metabolized by these enzymes), such as sulfonylureas or probenecid, the possibility of pharmacokinetic interaction should be taken into account.
When combined with hypoglycemic agents for oral administration (for example, sulfonylureas, nateglinide), an interaction mediated by CYP2C9 is possible, which can lead to an increase in the concentration of both hypoglycemic agents and meloxicam in the blood. Patients at the same time taking meloxicam with sulfonylurea or nateglinide should carefully monitor the concentration of glucose in the blood due to the possibility of hypoglycemia.
Dosage and administration
The method of application and the dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular preparation with the indications for use and the dosage regimen should be strictly observed.
For oral administration - 7.5-15 mg / day; the maximum dose is 15 mg / day.
Rectally - 7.5 mg 1 time / day, in more severe cases, 15 mg 1 time / day.
For i / m administration - 7.5 mg or 15 mg 1 time / day, depending on the intensity of the pain and the severity of the inflammatory process.
The total dose of meloxicam used in the form of different dosage forms should not exceed 15 mg / day.
Patients with gastrointestinal diseases require regular monitoring. If there is a gastrointestinal ulcerative lesion or gastrointestinal bleeding with meloxicam, it is necessary to cancel.
Gastrointestinal ulcers, perforation or bleeding can occur during the use of NSAIDs at any time both in the presence of alarming symptoms or information about serious gastrointestinal complications in the anamnesis, or in their absence. The consequences of these complications are generally more serious for the elderly.
When using meloxicam, serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis can develop. 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 observed, as a rule, during the first month of treatment. In the event of the first signs of skin rash, changes in the mucous membranes or other signs of hypersensitivity, consideration should be given to stopping the use of meloxicam. Cases are described when taking NSAIDs to increase the risk of developing serious cardiovascular thrombosis, myocardial infarction, angina attack, possibly fatal. This risk increases with prolonged use of the drug, as well as in patients with a history of the above diseases and 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 decreased BCC can lead to decompensation of latent renal failure. After discontinuation of NSAIDs, kidney function is usually restored to its original level. The most at risk of developing this reaction are elderly patients, patients who have dehydration, congestive heart failure, liver cirrhosis, nephrotic syndrome or acute renal impairment, patients taking diuretics, ACE inhibitors, angiotensin II receptor antagonists, and also patients who have undergone serious surgical interventions that lead to hypovolemia. In such patients, at the beginning of therapy, diuresis and renal function should be carefully monitored. The use of NSAIDs together with diuretics can lead to a delay in sodium, potassium and water, as well as to a decrease in the natriuretic action of diuretics. As a result, in susceptible patients, there may be an increase in signs of heart failure or hypertension. Therefore, careful monitoring of the condition of such patients is necessary, as well as maintaining adequate hydration.
Prior to treatment, a study of kidney function is necessary. In the case of combination therapy, kidney function should also be monitored.
When using meloxicam (as well as most other NSAIDs), an occasional increase in the activity of transaminases in serum or other indicators of liver function is 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 canceled, and the detected laboratory changes should be monitored.
Weakened or emaciated patients may be less likely to tolerate adverse events, and therefore, such patients should be carefully monitored.
Like other NSAIDs, meloxicam can mask the symptoms of a major infectious disease.
As a means of inhibiting the synthesis of COX / prostaglandin, meloxicam can affect fertility, and therefore is not recommended for women who have difficulty conceiving. In women undergoing examination on this occasion, the removal of meloxicam is recommended. In patients with mild to moderate renal failure (CC> 25 ml / min), dose adjustment is not required.
In patients with cirrhosis (compensated), dose adjustment is not required.
Impact on the ability to drive vehicles
When driving and working with mechanisms, the possibility of developing dizziness, drowsiness, visual impairment, or other disorders of the central nervous system should be taken into account. During the treatment period, patients must be careful when driving vehicles and engaging in other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.