Pharmacological properties of the drug Celecoxib
Nonsteroidal anti-inflammatory drug, specific COX-2 inhibitor, representative of the coxib class. Due to the specific inhibition of the activity of the COX-2 isoenzyme, the formation of prostaglandins is inhibited. Celecoxib has virtually no inhibitory effect on COX-1. An increase in COX-2 activity in response to proinflammatory factors leads to the synthesis and accumulation of prostaglandins, primarily prostaglandin E2, which cause the development of inflammation, edema and pain. By blocking their formation, celecoxib exhibits anti-inflammatory and analgesic effects. Celecoxib has a very low degree of affinity for COX-1, therefore, when used in therapeutic doses, it does not cause disruption in the synthesis of constitutional prostaglandins and does not have a negative effect on physiological processes in tissues, primarily in the stomach, intestines, and does not affect platelet function. When used in therapeutic doses, celecoxib does not cause side effects characteristic of non-selective COX inhibitors, in particular the development of gastric and duodenal ulcers, other complications in the upper gastrointestinal tract (bleeding, perforation), as well as inhibition of COX-1-dependent platelet aggregation. The incidence of serious complications from the upper gastrointestinal tract during treatment with celecoxib does not differ significantly from that with placebo and is approximately 8 times lower than with treatment with nonspecific COX inhibitors. When taken orally on an empty stomach, celecoxib is well absorbed from the digestive tract; the maximum concentration in the blood plasma is reached after 2–3 hours. Concomitant food intake slows down the absorption of celecoxib by approximately 1 hour. The pharmacokinetics of celecoxib is linear and proportional to the dose. The degree of binding to blood plasma proteins is about 97%. Celecoxib is metabolized in the liver by hydroxylation, oxidation and partly glucuronidation. Excreted mainly in the form of metabolites, less than 1% of the dose is excreted unchanged in the urine. With repeated use, the half-life is 8–12 hours, and equilibrium plasma concentrations are achieved within 5 days. The volume of distribution at steady state in adults is approximately 500 L/70 kg, indicating a wide distribution of celecoxib in tissues. Celecoxib penetrates the BBB and placental barrier.
Side effects of the drug Celecoxib
Rarely - pain in the epigastric region, nausea, vomiting, heartburn, anorexia, diarrhea; with long-term use in high doses - ulceration of the mucous membrane of the digestive tract, gastrointestinal bleeding, bleeding from the gums, increased activity of liver transaminases; headache, dizziness, drowsiness or insomnia, depression, agitation; hearing loss, tinnitus; increased blood pressure, tachycardia; decreased resistance to respiratory tract infections, sore throat, cough, shortness of breath, bronchospasm; renal failure, edema syndrome; agranulocytosis, leukopenia, anemia, thrombocytopenia; allergic reactions (skin itching, rash, urticaria, photosensitivity, Quincke's edema); alopecia, sweating.
Special instructions for the use of the drug Celecoxib
In patients with peptic ulcers of the stomach or duodenum, treatment can begin only after complete scarring of the ulcer. Fluid retention and peripheral edema have been reported in some patients taking celecoxib, and therefore celecoxib should be used with caution in patients with heart failure or in conditions where there is a potential risk of fluid retention. In patients with severe liver and kidney disease, celecoxib should only be used in exceptional cases under the supervision of a physician. The safety of use during pregnancy has not been established, therefore celecoxib should not be prescribed to pregnant women unless absolutely necessary. The effect of celecoxib on closure of the ductus arteriosus has not been studied in humans, therefore the use of celecoxib in the third trimester of pregnancy should be avoided. Celecoxib passes into breast milk at concentrations similar to those in plasma. No studies have been conducted on the safety of its use during breastfeeding, therefore celecoxib should not be prescribed during this period.
Simcoxib
The drug Simcoxib, given its antipyretic effect, can reduce the diagnostic significance of a symptom such as fever and affect the diagnosis of infection.
Effect on fertility
According to the mechanism of action, when using NSAIDs, including celecoxib, some women may develop changes in the ovaries, which can cause complications during pregnancy or impair fertility. In women who are planning pregnancy or undergoing evaluation for infertility, discontinuation of NSAIDs, including celecoxib, should be considered.
Effect on the cardiovascular system
Simcoxib, like all coxibs, may increase the risk of serious cardiovascular events such as blood clots, myocardial infarction, and stroke, which can be fatal. The risk of these reactions may increase with the dose, duration of use of the drug, as well as in patients with diseases of the cardiovascular system and risk factors for such diseases. To reduce the risk of these reactions in patients taking Simcoxib, it should be used in the lowest effective doses and for the shortest possible course (at the discretion of the treating physician).
The attending physician and patient should be aware of the possibility of such complications, even in the absence of previously known symptoms of impaired cardiovascular function. Patients should be informed of the signs and symptoms of adverse cardiovascular effects and measures to take if they occur.
When using NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass surgery for the treatment of pain in the first 10-14 days, an increase in the incidence of myocardial infarction and cerebrovascular accidents is possible.
Due to the weak effect of celecoxib on platelet function, it cannot be a substitute for acetylsalicylic acid for the prevention of thromboembolism. Also, in this regard, antiplatelet therapy (for example, acetylsalicylic acid) should not be discontinued in patients at risk of developing thromboembolic complications.
Like all NSAIDs, celecoxib can lead to an increase in blood pressure, which can also cause complications from the cardiovascular system. All NSAIDs, including celecoxib, should be used with caution in patients with arterial hypertension. Monitoring of blood pressure should be carried out at the beginning of therapy with celecoxib, as well as during the course of treatment.
Effect on the gastrointestinal tract
Extremely rare cases of gastrointestinal perforation, ulceration, and bleeding have occurred in patients taking celecoxib. The risk of developing these complications during treatment with NSAIDs is highest in the elderly, patients with cardiovascular diseases, patients simultaneously receiving acetylsalicylic acid, and patients with gastrointestinal diseases such as ulcers, bleeding, inflammatory processes in the acute stage and in history .
Other risk factors for the development of bleeding from the gastrointestinal tract are simultaneous use with oral glucocorticosteroids and anticoagulants, a long period of NSAID therapy, smoking, and alcohol consumption. Most spontaneous reports of serious gastrointestinal side effects were in elderly and debilitated patients.
Combined use with oral anticoagulants
When NSAIDs are used simultaneously with oral anticoagulants, the risk of bleeding increases. Caution is advised when using these drugs together.
Oral anticoagulants include warfarin, coumarin anticoagulants, and direct oral anticoagulants (eg, apixaban, dabigatran, and rivaroxaban). Serious (some fatal) bleeding has been reported in patients receiving concomitant treatment with warfarin or similar agents. Since an increase in prothrombin time (international prothrombin time (INR)) has been reported, anticoagulant activity and/or INR should be monitored in patients receiving concomitant therapy with oral anticoagulants after initiating treatment with Simcoxib or changing its dose.
Fluid retention and swelling
As with other drugs that inhibit prostaglandin synthesis, some patients taking Simcoxib may experience fluid retention and edema, so caution should be exercised when using this drug in patients with conditions predisposing or worsened by fluid retention. Patients with a history of heart failure or hypertension should be closely monitored.
Effect on kidney function
NSAIDs, including celecoxib, may have toxic effects on renal function. Celecoxib was found to be no more toxic than other NSAIDs. Simcoxib should be used with caution in patients with impaired renal function, heart failure, impaired liver function and in elderly patients. Renal function in such patients should be carefully monitored (see section "Dosage and Administration").
Caution should be exercised when using Simcoxib in patients with dehydration. In such cases, it is advisable to first rehydrate and then begin therapy with Simcoxib.
Effect on liver function
Simcoxib should not be used in patients with severe hepatic impairment (Child-Pugh class C). Simcoxib should be used with caution when treating patients with moderate hepatic impairment and the initial recommended dose of the drug should be reduced by half (see section "Dosage and Administration").
Severe liver reactions have occurred in some cases, including fulminant hepatitis (sometimes fatal), liver necrosis, and liver failure (sometimes fatal or requiring liver transplantation). Most of these reactions occurred 1 month after starting celecoxib.
Patients with symptoms and/or signs of hepatic impairment, or those patients in whom laboratory tests have demonstrated hepatic impairment, should be closely monitored for the development of more severe hepatic reactions during treatment with Simcoxib.
Anaphylactic reactions
Cases of anaphylactic reactions have been reported while taking Simcoxib (see section "Contraindications").
Serious skin reactions
Very rarely, serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with celecoxib, some of which have been fatal. The risk of such reactions occurring is higher in patients at the beginning of therapy; in most reported cases, such reactions began in the first month of therapy. Stop taking Simcoxib if skin rash, changes in mucous membranes, or other signs of hypersensitivity occur.
Glucocorticosteroid therapy
Simcoxib cannot replace glucocorticosteroids or be used as a treatment for glucocorticosteroid deficiency.
Inhibition of the function of the CYP2D6 isoenzyme
Celecoxib has been found to be a moderate inhibitor of the CYP2D6 isoenzyme. During the period of initiation of therapy with celecoxib, the dose of drugs metabolized by the CYP2D6 isoenzyme should be reduced, and after completion of treatment with celecoxib, the dose of these drugs should be increased (see section “Interaction with other drugs”).
Drug interactions Celecoxib
The anticoagulant activity of warfarin or other anticoagulants should be monitored, especially within a few days after starting treatment with celecoxib or when changing its dosage regimen, as this increases the risk of bleeding complications. The effect of celecoxib on the anticoagulant activity of warfarin at a dose of 2–5 mg/day was studied in healthy volunteers. It was noted that celecoxib does not affect the prothrombin time, however, according to post-marketing studies, cases of bleeding were reported due to an increase in prothrombin time in elderly patients who were simultaneously taking warfarin and celecoxib. There was no effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of drugs that are substrates of CYP 2C9 (glibenclamide, phenytoin, tolbutamide). In patients concomitantly taking the CYP2C9 inhibitor fluconazole, treatment with celecoxib should be initiated with the latter at the minimum recommended dose; Use celecoxib with caution in combination with other CYP2C9 inhibitors. Celecoxib inhibits CYP 2D6, although it is not a substrate of CYP2D6. In vivo studies did not reveal a clinically significant interaction between celecoxib and paroxetine (CYP 2D6 substrate and inhibitor). The CYP2C19 enzyme may play a very minor role in the metabolism of celecoxib (about 1%). In in vivo , celecoxib did not affect the clearance of phenytoin (a CYP2C19 substrate) after a single dose. The risk of interaction with CYP2C19 substrates may not be taken into account. No significant interaction of celecoxib with ketoconazole (CYP 3A4 inhibitor), as well as with methotrexate and lithium salts was detected. Non-absorbable antacids (aluminum and magnesium compounds) reduce the degree of absorption of celecoxib by 10%, which has no clinical significance. Celecoxib can be prescribed in combination with acetylsalicylic acid in low doses. Given the lack of effect on platelet aggregation, celecoxib is not an alternative drug to acetylsalicylic acid for the prevention of complications from the cardiovascular system.
Celecoxib
The drug Celecoxib, given its antipyretic effect, can reduce the diagnostic significance of a symptom such as fever and affect the diagnosis of infection.
Effect on the cardiovascular system
Celecoxib, like all coxibs, may increase the risk of serious cardiovascular events such as blood clots, myocardial infarction, and stroke, which can be fatal. The risk of these reactions may increase with the dose, duration of use of the drug, as well as in patients with diseases of the cardiovascular system and risk factors for such diseases. To reduce the risk of these reactions in patients taking Celecoxib, it should be taken in the lowest effective doses and for the shortest possible duration (at the discretion of the treating physician). The attending physician and patient should be aware of the possibility of such complications occurring even in the absence of previously known symptoms of impaired cardiovascular function. Patients should be informed of the signs and symptoms of adverse cardiovascular effects and measures to take if they occur.
When using NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass surgery for the treatment of pain in the first 10-14 days, an increase in the incidence of myocardial infarction and cerebrovascular accidents is possible.
Due to the weak effect of celecoxib on platelet function, it cannot be a substitute for acetylsalicylic acid for the prevention of thromboembolism. Also, in this regard, antiplatelet therapy (for example, acetylsalicylic acid) should not be discontinued in patients at risk of developing thromboembolic complications.
Like all NSAIDs, celecoxib can lead to an increase in blood pressure, which can also cause complications from the cardiovascular system. All NSAIDs, including celecoxib, should be used with caution in patients with arterial hypertension. Monitoring of blood pressure should be carried out at the beginning of therapy with celecoxib, as well as during the course of treatment.
Effect on the gastrointestinal tract (GIT)
Extremely rare cases of perforation, ulceration and bleeding from the gastrointestinal tract have been observed in patients taking celecoxib. The risk of developing these complications during treatment with NSAIDs is highest in elderly patients, patients with cardiovascular diseases, patients simultaneously receiving acetylsalicylic acid, and patients with gastrointestinal diseases such as ulcers, bleeding, inflammatory processes in the acute stage and in history. Other risk factors for the development of bleeding from the gastrointestinal tract are simultaneous use with oral glucocorticosteroids and anticoagulants, a long period of NSAID therapy, smoking, and alcohol consumption.
Most spontaneous reports of serious gastrointestinal side effects were in elderly and debilitated patients.
Combined use with oral anticoagulants
When NSAIDs are used simultaneously with oral anticoagulants, the risk of bleeding increases. Caution is advised when using these drugs together. Oral anticoagulants include warfarin, coumarin anticoagulants, and direct oral anticoagulants (eg, apixaban, dabigatran, and rivaroxaban). Serious (some fatal) bleeding has been reported in patients receiving concomitant treatment with warfarin or similar agents. Since an increase in prothrombin time (international prothrombin time (INR)) has been reported, anticoagulant activity and/or INR should be monitored in patients concomitantly receiving warfarin or coumarin anticoagulants after initiating treatment with Celecoxib or changing its dose.
Fluid retention and swelling
As with other drugs that inhibit prostaglandin synthesis, some patients taking Celecoxib may experience fluid retention and edema, so caution should be exercised when using this drug in patients with conditions predisposing or worsened by fluid retention. Patients with a history of heart failure or hypertension should be closely monitored.
Effect on kidney function
NSAIDs, including celecoxib, may have toxic effects on renal function. Celecoxib was found to be no more toxic than other NG1VPs. Celecoxib should be used with caution in patients with impaired renal function, heart failure, impaired liver function and in elderly patients. Renal function in such patients should be carefully monitored (see section "Dosage and Administration").
Caution should be exercised when using Celecoxib in patients with dehydration. In such cases, it is advisable to first rehydrate and then begin therapy with Celecoxib.
Effect on liver function
Celecoxib should not be used in patients with severe hepatic impairment (Child-Pugh class C). Celecoxib should be used with caution when treating patients with moderate hepatic impairment and the initial recommended dose should be reduced by half (see section "Dosage and Administration").
Severe liver reactions have occurred in some cases, including fulminant hepatitis (sometimes fatal), liver necrosis, and liver failure (sometimes fatal or requiring liver transplantation). Most of these reactions occurred 1 month after starting celecoxib.
Patients with symptoms and/or signs of hepatic impairment, or those patients in whom laboratory tests have demonstrated hepatic impairment, should be closely monitored for the development of more severe hepatic reactions during treatment with Celecoxib.
Anaphylactic reactions
Cases of anaphylactic reactions have been reported when taking celecoxib (see section "Contraindications").
Serious skin reactions
In extremely rare cases, serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with celecoxib, some of which have been fatal. The risk of such reactions occurring in patients at the beginning of therapy is higher; in most reported cases, such reactions began in the first month of therapy. Stop taking Celecoxib if skin rash, changes in mucous membranes, or other signs of hypersensitivity occur.
Glucocorticosteroid therapy
Celecoxib cannot replace glucocorticosteroids or be used as a treatment for glucocorticosteroid deficiency.
Inhibition of the function of the CYP2D6 isoenzyme.
Celecoxib has been
found to be a moderate inhibitor of the CYP2D6 isoenzyme. During the period of initiation of therapy with celecoxib, the dose of drugs metabolized by the CYP2D6 isoenzyme should be reduced, and after completion of treatment with celecoxib, the dose of these drugs should be increased (see section “Interaction with other drugs”).
