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Active ingredients
Celecoxib
Release form
Capsules
Composition
Active ingredient: sodium hyaluronate with a molecular weight of about 1.6 million Da. Excipients: Sodium chloride; sodium monohydrogen phosphate; lemon acid; water for injections
Pharmacological effect
Anti-inflammatory, analgesic
Pharmacokinetics
Suction. When taken on an empty stomach, celecoxib is well absorbed, reaching Cmax in the blood plasma after approximately 2-3 hours. Cmax in the blood plasma after taking 200 mg of celecoxib is 705 ng / ml. The absolute bioavailability of celecoxib has not been studied. Cmax and AUC are approximately proportional to the accepted dose in the range of therapeutic doses up to 200 mg 2 times a day, when using celecoxib in higher doses, the degree of increase in Cmax and AUC is less proportional. The influence of food intake. Taking celecoxib simultaneously with fatty foods increases the time to reach Cmax by about 4 hours and increases absorption by about 20%. Distribution. The degree of binding to plasma proteins does not depend on the plasma concentration of celecoxib and is about 97%. Celecoxib does not bind to red blood cells. Celecoxib penetrates the BBB. Metabolism. Celecoxib is metabolized mainly by the participation of the cytochrome P450 (CYP) CYP2C9 isoenzyme in the liver by hydroxylation, oxidation and partially glucuronidation (see "Interaction"). The resulting metabolites are pharmacologically inactive with respect to COX-1 and -2. The activity of the CYP2C9 isoenzyme is reduced in patients with genetic polymorphism, such as the polymorphism homozygous for the isoenzyme CYP2C9 * 3, which leads to a decrease in the efficiency of enzymes. Inference. Celecoxib is excreted through the intestines and by the kidneys as metabolites (57 and 27%, respectively), less than 1% of the dose taken - unchanged. With repeated use, T1 / 2 is 8–12 hours, and clearance is about 500 ml / min. With repeated use of Css in the blood plasma are achieved by the 5th day of admission. The variability of the main pharmacokinetic parameters (AUC, Cmax, T1 / 2) is about 30%. The average Vss is about 500 l / 70 kg in young healthy patients, which indicates a wide distribution of celecoxib in the tissues. Selected patient groups Patients of advanced age. In patients older than 65 years, there is a 1.5–2 times increase in average Cmax and AUC values, which is largely due to changes in body weight rather than age (in elderly patients, as a rule, there is a lower average body weight than in younger peoplewhereby, ceteris paribus, higher celecoxib concentrations are achieved. For the same reason, older women usually have a higher plasma concentration of celecoxib than older men. These pharmacokinetic features, as a rule, do not require dose adjustment. However, in elderly patients with a body weight of less than 50 kg, treatment should be initiated with the minimum recommended dose. Race. The representatives of the Negroid race AUC celecoxib is about 40% higher than that of the Caucasians. The causes and clinical significance of this fact are unknown, therefore, treatment of people of the Negroid race is recommended to begin with the minimum recommended dose. Liver dysfunction. Celecoxib plasma concentrations in patients with mild hepatic insufficiency (class A according to the Child-Pugh classification) do not change significantly. In patients with moderately severe liver failure (Child-Pugh class B), plasma concentration of celecoxib can be almost doubled. Impaired renal function. In elderly patients with GFR> 65 ml / min / 1.73 m2, associated with age-related changes, and in patients with GFR of 35–60 ml / min / 1.73 m2, the pharmacokinetics of celecoxib does not change. There is no significant correlation between serum creatinine concentration (or creatinine clearance) and celecoxib clearance. It is assumed that the presence of severe renal failure does not affect the clearance of celecoxib, since the main route of its elimination is the transformation in the liver into inactive metabolites.
Indications
Symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis; pain syndrome (back pain, musculoskeletal, postoperative and other types of pain); treatment of primary dysmenorrhea.
Contraindications
Hypersensitivity to celecoxib or any other component of the drug; hypersensitivity to other sulfonamide derivatives; complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including a history of); condition after coronary artery bypass surgery; active erosive and ulcerative lesions of the mucous membrane of the stomach or duodenum, peptic ulcer of the stomach and duodenum in the acute stage or gastrointestinal bleeding; inflammatory bowel disease (Crohn's disease,ulcerative colitis) in the acute phase; heart failure (II – IV functional class according to NYHA classification); clinically confirmed ischemic heart disease, peripheral arterial diseases and cerebrovascular diseases in the severe stage; hemorrhagic stroke; subarachnoid hemorrhage; pregnancy; breastfeeding period (see. "Use during pregnancy and lactation"); severe liver failure (Child-Pugh class C) (no experience with use); severe renal failure (Cl creatinine less than 30 ml / min), progressive kidney disease, confirmed hyperkalemia (no experience with the application); age up to 18 years (no experience of use); lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome (Dilax preparation contains lactose). With caution: gastrointestinal diseases (peptic ulcer of the stomach or duodenum, ulcerative colitis, Crohn's disease, history of bleeding), Helicobacter pylori infection, simultaneous use with digoxin, anticoagulants (for example, warfarin), antiplatelet agents (eg, acetylsalicylic acrylate, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiaggregants, antiplatelet agents for oral administration (for example, prednisolone), diuretics, SSRIs (for example, citalopram, fluoxetine, paroxetine, sertraline), CYP2C9 isoenzyme inhibitors, in patients who are slow metabolizers or have suspicion of such a condition, fluid retention and edema, moderate liver function impairment (see “Special Instructions”), history of liver disease, hepatic porphyria, impaired kidney function (Cl creatinine 30–60 ml / min), a significant decrease in BCC (including after surgery), diseases of the cardiovascular system, including ischemic heart disease, arterial hypertension (see “Special Instructions”), cerebrovascular diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, peripheral arterial disease, prolonged use of NSAIDs, severe somatic diseases, elderly patients (including receiving diuretics, weakened patients with low body mass), smoking, tuberculosis, alcoholism.
Use during pregnancy and lactation
Experience with celecoxib during pregnancy is insufficient.The potential risk of using Dilax during pregnancy has not been established, but it cannot be ruled out. When using NSAIDs, including celecoxib, due to inhibition of GHG synthesis, some women may develop changes in the ovaries, which can cause complications during pregnancy. When planning a pregnancy or conducting an examination for infertility, consideration should be given to abolishing NSAIDs, including celecoxib. Celecoxib, belonging to the group of inhibitors of GHG synthesis, when used during pregnancy, especially in the third trimester, can cause weakness of labor and premature closure of the ductus arteriosus. The use of inhibitors of GHG synthesis in early pregnancy can adversely affect the course of pregnancy. There are limited data on the excretion of celecoxib in breast milk. Given the potential risk of side effects in the child and the need for celecoxib for the mother, the appropriateness of breastfeeding should be evaluated.
Dosage and administration
Inside, without chewing, drinking water, regardless of the meal. Since the risk of cardiovascular complications may increase with an increase in the dose and duration of the drug Dilax, the minimum effective dose of the drug should be taken as short a course as possible. The maximum recommended daily dose for long-term use is 400 mg. Symptomatic treatment of osteoarthritis. The recommended dose is 200 mg / day in 1 or 2 doses. Symptomatic treatment of rheumatoid arthritis. The recommended dose is 100 or 200 mg 2 times a day. Symptomatic treatment of ankylosing spondylitis. The recommended dose is 200 mg / day in 1 or 2 doses. In some patients, the effectiveness of the use of 400 mg 2 times a day. Treatment of pain and primary dysmenorrhea. The recommended initial dose is 400 mg, followed by, if necessary, receiving an additional dose of 200 mg on the first day. In the following days, the recommended dose is 200 mg 2 times a day, as needed. Elderly patients. Usually, dose adjustment is not required. However, in patients with a body weight of less than 50 kg, it is better to begin treatment with the minimum recommended dose. Liver dysfunction.In patients with mild hepatic impairment (class A according to the Child-Pugh classification), dose adjustment is not required. In the case of moderate liver failure (Child-Pugh class B), treatment should begin with the minimum recommended dose. Experience with the use of the drug Dilax in patients with severe liver failure (class C according to the Child-Pugh classification) is not (see "Contraindications"). Impaired renal function. In patients with mild to moderate severity of renal failure, dose adjustment is not required. Experience with the use of the drug Dilax in patients with severe renal insufficiency is not (see "Special instructions", "Contraindications"). Simultaneous use with fluconazole. Patients taking fluconazole (an inhibitor of the isoenzyme CYP2C9), Dilax should be taken in the minimum recommended dose. Caution should be exercised when used simultaneously with other inhibitors of the isoenzyme CYP2C9. Slow metabolism of CYP2C9 isoenzyme substrates. In patients who are slow metabolizers or suspected of such a condition, Dilax should be used with caution, since this can lead to high concentrations of celecoxib in plasma. In such patients, the initial recommended dose should be reduced by 2 times.
Side effects
Classification of the incidence of side effects WHO: very often - ≥1 / 10; often from ≥1 / 100 to <1/10; infrequently - from ≥1 / 1000 to <1/100; rarely from ≥ 1/10000 to <1/1000; very rarely from <1/10000. On the part of the cardiovascular system: often - peripheral edema, increased blood pressure, including weighting of the course of arterial hypertension; infrequently - hot flashes, palpitations; rarely - CHF, arrhythmia, tachycardia, ischemic stroke and myocardial infarction. On the part of the digestive system: often - abdominal pain, diarrhea, dyspepsia, flatulence, vomiting; infrequently - diseases of the teeth (post-extraction alveolar alveolitis); rarely - a gastric ulcer and duodenal ulcer, ulceration of the esophagus; very rarely - intestinal perforation, pancreatitis. On the part of the nervous system: often - dizziness, insomnia; infrequently - anxiety, increased muscle tone, drowsiness; rarely - confusion (psychosis). Urinary system: often - urinary tract infection. On the part of the respiratory system: often - bronchitis, cough, sinusitis, infections of the upper respiratory tract; infrequently - pharyngitis, rhinitis. For the skin: often - itching (includinggeneralized), skin rash; infrequently - urticaria, ecchymosis; rarely - alopecia. From the side of blood-forming organs: infrequently - anemia; rarely - thrombocytopenia. On the part of the senses: infrequently - tinnitus, blurred visual perception. Laboratory indicators: infrequently - increased activity of liver enzymes (including ALT and AST). Allergic reactions: rarely - angioedema; very rarely - bullous eruptions (bullous dermatitis). Other: infrequently - exacerbation of allergic diseases (hypersensitivity), flu-like syndrome, accidental injuries, swelling of the face. According to post-marketing surveillance Allergic reactions: very rarely - anaphylaxis (anaphylactic reactions). On the part of the nervous system: rarely - hallucinations; very rarely - cerebral hemorrhages, aseptic meningitis, loss of taste, loss of smell. From the senses: infrequently - conjunctivitis. From the CCC: rarely - pulmonary embolism; very rarely - vasculitis. On the part of the digestive system: rarely - gastrointestinal bleeding, hepatitis; very rarely - liver failure, fulminant hepatitis, liver necrosis (see "Special instructions", "Effect on the function of the liver"), cholestasis, cholestatic hepatitis, jaundice. For the skin: rarely - photosensitivity reactions; very rarely - Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug rash combined with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome), acute generalized exanthematic pustus, exfoliative dermatitis. From the urinary system: rarely - acute renal failure (see "Special instructions", subsection "Impact on renal function"), hyponatremia; very rarely - interstitial nephritis, nephrotic syndrome, minimal renal dysfunction. From the reproductive system: rarely - violation of the menstrual cycle; frequency unknown - decrease in fertility in women * (see. "Use during pregnancy and lactation"). Other: Infrequent - pain in the chest. * Women planning pregnancy were excluded from the study, so they were not taken into account when calculating the frequency of occurrence.
Overdose
Clinical data on overdose is limited.A single dose of up to 1200 mg and repeated use of a dose of up to 1200 mg 2 times a day were not accompanied by clinically significant side effects. Treatment: if overdose is suspected, supportive therapy should be performed. Dialysis is presumably not effective, since Celecoxib has a high association with plasma proteins (97%).
Interaction with other drugs
In vitro studies have shown that celecoxib, although not a substrate of the CYP2D6 isoenzyme, inhibits its activity. Therefore, there is the likelihood of drug interaction in vivo with drugs whose metabolism is associated with the CYP2D6 isoenzyme. Warfarin and other anticoagulants: when used simultaneously, prolongation of PT is possible. Fluconazole, ketoconazole: with the simultaneous use of 200 mg of fluconazole 1 time per day, an increase in plasma concentration of celecoxib in plasma is observed 2 times, which is associated with inhibition of celecoxib metabolism by fluconazole through the CYP2C9 isoenzyme. Patients taking fluconazole (an inhibitor of the isoenzyme CYP2C9), celecoxib should be used in the minimum recommended dose (see. "
Dosage and administration
"). Ketoconazole (a CYP3A4 isoenzyme inhibitor) does not have a clinically significant effect on celecoxib metabolism. ACE inhibitors / antagonists of APA II: Inhibition of the synthesis of PG can reduce the antihypertensive effect of ACE / APA II inhibitors. This interaction should be considered with the simultaneous use of celecoxib with ACE / APA II inhibitors. However, no significant pharmacodynamic interaction with lisinopril was noted with respect to the effect on blood pressure. In elderly patients, in patients with dehydration (including patients receiving diuretic therapy) or in patients with impaired renal function, the simultaneous use of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, can lead to a deterioration in renal function, including acute renal failure. Typically, these effects are reversible after the cancellation of NSAIDs. Diuretics: NSAIDs in some patients may reduce the natriuretic effect of furosemide and thiazides by reducing renal GH synthesis. This must be considered when using celecoxib. Contraceptives for oral administration: celecoxib does not have a clinically significant effect on the pharmacokinetics of the combined contraceptive drug (1 mg norethisterone / 35 μg ethinyl estradiol).Lithium: with the simultaneous use of lithium salts in a dose of 450 mg 2 times a day and celecoxib in a dose of 200 mg 2 times a day, an increase in plasma lithium concentration by about 17% was noted. Patients taking lithium preparations should be closely monitored when celecoxib is used or withdrawn. Other NSAIDs: the simultaneous use of celecoxib and other NSAIDs (not containing acetylsalicylic acid) should be avoided (the risk of side effects increases). Other drugs: there were no clinically significant interactions between celecoxib and antacids (magnesium / aluminum hydroxide), omeprazole, methotrexate, glibenclamide, phenytoin or tolbutamide. Celecoxib does not affect the antiplatelet effect of acetylsalicylic acid in low doses. Celecoxib does not have an antiplatelet effect on platelets, so they should not replace acetylsalicylic acid in order to prevent cardiovascular diseases. In healthy volunteers, NSAIDs do not affect the pharmacokinetics of digoxin. However, with simultaneous use of digoxin and indomethacin and ibuprofen, an increase in the concentration of digoxin in the blood plasma was observed in patients. This must be taken into account when used simultaneously with other drugs that increase the concentration of digoxin in the blood plasma. No information is available on the interaction of celecoxib and digoxin. Given the other effects of celecoxib on cardiovascular system, it should be taken with caution along with digoxin. In this case, it is recommended to carefully monitor adverse reactions. Celecoxib is predominantly metabolized in the liver by the CYP2C9 isoenzyme. Since barbiturates are inducers of the CYP2C9 isoenzyme, with simultaneous use with celecoxib, a decrease in plasma concentration of the latter can be noted.special instructions
The drug Dilax, which has antipyretic effects, can reduce the diagnostic value of fever, which makes it difficult to diagnose the infection. Impact on the CAS. Celecoxib, like all Coxibs, can increase the risk of developing serious complications from CVS, such as thrombosis, myocardial infarction and stroke, which can be fatal.The risk of these reactions increases with increasing dose, the duration of the drug, as well as in patients with diseases or risk factors for the development of cardiovascular system. In order to reduce the risk of these reactions, the drug Dilax should be used in the minimum effective doses and the shortest possible short course (at the discretion of the attending physician). The attending physician and patient should consider the possibility of the development of such complications even in the absence of previously known symptoms of impaired CVS function. Patients should be informed about the symptoms of serious adverse effects on the side of the CAS and measures to be taken 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, it is possible to increase the incidence of myocardial infarction and cerebral circulation disorders. Celecoxib does not have an antiplatelet effect on platelets, so they should not replace acetylsalicylic acid in order to prevent thromboembolism. Also in this regard, antiplatelet therapy (for example, acetylsalicylic acid) should not be canceled in patients at risk of developing thromboembolic complications. Like all NSAIDs, celecoxib can lead to an increase in blood pressure, which can cause complications from the CVS. Like other NSAIDs, celecoxib should be used with caution in patients with arterial hypertension. Blood pressure should be monitored at the beginning and during celecoxib therapy. Effect on the digestive system. Celecoxib patients had extremely rare cases of perforation, ulceration and bleeding from the gastrointestinal tract. The risk of developing these complications when using NSAIDs is highest in elderly patients, patients with cardiovascular diseases, patients receiving acetylsalicylic acid at the same time, and patients with such gastrointestinal diseases as ulcers, bleeding, inflammation in the acute stage and in history. Other risk factors for the development of bleeding from the gastrointestinal tract are the simultaneous use of corticosteroids for oral or anticoagulants, long-term NSAID therapy, smoking, and ethanol. Most spontaneous reports of serious fatal adverse reactions were observed in elderly and debilitated patients. Simultaneous use with warfarin and other anticoagulants.It was reported that serious (some of them were fatal) bleeding in patients who used warfarin or similar agents along with celecoxib. Given the presence of reports of prolongation of PV, after the start of treatment with Dilax or when changing its dose, blood clotting indicators should be monitored. Fluid retention and edema. As with the use of other drugs that inhibit the synthesis of PG, some patients taking Dilax may experience fluid retention and edema, so care should be taken when using the drug in patients with conditions predisposing or worsening due to fluid retention. Patients with a history of heart failure or arterial hypertension should be closely monitored. Impact on renal function. NSAIDs, incl. and celecoxib may have a toxic effect on kidney function. It was found that celecoxib is not more toxic than other NSAIDs. The drug Dilaxes should be used with caution in patients with impaired renal function, heart failure, impaired liver function, in patients taking diuretics, ACE inhibitors, ARA II, and in elderly patients. It is necessary to carefully monitor the kidney function in these patients. Care should also be taken in patients with dehydration. In such cases, it is advisable to rehydrate, and then begin therapy with Dilax. Effect on liver function. Dilax's drug should not be used in patients with severely severe liver dysfunction (class C according to the Child-Pugh classification). Patients with moderate hepatic insufficiency (class B according to Child-Pugh classification) should be used with caution and in the minimum effective dose. In rare cases, severe hepatic dysfunction was observed, including fulminant hepatitis (sometimes fatal), liver necrosis and liver failure (sometimes fatal or the need for liver transplantation). Most of these reactions developed after 1 month. after starting receiving celecoxib. Patients with symptoms and / or signs of abnormal liver function, or those patients who have abnormal liver function detected by laboratory methods, should be carefully monitored for more severe liver reactions during treatment with Dilax. Anaphylactic reactions.When taking the drug Dilax were reported cases of anaphylactic reactions. Serious reactions from the skin. It has been extremely rare for celecoxib to have severe skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which were fatal. The risk of such reactions is higher at the beginning of therapy, in most cases noted they occurred in the first month of therapy. If a skin rash, mucosal changes or other signs of hypersensitivity appear, you should stop taking Dilax. GKS therapy. It is not necessary to replace the therapy of corticosteroids with Dilax in the treatment of corticosteroids. Special information on excipients. Dilax contains lactose, therefore the drug is contraindicated in patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome. Influence on the ability to drive a car and control mechanisms. Care must be taken when driving and engaging in other potentially hazardous activities that require increased concentration and psychomotor speed, because Dilax may cause dizziness and other side effects that may affect these abilities.