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The composition and form of issue:
Capsules. 1 capsule contains:
celecoxib 100mg or 200mg
excipients: lactose monohydrate, sodium lauryl sulfate, povidone K30, croscarmellose sodium magnesium stearate
shell: titanium dioxide, gelatin
ink for capsules of 100 mg: ink blue SB-6018 (contain shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia water, varnish aluminum blue FD&C Blue # 2 based on dye indigotina (E132)
ink for capsules of 200 mg: ink yellow SB-3002 (contain shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia water, iron oxide yellow dye (E172)
in blister 10 PCs. in a pack of cardboard 1, 2, 3, 4, 5 or 10 blisters.
Description of dosage form:
Capsule 100 mg: opaque white or almost white, solid gelatin, with markings white on blue stripes: “100” — on one part and “7767” — on the other part of the capsule.
200 mg capsule: opaque white or almost white, solid gelatin, with markings white on yellow stripes: “200” — on one part and “7767” — on the other part of the capsule..
Capsule contents: white or almost white granulate.
Suction. When taken on an empty stomach celecoxib is well absorbed, reaching Cmax in plasma is about 2-3 h. Cmax in plasma after ingestion of 200 mg — 705 ng/ml. the Absolute bioavailability of the drug has not been investigated. Cmax and AUC are approximately proportional to the dose taken in the dose range up to 200 mg twice a day when the drug is used in higher doses, the degree of increase in Cmax and AUC occurs less proportionally.
The impact of eating. Welcome celecoxib together with fatty foods increases the time to reach Cmax by about 1-2 hours and increases full absorption by about 20%.
Distribution. Binding to plasma proteins does not depend on the concentration and is about 97%, celecoxib does not bind to red blood cells. The drug penetrates through the BBB.
Metabolism. Celecoxib is metabolized in the liver by gidrauxilirovania, oxidation and part of glukuronirovania. Metabolism occurs mainly by cytochrome P450 CYP2C9 (see “Interactions”). The metabolites found in the blood, pharmacologically inactive against COX-1 and COX-2.
The activity of cytochrome P450 CYP2C9 is reduced in individuals with genetic polymorphisms such as homozygous for the CYP2C9*3 polymorphism, which leads to a decrease in the efficiency of the enzymes.
Breeding. Celecoxib is metabolized in the liver, excreted in the feces and urine as metabolites (57 and 27%, respectively), less than 3% of the dose — unchanged. With repeated application of T1/2 is 8-12 hours and clearance is about 500 ml/min. With repeated use CSS in plasma is reached by the 5th day. The variability of the main pharmacokinetic parameters (AUC, Cmax, T1/2) is about 30%. The average VSS equal to approximately 400 L.
Elderly patient. In patients older than 65 years, there is an increase in 1, 5-2 times the average values of Cmax, AUC celecoxib, 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 people, due to which, under other equal conditions, higher concentrations of celecoxib are achieved). For the same reason, older women usually have a higher concentration of the drug in plasma than older men. These features of pharmacokinetics, as a rule, do not require dose adjustment. However, in elderly patients weighing less than 50 kg, treatment should begin with the lowest recommended dose.
Race. Have a representative of the Negroid race celecoxib AUC is about 40% higher than that of Europeans. The causes and clinical significance of this fact are unknown, so the treatment of such patients is recommended to start with the minimum recommended dose.
Impaired liver function. Celecoxib concentration in plasma in patients with mild hepatic insufficiency (class A according to Child-Pugh) change slightly. In patients with hepatic insufficiency of moderate severity (class b Child-Pugh) celecoxib concentration in plasma may increase by almost 2 times.
The impairment of renal function. In patients with chronic renal failure at glomerular filtration rate (GFR) >65 ml/min/1, 73 m2 or equal to 35-60 ml/min/1, 73 m2, the pharmacokinetics of celecoxib does not change. Not found significant relationships between serum creatinine (or creatinine clearance), and clearance celecoxib. It is assumed that the presence of severe renal insufficiency does not affect the clearance of celecoxib, since the main way of its removal is the transformation of the liver into inactive metabolites.
Description of the pharmacological action:
Celecoxib has anti-inflammatory, analgesic and antipyretic action by blocking the formation of inflammatory PG, mainly due to the inhibition of COX-2. The induction of COX – 2 occurs in response to inflammation and leads to the synthesis and accumulation of PG, especially PGE2, while there is an increase in the manifestations of inflammation (swelling and pain). In therapeutic doses, celecoxib does not significantly inhibit COX-1 in humans and does not affect PG synthesized as a result of Cox-1 activation, and does not affect normal physiological processes associated with COX-1 and occurring in tissues, primarily in the tissues of the stomach, intestines and platelets.
The impact on renal function. Celecoxib reduces the urinary excretion of ПГЕ2 and 6-keto-ПГF1 (metabolite of prostacyclin), but no effect on serum thromboxane B2 and the urinary excretion of 11-dehydro-thromboxane B2, a thromboxane metabolite (both products of COX-1). Celecoxib does not cause a decrease in GFR in elderly patients and persons with chronic renal insufficiency, transitory decrease in sodium excretion. Patients with arthritis of the observed incidence of peripheral edema, hypertension, and heart failure is comparable to that in patients receiving non-selective COX inhibitors, which have inhibitory activity against COX-1 and COX-2.
With caution should designate celebrex under the following conditions:
Application during pregnancy and breast-feeding:
There is a lack of sufficient data on the use of celecoxib in pregnant women. Potential risks of using Celebrex during pregnancy has not been established but cannot be excluded. Celecoxib, belonging to the group of inhibitors of PG synthesis, when taken during pregnancy, especially in the III trimester, can cause weakness of uterine contractions and premature closure of the arterial duct in the fetus.
There is limited evidence that celecoxib is excreted in breast milk. Considering the potential for side effects from celecoxib have fed a baby, you should assess whether to continue breastfeeding, given the importance of the reception of Celebrexa mother.
Against the background of the reception of the Cemebrex, the following reactions are possible from organs and systems with the following frequency gradation: often — &ge1 but <10% infrequently — &ge0, 1 and <1% rarely — &ge0, 01 and <0, 1%.
General: often the exacerbation of allergic diseases, flu-like symptoms, accidental injuries.
From the CCC: often-peripheral edema infrequently-weighting of arterial hypertension, increased blood PRESSURE, arrhythmia, hot flashes, heartbeat, tachycardia rarely — manifestation of congestive heart failure, ischemic stroke and myocardial infarction.
By the blood: often — abdominal pain, diarrhea, dyspepsia, flatulence, diseases of the teeth (alveolus postextraction alveolitis) rare — rarely, vomiting — stomach ulcer and duodenum, esophageal ulceration, intestinal perforation, pancreatitis.
From the Central nervous system: often — dizziness, increased muscle tone, insomnia.
From the kidneys and urinary system: often — urinary tract infection.
From the respiratory system: often — bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections.
From the skin: often-itching, skin rash infrequently-alopecia, urticaria.
In the blood: rare — anemia, ekhimozy, thrombocytopenia.
From the sensory organs: rare — tinnitus, blurred vision.
Mental status: rare — anxiety, drowsiness, rarely — confusion.
The immune system: rare — angioneurotic edema, bullous rashes.
From the hepatobiliary system: rarely – increased activity of liver enzymes.
Side effects are identified during post-marketing observations
From the immune system: anaphylaxis.
Mental status: hallucinations.
From the nervous system: loss of taste, loss of smell, aseptic meningitis.
From the organ of vision: conjunctivitis.
From vessels: vasculitis, hemorrhage in the brain.
From the digestive tract: gastrointestinal bleeding.
From the hepatobiliary system: hepatitis, liver failure (see section” Special instructions”, subsection”Influence on liver function”).
From the kidney and urinary system: acute renal failure (see section “Special instructions”, subsection “influence on kidney function”), interstitial nephritis, hyponatremia.
From the skin: photosensitivity reactions, skin peeling (including multiform erythema and Stevens-Johnson syndrome), toxic epidermal necrolysis, acute generalized exanthematous pustules.
On the part of the reproductive system: violation of the menstrual cycle.
Respiratory, thoracic and mediastinal disorders: pulmonary embolism.
Systemic disorders: chest pain.
In vitro studies showed that celecoxib, although not a substrate of CYP2D6, but inhibits its activity. Therefore, there is a possibility of drug interaction in vivo with drugs, metabolism of which is associated with cytochrome CYP2D6.
Warfarin and other anticoagulants: while taking may increase PV.
Fluconazole, ketoconazole: patients taking fluconazole (CYP2C9 inhibitor), celecoxib should be administered at the lowest recommended dose (see “dosage and Administration”). Ketoconazole (CYP3A4 inhibitor) has no clinically significant effect on the metabolism of celecoxib.
ACE inhibitors / angiotensin II antagonists: inhibition of PG synthesis can reduce the antihypertensive effect of ACE inhibitors/angiotensin II antagonists. This interaction should be taken into account in appointing celecoxib in conjunction with ACE inhibitors/angiotensin II antagonists. However, there was no significant pharmacodynamic interaction with lisinopril in relation to the effect on blood PRESSURE.
Diuretics: previously known NSAIDs in some patients can reduce the natriuretic effect of furosemide and thiazides at the expense of reduced renal synthesis of PG, it should be kept in mind when assigning celecoxib.
Oral contraceptives: there was no clinically significant effect on the pharmacokinetics of contraceptive combination (1 mg of norethisterone/35 µg of ethinyl estradiol).
Lithium: there was an increase in the concentration of lithium in plasma by about 17% with co-administration of lithium and celecoxib. Patients receiving lithium therapy should be under careful surveillance when assigning or canceling celecoxib.
Other NSAIDs: simultaneous use of celecoxib and other NSAIDs (not containing acetylsalicylic acid) should be avoided.
Other drugs: there were no clinically significant interactions between celecoxib and antacids (aluminium – and magnesium-containing drugs), omeprazole, methotrexate, glibenclamide, phenytoin or tolbutamide.
Celecoxib does not affect the antiplatelet action of acetylsalicylic acid, so it can not be considered as a replacement of acetylsalicylic acid, prescribed for the prevention of cardiovascular disease.
Method of application and doses:
Inside, not liquid, squeezed water, regardless of meals.
Since the risk of possible cardiovascular complications may increase with an increase in the dose and duration of medication, it should be prescribed as short courses and in the lowest recommended doses. The maximum recommended daily dose for long-term administration-400 mg.
Symptomatic treatment of osteoarthritis: the recommended dose is 200 mg per day for 1 or 2 admission. Safety of doses up to 400 mg twice a day was noted.
Symptomatic treatment of rheumatoid arthritis: the recommended dose is 100 or 200 mg twice a day. Safety of doses up to 400 mg twice a day was noted.
Symptomatic treatment of ankylosing spondylitis: the recommended dose is 200 mg per day for 1 or 2 admission. According to the doctor’s prescription, the dose can be increased to 400 mg per day.
Treatment of pain and primary dysmenorrhea: the recommended starting dose is 400 mg, followed if necessary by further doses of 200 mg on the first day. In the following days, the recommended dose is 200 mg 2 times a day, if necessary.
Elderly patient. Usually dose adjustment is not required. However, in patients weighing less than 50 kg treatment is better to start with the lowest recommended dose.
Impaired liver function. In patients with mild hepatic insufficiency (class a according to the Child-Pugh classification), dose correction is not required, in the case of moderate hepatic insufficiency (class B according to the Child-Pugh classification), treatment should begin with the minimum recommended dose.
The impairment of renal function. In patients with mild to moderate renal failure dose adjustment is not required. Experience in the use of the drug in patients with severe renal insufficiency is not (see. “Special instructions”).
Concurrent use of fluconazole. Patients, receiving fluconazole (inhibitor of CYP2C9), celebrex should assign the minimum recommended dose.
Clinical experience of overdose is limited. Single doses up to 1200 mg and multiple doses up to 1200 mg in 2 doses per day were used without clinically significant side effects.
Treatment: if an overdose is suspected, appropriate maintenance therapy should be provided. Presumably dialysis is not an effective method of removing the drug from the blood, due to the high degree of binding of the drug with protein.
Impact on SSS. Celecoxib, like all coxibe, can increase the risk of serious complications from the CCC, such as thrombosis, myocardial infarction and stroke, which can lead to death. The risk of these reactions may increase with the duration of taking the drug, as well as in patients with CCC diseases. To reduce the risk of these reactions in patients taking tselebrex, it should be prescribed in the lowest recommended doses and for the shortest periods (at the discretion of the attending physician). The attending physician and patient should bear in mind the possibility of such complications even in the absence of previously known cardiovascular symptoms. Patients should be informed about the signs and symptoms of adverse effects on CCC and the measures to be taken in case of their occurrence.
All NSAIDs, including celecoxib, in patients with arterial hypertension should be used with caution. Monitoring of blood PRESSURE should be carried out at the beginning of therapy with celecoxib, as well as during the course of treatment.
The effect on the gastrointestinal tract. Patients, taking celecoxib, there were extremely rare cases of perforation, ulceration and bleeding from the gastrointestinal tract. The risk of developing these complications in the treatment of NSAIDs is highest in older people with cardiovascular diseases, patients receiving acetylsalicylic acid, and patients with gastrointestinal diseases such as ulcers, bleeding in the acute stage and history. Most spontaneous reports of severe side effects on the gastrointestinal tract were among elderly and weakened patients.
Sharing with warfarin and other anticoagulants. Serious (some of them fatal) bleeding was reported in patients receiving concomitant treatment with warfarin or similar agents. Because reported an increase in PV after initiation of treatment with Celebrex or change the dose should be monitored anticoagulant activity.
Fluid retention and swelling. As the use of other drugs, inhibiting the synthesis of PG, the number of patients receiving celebrex may experience fluid retention and swelling, so care should be taken in appointing the drug to patients with conditions that predispose to fluid retention or worsen when it occurs. Patients with a history of heart failure or hypertension should be under close supervision.
The impact on renal function. Celebrex should be used with caution in patients with impaired renal function. Kidney function in such patients should be carefully monitored.
Caution must be exercised in the appointment therapy Celebrexa patients with dehydration. In such cases it is advisable to first carry out the rehydration, and then start therapy with Celebrex.
Influence on liver function. Celebrex should be used with caution in patients with hepatic impairment moderate and to assign the smallest recommended dose.
In some cases we observed severe reactions in the liver, including fulminant hepatitis (sometimes fatal), liver necrosis (sometimes with a fatal outcome or need liver transplantation). Most of these reactions developed within 1 month after receiving celecoxib.
Patients with symptoms and/or signs of liver dysfunction or those patients who are diagnosed with the liver laboratory methods, should be under careful observation for the development of more severe reactions in the liver during treatment with Celebrex.
Anaphylactic reaction. Upon receipt of Celebrex have been reported cases of anaphylactic reactions.
Celebrex, given antipyretic effect, can reduce the diagnostic significance of such symptoms as fever and affect the diagnosis of infection.
Serious reactions from the skin. Very rarely when taking celecoxib was marked by serious reactions of the skin such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of them were fatal. The higher the risk of such reactions in patients at the beginning of therapy, in most cases, such reactions began in the first month of therapy. It is necessary to stop taking Celebrex when skin rash, changes in the mucous membranes or other signs of hypersensitivity.
Effects on ability to drive a car or operate machinery. The influence of celecoxib on the ability to drive and control mechanisms has not been investigated. But based on its pharmacodynamic properties and overall safety profile, it seems unlikely that celebrex is having such an impact.
|The purpose of the medication||Coxibes|