2010/06/16

Celebrex

Composition, structure and packing

Hard gelatin capsules, white or nearly white, opaque, with white markings on the blue stripes: "100" - on one side and "7767" - on the other; content capsules - granulated white or nearly white. 1 capsule. celecoxib 100 mg. Excipients: lactose monohydrate, sodium lauryl sulphate, povidone K30, croscarmellose sodium, magnesium stearate. The composition of the shell: gelatin, titanium dioxide.

Hard gelatin capsules, white or nearly white, opaque, with white markings on the yellow strips: "200" - on one side and "7767" - on the other; content capsules - granulated white or nearly white. The composition of ink blue (SB-6018): shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia, paint aluminum blue FD & C Blue # 2 dye indigotine (E132).

1 capsule. celecoxib 200 mg. Excipients: lactose monohydrate, sodium lauryl sulphate, povidone K30, croscarmellose sodium, magnesium stearate. The composition of the shell: gelatin, titanium dioxide. The composition of yellow ink (SB-3002): shellac, ethanol, isopropanol, butanol, propylene glycol, ammonia, color iron oxide yellow (E172).

Clinico-pharmacological group: NSAID. Highly selective inhibitor of COX-2.

Pharmacological action

NSAIDs. Celecoxib has anti-inflammatory, analgesic and antipyretic effect, blocking the formation of inflammatory prostaglandins mainly due to inhibition of COX-2. Induction of COX-2 occurs in response to the inflammatory process and leads to the synthesis and accumulation of prostaglandins, especially prostaglandin E2, thus there is a growing manifestations of inflammation (swelling and pain). In therapeutic doses in humans celecoxib did not significantly inhibit COX-1 and has no effect on prostaglandins, synthesized by the activation of COX-1 and has no effect on normal physiological processes associated with COX-1 and occur in tissues, especially in the tissues of the stomach, intestines and blood platelets.

Celecoxib reduces urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1 (metabolite of prostacyclin), but has no effect on serum thromboxane B2 and urinary excretion of 11-dehydro-thromboxane B2 metabolite of thromboxane (both - the products of COX-1). Celecoxib causes no reduction of glomerular filtration rate in elderly patients and patients with chronic renal insufficiency, transiently decreases the excretion of sodium.

Patients with arthritis of the observed incidence of peripheral edema, hypertension and heart failure is comparable with that in the intake of non-selective COX inhibitors, which have inhibitory activity against COX-1 and COX-2.

Pharmacokinetics

Absorption

When you receive an empty stomach celecoxib is well absorbed, reaching a Cmax in the plasma after about 2-3 hours after taking the drug at a dose of 200 g in the plasma Cmax was 705 ng / ml. The absolute bioavailability of the drug has not been investigated. Cmax and AUC are approximately proportional to the dose adopted in the range of doses up to 200 mg 2 times / d in the application of the drug in higher doses, the degree of increase Cmax and AUC of less than proportional. Acceptance of celecoxib together with fatty food increases the time to reach Cmax by approximately 1-2 h and increases the total absorption of approximately 20%.

Distribution

Binding to plasma proteins is not dependent on the concentration and amounts to about 97%, celecoxib does not bind to erythrocytes. Penetrates through the BBB. The average Vd in the equilibrium state is approximately 400 liters.

Metabolism

Celecoxib is metabolized in the liver by hydroxylation, oxidation, and part - glyukuronizatsii. Metabolism primarily occurs with the participation of isoenzyme CYP2C9.

Metabolites detected in the blood is not pharmacologically active against COX-1 and COX-2. CYP2C9 isoenzyme activity decreased in individuals with genetic polymorphisms, such as polymorphism homozygous for CYP2C9 * 3, which leads to a decrease in enzymatic activity.

Withdrawal

Celecoxib is metabolized in the liver, excreted in the feces and urine in the form of metabolites (57% and 27% respectively), less than 3% of applied dose - in an unchanged form. With repeated application of T1 / 2 is 8-12 h, and clearance of 500 ml / min. With repeated use of Css in plasma is achieved by Day 5. Variability of the main pharmacokinetic parameters (AUC, Cmax, T1 / 2) is about 30%.

Pharmacokinetics in special clinical situations

Patients older than 65 years have seen an increase of 1.5-2 times the mean values of Cmax and AUC of celecoxib, which has far more to changes in body weight rather than age (elderly patients tend to have lower average body weight than in persons younger, so they ceteris paribus, higher concentrations are achieved celecoxib). For the same reason that older women usually have higher drug concentration in plasma than in older men. These features of pharmacokinetics, as a rule, do not require dose adjustment. However, in elderly patients with body weight below 50 kg treatment should begin with the lowest recommended dose.

In a representative blacks celecoxib AUC by approximately 40% higher than that of Europeans. Causes and clinical significance of this fact is not known, so their treatment is recommended to start with the minimum recommended dose. Concentrations of celecoxib in plasma of patients with mild hepatic insufficiency (class A to Child-Pugh scale), slightly modified. Patients with hepatic insufficiency moderate (class B on a scale Child-Pugh) the concentration of celecoxib in plasma can be increased by almost 2-fold.

Patients with chronic renal insufficiency with glomerular filtration rate (GFR)> 65 ml/min/1.73 m2 in patients with glomerular filtration rate, equal to 35-60 ml/min/1.73 m2, the pharmacokinetics of celecoxib does not change. Not find any significant association between serum creatinine (or QA) and celecoxib clearance.

It is assumed that the presence of renal failure, severe does not affect the clearance of celecoxib, since the main way of his removal - the transformation of the liver to inactive metabolites.

Statement
symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis;
pain (back pain, musculoskeletal, postoperative and other comparable intensity of pain);
treatment of primary dysmenorrhea.

Dosage regimen

The drug, taken orally, regardless of the meal, the capsule did not chew, drinking water. Because the risk of possible cardiovascular complications may increase with dose and duration of admission Celebrex, it should be prescribed as short courses and in the smallest recommended doses. The maximum recommended daily dose of Propafenone - 400 mg.
For symptomatic treatment of osteoarthritis the recommended dose is 200 mg / day for 1 or 2 divided doses. Was noted security administration of the drug in doses up to 400 mg 2 times / day.
For symptomatic treatment of rheumatoid arthritis the recommended dose is 100 mg or 200 mg 2 times / day. Was noted security administration of the drug in doses up to 400 mg 2 times / day.
For symptomatic treatment of ankylosing spondylitis the recommended dose is 200 mg / day in 1 or 2 divided doses.
If necessary, the dose may be increased to 400 mg / day. In the treatment of pain and primary dysmenorrhea the recommended initial dose is 400 mg followed, if necessary, receive additional doses of 200 mg in 1 day. In the following days, the recommended dosage is 200 mg 2 times / day (if necessary).

Elderly patients are usually dose adjustment is required. However, patients with body weight below 50 kg treatment is best to start with lowest recommended dose.

In patients with mild hepatic insufficiency dose adjustment is required in case of hepatic failure, moderate treatment should be started with the minimum recommended dose.

In patients with renal insufficiency mild to moderate severity of dose correction is required. Experience of the drug in patients with renal failure severe yet. Patients receiving fluconazole (an inhibitor of CYP2C9), Celebrex should be prescribed in the recommended minimum dose.

Side effect

Often (≥ 1% and <10%)
On the part of the body as a whole: the aggravation of allergic diseases, flu-like syndrome, accidental injury.
Since the cardiovascular system: peripheral edema.
On the part of the digestive system: abdominal pain, diarrhea, dyspepsia, flatulence, tooth diseases (postekstraktsionny alveolar alveolitis).
From the central nervous system and peripheral nervous system: dizziness, increased muscle tone, insomnia.
From the urinary system: urinary tract infection.
On the part of the respiratory system: bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection. Dermatological reactions: itching, skin rash.

Sometimes (≥ 0.1% and <1%)
On the part of the hemopoietic system: Anemia, ecchymosis, thrombocytopenia.
Since the cardiovascular system: the heavier the flow of arterial hypertension, increased blood pressure, arrhythmia, flushing, palpitation, tachycardia.
From the senses: tinnitus, blurred vision.
On the part of the digestive system: vomiting.
From the CNS: anxiety, sleepiness. Dermatological reactions: alopecia, urticaria.

Rare (≥ 0.01% and <0.1%)
Since the cardiovascular system: a manifestation of congestive heart failure, ischemic stroke and myocardial infarction.
On the part of the digestive system: gastric and duodenal ulcer, ulceration of the esophagus, intestinal perforation, pancreatitis, increased liver enzymes. Allergic reaction: angioedema, bullous eruptions.
From the CNS: confusion. Adverse reactions identified in postmarketing observations Allergic reactions: anaphylaxis.
From the central nervous system and peripheral nervous system: hallucinations, aseptic meningitis.
From the sensory organs: the loss of taste, loss of smell.
Since the cardiovascular system: vasculitis.
From the Digestive System: gastrointestinal bleeding, hepatitis, hepatic failure.
From the urinary system: acute renal failure interstitial nephritis. Dermatological reactions: photosensitivity, skin peeling (including erythema multiforme and in Stevens-Johnson syndrome), toxic epidermal necrolysis, acute generalized exanthematous pustulosis.
On the part of the reproductive system: menstrual irregularities.

Contraindications
bronchial asthma, urticaria, or allergic reactions after taking aspirin or other NPVC, including other inhibitors of COX-2;
condition after the operation, coronary artery bypass grafting;
peptic ulcer exacerbation;
gastrointestinal bleeding;
inflammatory bowel disease;
heart failure (II-IV functional classes according to the classification NYHA);
clinically confirmed coronary heart disease;
peripheral arterial disease and cerebrovascular disease severe;
severe hepatic insufficiency (no experience in the application);
renal failure, severe (no experience in the application);
Pregnancy
Lactation (breastfeeding);
the age of 18 years (no experience with);
Hypersensitivity to the drug's components;
hypersensitivity to sulfonamides.

With care use in patients with gastrointestinal diseases (peptic ulcer disease, bleeding history), infection with Helicobacter pylori, with fluid retention and edema, abnormal liver function of moderate severity, cardiovascular system, cerebrovascular diseases, with dyslipidemia / hyperlipidemia, diabetes mellitus, with peripheral arterial disease, severe somatic diseases, in conjunction with anticoagulants (including with warfarin), with antiagregantami (including with acetylsalicylic acid, clopidogrel), SCS for oral (including with prednisolone) with selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline), with inhibitors of CYP2C9; in patients receiving long-term NSAID.

Pregnancy and lactation

Clinical experience with celecoxib during pregnancy is limited. The potential risks of Celebrex during pregnancy is not installed, but can not be excluded. Celecoxib, an inhibitor of prostaglandin synthesis, in the case of admission during pregnancy, especially in the III trimester, may cause weakness of the uterine contractions and premature closure of the ductus arteriosus. There is limited evidence that celecoxib is excreted in breast milk. Taking into account the potential for side effects while taking celecoxib, a child who is breastfed, should assess the appropriateness of continuing to breastfeed, given the importance of taking Celebrex for his mother.

Application for violations of liver function

Contraindications disturbancies liver function.

Application for violations of renal function

Contraindications disturbancies renal function.

Cautions

Celecoxib (like other NSAIDs) can increase the risk of serious complications in the cardiovascular system, such as blood clots, myocardial infarction and stroke, which can lead to death. The risk of these reactions may increase with duration of drug administration, as well as in patients with diseases of the cardiovascular system. To reduce the risk of these reactions in patients taking Celebrex, it should assign to the lowest recommended dose and shortest duration.

The attending physician and the patient should be kept 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 the cardiovascular system and the measures to be taken in case of their occurrence.

Precautions should be used celecoxib (and other NSAIDs) in patients with arterial hypertension. At the beginning of treatment Celebrex, as well as during the course of treatment should regularly monitor blood pressure. Patients who took celecoxib, we observed very rare cases of perforation, ulceration and bleeding from the gastrointestinal tract. The risk of developing these complications in the treatment of NSAIDs was highest in elderly patients with cardiovascular diseases in patients simultaneously receiving acetylsalicylic acid, and patients with gastrointestinal ulcers, bleeding in the acute phase and a history.

Most spontaneous reports of serious side effects from the gastrointestinal tract belonged to the elderly and immunocompromised patients. Reported serious, and some of them were fatal, bleeding in patients who received concomitant treatment with warfarin or similar means. As reported an increase in prothrombin time, after the start of treatment Celebrex or change the dose necessary to control the anticoagulant activity. As the use of other drugs that inhibit the synthesis of prostaglandins, in some patients taking Celebrex, may experience fluid retention and swelling, so caution should be exercised in the appointment of the drug to patients with conditions predisposing or deteriorating due to water retention.

Patients with cardiac insufficiency or a history of arterial hypertension should be monitored carefully. Celebrex should be used with caution in patients with impaired renal function. Renal function in such patients should be closely monitored. Caution appoint Celebrex patients with dehydration. In such cases it is expedient first to rehydration, and then begin treatment Celebrex. Celebrex should be used with caution in treating patients with hepatic insufficiency moderate and assign to the lowest recommended dose.

In some cases there is severe reaction from the liver, including fulminant hepatitis (sometimes fatal), liver necrosis (sometimes with fatal consequences or the need for liver transplantation). Most of these reactions developed after 1 month after starting celecoxib. Patients with symptoms of liver problems, or in case of violation of liver function laboratory methods require careful monitoring to ensure timely diagnosis of a severe reaction from the liver during treatment with celecoxib. When receiving celecoxib were reported cases of anaphylactic reactions.

Celebrex, given the antipyretic effect, may reduce the diagnostic significance of such symptoms as fever, and affect the diagnosis of infection. Very rarely, when receiving celecoxib have identified serious reaction from the skin, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, some of them fatal. The higher the risk of such reactions in patients beginning therapy, in most reported cases, such reactions begin in the first month of therapy. It should stop taking Celebrex with the appearance of skin rash, changes in the mucous membranes or other signs of hypersensitivity. Avoid the simultaneous application of celecoxib and other NPVC (not containing acetylsalicylic acid).

Effects on ability to drive vehicles and management mechanisms

Effect of celecoxib on the ability to drive vehicles and management mechanisms was not investigated. Based on the pharmacodynamic properties and the overall safety profile, it seems unlikely that Celebrex has such influence.

Overdose

Clinical experience of overdosage is limited. There were no clinically significant side effects at single dose of the drug in doses of up to 1.2 g and repeated admission at doses up to 1.2 mg / day in 2 divided doses. Treatment: with suspected overdose should ensure that the appropriate supportive therapy. Dialysis is not supposed to be an effective method for removal of celecoxib Blood, because of the high degree of plasma protein binding.

Drug Interactions

Studies in vitro have shown that celecoxib but not a substrate for CYP2D6, but also inhibits its activity. Therefore, it is likely drug interactions in vivo with drugs whose metabolism is related to cytochrome CYP2D6. In simultaneous reception with warfarin and other anticoagulants may increase prothrombin time.

Patients receiving fluconazole (an inhibitor of CYP2C9), celecoxib should be prescribed at the lowest recommended dose ketoconazole (an inhibitor of CYP3A4) has no clinically significant effect on the metabolism of celecoxib. Inhibition of prostaglandin synthesis may reduce the effect of ACE inhibitors and antagonists of angiotensin II. This interaction should be taken into account in the appointment of celecoxib in conjunction with ACE inhibitors / antagonists of angiotensin II. However, not noted a significant pharmacodynamic interactions with lisinopril on the impact on BP.

Known previously NSAIDs in some patients can reduce the natriuretic effect of furosemide and thiazides due to inhibition of renal prostaglandin synthesis, it should be borne in mind in the appointment of celecoxib. Not indicated clinically significant effect on the pharmacokinetics of celecoxib combined contraceptive preparations containing 1 mg noretisterona/35 mcg ethinyl estradiol),. Observed increase in the concentration of lithium in the plasma by approximately 17% by sharing a lithium and celecoxib.

Patients receiving lithium therapy should be monitored carefully in the appointment or termination of celecoxib. Not indicated clinically significant interaction between celecoxib and antacids (aluminum and magnesium), omeprazole; methotrexate, glibenclamide, phenytoin, or tolbutamide. Celecoxib does not affect the antiplatelet effects of aspirin, so it can not be considered a substitute for acetylsalicylic acid, appointed for the prevention of cardiovascular diseases.

Terms and Conditions of storage

The drug should be stored out of reach of children, dry place at temperatures from 15 ° to 30 ° C. Shelf life - 3 years.