Universal reference book for medicines
Product name: CELEBREX ® (CELEBREX ® )

Active substance: celecoxib

Type: NSAIDs.
Highly selective COX-2 inhibitor
Manufacturer: PFIZER MANUFACTURING DEUTSCHLAND (Germany) manufactured by PFIZER PHARMACEUTICALS (Puerto Rico) issuing quality control PFIZER MANUFACTURING DEUTSCHLAND (Germany)
Capsules hard gelatin, white or almost white, opaque, with markings white on blue stripes: "100" - on one part and "7767" on the other; the contents of the capsules are granules of white or almost white color.
1 caps.

celecoxib 100 mg

Excipients: lactose monohydrate 149.7 mg, sodium lauryl sulfate 8.1 mg, povidone K30 6.8 mg, croscarmellose sodium 2.7 mg, magnesium stearate 2.7 mg.

The composition of the coating: titanium dioxide - about 1.7 mg, gelatin - about 58.3 mg.

The composition of the blue ink SB-6018: shellac 22-27%, ethanol 33-38%, isopropanol 0.5-4%, butanol 4-8%, propylene glycol 3-6%, ammonia water 1-2% lacquer aluminum blue FD & C Blue # 2 based on the dye indigotine (E132) - 24-28%.

10 pieces.
- blisters (1) - packs of cardboard with control of the first opening.
Capsules hard gelatinous, white or almost white, opaque, with markings white on yellow strips: "200" - on one part and "7767" on the other;
the contents of the capsules are granules of white or almost white color.
1 caps.

celecoxib 200 mg

Excipients: lactose monohydrate - 49.8 mg, sodium lauryl sulfate - 8.1 mg, povidone K30 - 6.7 mg, croscarmellose sodium - 2.7 mg, magnesium stearate - 2.7 mg.

The composition of the coating: titanium dioxide - about 1.7 mg, gelatin - about 58.3 mg.

Composition of yellow ink SB-3002: shellac - 22-27%, ethanol - 33-38%, isopropanol - 3-7%, butanol - 4-9%, propylene glycol - 3-6%, ammonia water - 1-2% the colorant of iron oxide is yellow (E172) - 18-22%.

10 pieces.
- blisters (1) - packs of cardboard with control of the first opening.
10 pieces.
- blisters (3) - packs of cardboard with control of the first opening.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

NSAIDs.
Celecoxib has anti-inflammatory, analgesic and antipyretic effects, 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, in particular prostaglandin E 2 , with an increase in inflammation (swelling and pain). At therapeutic doses in humans, celecoxib does not significantly inhibit COX-1 and does not affect prostaglandins synthesized as a result of COX-1 activation, nor does it affect normal physiological processes associated with COX-1 and that occur in tissues, and primarily in the tissues of the stomach, intestines and platelets.
Influence on kidney function.
Celecoxib reduces urinary excretion of prostaglandin E 2 and 6-keto-prostaglandin F 1 (prostacyclin metabolite), but does not affect serum thromboxane B 2 and urinary excretion of 11-dehydro-thromboxane B 2 , metabolite of thromboxane (both products of COX-1 ). Celecoxib does not cause a decrease in GFR in elderly patients and patients with chronic renal failure, transiently reduces excretion of sodium. In patients with arthritis, the observed incidence of peripheral edema, arterial hypertension, and heart failure is comparable to that of non-selective COX inhibitors that have inhibitory activity against COX-1 and COX-2. The most pronounced effect was in patients receiving diuretic therapy. Nevertheless, there was no increase in the incidence of increased blood pressure and heart failure, and peripheral edema was mild and passed independently.
PHARMACOKINETICS

Suction

When taken on an empty stomach, celecoxib is well absorbed, reaching Cmax in plasma after about 2-3 hours. After taking the drug at a dose of 200 g, C max in plasma is 705 ng / ml.
Absolute bioavailability of the drug has not been studied. Cmax and AUC are approximately proportional to the dose taken in the dose range up to 200 mg 2 times / day; when using the drug at higher doses, the degree of increase in C max and AUC is less proportional.
Effect of food intake: taking celecoxib together with fatty foods increases the time to reach Cmax by about 1-2 hours and increases the total 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.
Penetrates through the BBB.
The average V d in the equilibrium state is approximately 500 l / 70 kg in young healthy adult patients, indicating a wide distribution of celecoxib in the tissue.

Metabolism

Celecoxib is metabolized in the liver by hydroxylation, oxidation, and partially - glucuronization.
Metabolism mainly occurs with the participation of the isoenzyme CYP2C9. Metabolites found in the blood are not pharmacologically active against COX-1 and COX-2.
The activity of the CYP2C9 isoenzyme is reduced in individuals with genetic polymorphism, such as polymorphism homozygous for CYP2C9 * 3, which leads to a decrease in enzymatic activity.

Excretion

Celecoxib is metabolized in the liver, excreted in feces and urine in the form of metabolites (57% and 27%, respectively), less than 3% of the accepted dose - in unchanged form.
At repeated application T 1/2 is 8-12 hours, and the clearance is about 500 ml / min. At repeated application C ss in plasma it is reached by 5 day.
The variability of the main pharmacokinetic parameters (AUC, C max , T 1/2 ) is about 30%.

Pharmacokinetics in special clinical cases

In patients older than 65 years, the mean C max and AUC of celecoxib are 1.5-2 times higher, which is more due to changes in body weight than in age (in older patients, as a rule, a lower average body weight is observed than in people of a younger age, so they, with other conditions being equal, achieve higher concentrations of celecoxib).
For the same reason, older women usually have a higher plasma concentration of the drug than older men. These features of pharmacokinetics, as a rule, do not require dose adjustment. However, in elderly patients with a body weight below 50 kg, treatment with the lowest recommended dose should be started.
The representative Negroid race AUC of celecoxib is about 40% higher than that of Europeans.
The causes and the clinical significance of this fact are not known, therefore it is recommended to start their treatment with the minimum recommended dose.
Violation of the function of the liver.
Concentrations of celecoxib in plasma in patients with mild liver failure (class A on the Child-Pugh scale) vary slightly. In patients with moderate hepatic insufficiency (class B on the Child-Pugh scale), the concentration of celecoxib in plasma can almost double.
Impaired renal function.
In patients with chronic renal failure with GFR> 65 ml / min / 1.73 m 2 and in patients with GFR of 35-60 ml / min / 1.73 m 2 , the pharmacokinetics of celecoxib do not change. There is no significant relationship between the serum creatinine (or KK) content and the clearance of celecoxib. It is assumed that the presence of severe renal insufficiency does not affect the clearance of celecoxib, since the main way of its elimination is conversion into 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.

DOSING MODE

The drug is taken orally, regardless of food intake, without chewing, washing with water.

Since the risk of possible cardiovascular complications may increase with increasing dose and duration of Celebrex ® , it should be given as short courses and at the lowest effective doses.
The maximum recommended daily dose for long-term admission is 400 mg.
With symptomatic treatment of osteoarthritis, the recommended dose is 200 mg / day for 1 or 2 doses.

With the symptomatic treatment of rheumatoid arthritis, the recommended dose is 100 mg or 200 mg 2 times / day.

With symptomatic treatment of ankylosing spondylitis, the recommended dose is 200 mg / day in 1 or 2 doses.
Some patients noted the effectiveness of the drug at a dose of 400 mg 2 times / day.
In the treatment of pain syndrome and primary dysmenorrhea, the recommended initial dose is 400 mg, followed, if necessary, by taking an additional dose of 200 mg on the first day.
In the following days, the recommended dose is 200 mg 2 times / day, if necessary.
Older patients usually do not need dose adjustment.
However, in patients with a body weight below 50 kg, treatment should be started with the lowest recommended dose.
In patients with mild hepatic insufficiency (class A on the Child-Pugh scale), dose adjustment is not required.
In the case of a moderate degree of hepatic insufficiency (class B on the Child-Pugh scale), treatment should begin with the minimum recommended dose. Experiments with the use of the drug in patients withsevere hepatic insufficiency (class C on the Child-Pugh scale) do not.
In patients with mild to moderate renal insufficiency, dose adjustment is not required.
The experience of using the drug in patients with renal insufficiency is not severe .
For patients taking fluconazole (CYP2C9 inhibitor), Celebrex ® should be given at the lowest recommended dose.
With caution, the drug should be used concurrently with other inhibitors of the isoenzyme CYP2C9.
Celebrex ® should be used with caution in patients who are slow metabolizers or suspected of such a condition, since
this can lead to the accumulation of high concentrations of celecoxib in the blood plasma. In such patients, the initial recommended dose of the drug should be reduced by a factor of 2.
SIDE EFFECT

Often (? 1% and <10%)

Common reactions: exacerbation of allergic diseases, flu-like syndrome, accidental trauma.

From the cardiovascular system: peripheral edema.

On the part of the digestive system: abdominal pain, diarrhea, dyspepsia, flatulence, dental diseases (post-extraction alveolitis).

From the nervous system: dizziness, increased muscle tone, insomnia.

From the urinary system: infection of the urinary tract.

On the part of the respiratory system: bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections.

From the skin: skin itch, skin rash.

Infrequently (? 0.1% and <1%)

General reactions: swelling of the face.

On the part of the hematopoiesis system: anemia, ecchymosis, thrombocytopenia.

From the cardiovascular system: weighting the course of arterial hypertension, increased blood pressure, arrhythmia, hot flashes, palpitation, tachycardia.

From the senses: tinnitus, blurred vision.

On the part of the digestive system: vomiting.

From the nervous system: anxiety, drowsiness.

From the skin: alopecia, urticaria.

Rarely (? 0.01% and <0.1%)

From the cardiovascular system: the manifestation of congestive heart failure, ischemic stroke and myocardial infarction.

On the part of the digestive system: gastric and duodenal ulcers, ulceration of the esophagus, intestinal perforation, pancreatitis, increased activity of hepatic enzymes.

Allergic reactions: angioedema, bullous eruptions.

From the nervous system: confusion.

Adverse reactions detected during post-marketing observations

Allergic reactions: anaphylaxis.

From the side of the nervous system: hallucinations, aseptic meningitis.

From the senses: loss of taste, loss of smell.

From the cardiovascular system: vasculitis, hemorrhages in the brain.

On the part of the digestive system: gastrointestinal bleeding, hepatitis, hepatic insufficiency, fulminant hepatitis, liver necrosis, cholestasis, cholestatic hepatitis, jaundice.

From the side of the urinary system: acute renal failure, interstitial nephritis, nephrotic syndrome, minimal renal dysfunction.

On the part of the skin: photosensitization, skin peeling (including with erythema multiforme and Stevens-Johnson syndrome), toxic epidermal necrolysis, drug rash in combination with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome), acute generalized exanthematous pustulosis.

On the part of the reproductive system: violation of the menstrual cycle, decreased fertility in women.

From the respiratory system: embolism of the pulmonary arteries.

Other: hyponatremia, chest pain.

CONTRAINDICATIONS

- bronchial asthma, hives, or allergic reactions after taking acetylsalicylic acid or other NSAIDs, including other COX-2 inhibitors;

- condition after aortocoronary bypass surgery;

- Peptic ulcer in the phase of exacerbation;

- gastrointestinal hemorrhage;

- Inflammatory bowel disease;

- Heart failure (II-IV functional classes according to the NYHA classification);

- clinically confirmed CHD;

- diseases of peripheral arteries and cerebrovascular diseases of severe degree;

- severe hepatic insufficiency (no experience of application);

- severe renal failure (no experience of use);

- Pregnancy;

- lactation period (breastfeeding);

- children's and adolescence under 18 years (no experience of application);

- hypersensitivity to the components of the drug;

- hypersensitivity to sulfonamides.

Precautions should be taken with the preparation for gastrointestinal diseases (peptic ulcer disease, bleeding history), Helicobacter pylori infection, fluid retention and edema, violations of the liver function of moderate severity, cardiovascular system diseases, cerebrovascular diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, with diseases of peripheral arteries, severe somatic diseases;
simultaneously with anticoagulants (including with warfarin), with antiaggregants (including with acetylsalicylic acid, clopidogrel), GCS for oral administration (including with prednisolone), with selective serotonin reuptake inhibitors (citalopram , fluoxetine, paroxetine, sertraline), with inhibitors of the isoenzyme CYP2C9; in patients receiving long-term NSAIDs; in patients who are slow metabolizers or are suspected of such a condition.
PREGNANCY AND LACTATION

Clinical experience with celecoxib during pregnancy is limited.
The potential risk of using Celebrex ® during pregnancy is not established, but can not be ruled out.
In accordance with the mechanism of action, with NSAIDs, including celecoxib, some women may develop ovarian changes, which can lead to complications during pregnancy.
Women who plan pregnancy or are undergoing infertility examinations should consider withdrawing NSAIDs, including celecoxib.
Celecoxib, belonging to the group of inhibitors of prostaglandin synthesis, in case of admission during pregnancy, especially in the third trimester, can cause weakness of uterine contractions and premature closure of the arterial duct.
The use of inhibitors of prostaglandin synthesis in the early stages of pregnancy can adversely affect the course of pregnancy.
There is limited evidence that celecoxib is excreted in breast milk.
Studies have shown that celecoxib is excreted in breast milk at very low concentrations.Nevertheless, taking into account the potential for the development of side effects from celecoxib in the infant fed, the feasibility of abolishing either breastfeeding or taking celecoxib should be considered, given the importance of taking Celebrex ® for the mother.
APPLICATION FOR FUNCTIONS OF THE LIVER

Contraindicated in severe impairment of kidney function.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindicated in severe violations of liver function.

APPLICATION FOR CHILDREN

Contraindication: age under 18 years (no experience of use).

SPECIAL INSTRUCTIONS

Celebrex ® , considering the antipyretic effect, can reduce the diagnostic significance of such a symptom as fever, and affect the diagnosis of infection.

Influence on the cardiovascular system.
Celecoxib (like all coxibs) can increase the risk of serious complications from the cardiovascular system, such as thrombosis, myocardial infarction and stroke, which can lead to death. The risk of these reactions may increase with the duration of the drug, as well as in patients with diseases of the cardiovascular system. To reduce the risk of these reactions in patients taking Celebrex ® , it should be administered at the lowest recommended doses and for the shortest possible periods. The attending physician and patient should keep in mind the possibility of such complications even in the absence of previously known cardiovascular symptoms. Patients should be informed of the signs and symptoms of adverse effects on the cardiovascular system and the measures to be taken if they occur.
When using NSAIDs (selective inhibitors of COX-2) in patients after an operation of aortocoronary shunting for the treatment of pain in the first 10-14 days, an increase in the incidence of myocardial infarction and cerebral circulation disorders is possible.

Due to the weak effect of celecoxib on the function of platelets, it can not be a substitute for acetylsalicylic acid for the prevention of thromboembolism.
Also, therefore, antiplatelet therapy (eg, acetylsalicylic acid) should not be discontinued in patients at risk of developing thromboembolic complications.
Like other NSAIDs, celecoxib may lead to an increase in blood pressure, which increases the risk of complications from the cardiovascular system.
In patients with hypertension all NSAIDs, including and celecoxib should be used with caution. Should regularly monitor the blood pressure at the beginning of therapy with celecoxib and throughout the course of treatment.
Impact on the gastrointestinal tract.In patients taking celecoxib, very rare cases of perforation, ulceration, and bleeding from the gastrointestinal tract. The risk of these complications in the treatment of NSAID is highest in the elderly, patients with cardiovascular disease, in patients concomitantly receiving acetylsalicylic acid, and patients with ulcerative lesions of the gastrointestinal tract, inflammatory diseases in the acute phase and in history. Other risk factors of bleeding from the gastrointestinal tract are the simultaneous use of oral corticosteroids and anticoagulants, NSAIDs long period of therapy, smoking, use of alcohol. Most spontaneous reports of serious side effects from the stomach belonged to the elderly and immunocompromised patients.
The combined use of warfarin and other anticoagulants.It reported serious and some of them were fatal, bleeding in patients who received concomitant treatment with warfarin or similar means. As it reported an increase in prothrombin time, after the beginning of treatment with Celebrex ® or change the dose necessary to control the anticoagulant activity.
Fluid retention and edema. As with other drugs that inhibit prostaglandin synthesis, for a number of patients taking Celebrex ®May be marked fluid retention and swelling, so caution should be exercised in the appointment of the drug to patients with states predisposing or deteriorating due to fluid retention. Patients with heart failure or a history of hypertension should be monitored carefully.
Effects on renal function. NSAIDs, including and celecoxib may have a toxic effect on renal function. It was found that not celecoxib has higher toxicity as compared to other NSAIDs. Celebrex ® should be used with caution in patients with renal dysfunction, heart failure, impaired liver function and in elderly patients. Renal function in such patients should be carefully monitored.
Should be used with caution Celebrex ® patients with dehydration. In such cases it is advisable to first conduct a rehydration, and then start therapy with Celebrex ® .
The effect on the liver function. Celebrex ®should be used with caution in patients with hepatic insufficiency of moderate severity and administered in the lowest recommended dose. In some instances, severe reactions were observed from the liver, including fulminant hepatitis (sometimes fatal), hepatic necrosis (sometimes fatal or the need for liver transplantation). Most of these reactions occur within 1 month after initiation of celecoxib. Patients with liver dysfunction symptoms or in case of dysfunction of liver laboratory methods require careful monitoring for timely diagnosis of more severe reactions in the liver during the treatment with Celebrex ® .
Anaphylactic reactions. When receiving the drug Celebrex ®cases of anaphylactic reactions have been reported.
Serious reactions from the skin. Extremely seldom when receiving celecoxib serious reactions were observed from the side of the skin, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, some of them fatal. Higher risk of such reactions in patients in the early treatment, most reported cases, such reactions started during the first month of therapy. It should stop taking the drug Celebrex ® at occurrence of skin rash, changes in the mucous membranes or other signs of hypersensitivity.
SCS therapy. Celebrex ® It can not substitute for corticosteroids or used as glucocorticoid therapy failure.
Impact on the ability to drive vehicles and manage mechanisms

Influence of celecoxib on the ability to drive vehicles and management mechanisms have not been studied. Based on the pharmacodynamic properties and the general safety profile, it seems unlikely that Celebrex ® has such influence.
OVERDOSE

The clinical experience of overdose is limited. There were no clinically significant side effects at single dose of the drug at a dose of 1.2 g and reception in multiple doses up to 1.2 mg / day in 2 divided doses.
Treatment: in cases of suspected overdose should ensure that appropriate supportive therapy. Presumably dialysis is not an efficient method of removing blood from celecoxib, due to the high degree of binding to plasma proteins.
DRUG INTERACTION

In vitro studies have shown that celecoxib although not a substrate of CYP2D6, but inhibits its activity. Therefore, there is a possibility of drug interactions with drugs in vivo, which is associated with metabolism by cytochrome CYP2D6.
When concomitantly with warfarin, and other anticoagulants may increase the prothrombin time.
With simultaneous use of fluconazole in a dose of 200 mg 1 time / day of celecoxib marked increase in plasma concentration is 2 times. This effect is associated with inhibition of metabolism by isozyme celecoxib fluconazole CYP2C9. Patients receiving fluconazole (inhibitor of CYP2C9), celecoxib should be used at the lowest recommended dose. Ketoconazole (an inhibitor of isozyme CYP3A4) did not have a clinically meaningful effect on the metabolism of celecoxib.
Inhibition of prostaglandin synthesis can reduce the effect of ACE inhibitors and antagonists of angiotensin II. This interaction should be taken into account when assigning celecoxib together with ACE inhibitors / antagonists of angiotensin II. However, there was no significant pharmacodynamic interaction with lisinopril on the effect on blood pressure.
Elderly patients, patients with dehydration (including receiving therapy with diuretics) or patients with impaired renal function simultaneous use of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors may lead to a deterioration of renal function, including possible acute renal failure. Usually, these effects are reversible.
Previously known NSAIDs, some patients can reduce the natriuretic effect of furosemide and thiazides due to inhibition of renal prostaglandin synthesis, it should be borne in mind when assigning celecoxib.
There was no clinically significant effect on the pharmacokinetics of celecoxib combined contraceptive preparations containing 1 mg norethisterone / 35 mcg of ethinyl estradiol.
There was an increase in plasma lithium concentration by about 17% when co-administered celecoxib lithium. Patients on lithium therapy should be closely monitored in the appointment or revocation of celecoxib.
There were no clinically significant interaction between celecoxib and antacids (aluminum and magnesium preparations), omeprazole, methotrexate, glibenclamide, tolbutamide or phenytoin.
Celecoxib does not affect the antiplatelet effect of aspirin, low-dose received. Celecoxib has a weak effect on platelet function, so it can not be considered a substitute for acetylsalicylic acid assignable for the prevention of cardiovascular diseases.
Avoid the simultaneous application of celecoxib with other NSAIDs (not containing acetylsalicylic acid).
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be kept out of the reach of children, dry place at a temperature of from 15 ° to 30 ° C.
Shelf life - 3 years.
The information is provided for your information, do not self-medicate, it is dangerous for your health.

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