Celebrex capsules 100mg, No. 10

• Symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis;

• pain syndrome: back pain, musculoskeletal, postoperative and other types of pain;

• treatment of primary dysmenorrhea.

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

Since the risk of possible cardiovascular complications may increase with an increase in the dose and duration of taking CelebrexЃ, it should be prescribed in the shortest possible courses and in the lowest effective doses. The maximum recommended daily dose for long-term use is 400 mg.

For symptomatic treatment of osteoarthritis, the recommended dose is 200 mg / day for 1 or 2 doses.

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

For symptomatic treatment of ankylosing spondylitis, the recommended dose is 200 mg / day in 1 or 2 doses. In some patients, the efficacy of the drug at a dose of 400 mg 2 times / day was noted.

In the treatment of pain and primary dysmenorrhea, the recommended starting dose is 400 mg, followed, if necessary, by taking an additional dose of 200 mg on day 1. On the following days, the recommended dose is 200 mg 2 times / day, as needed.

Elderly patients usually do not need dose adjustment. However, in patients weighing less than 50 kg, it is better to start treatment with the lowest recommended dose.

In patients with mild hepatic impairment (class A on the Child-Pugh scale), dose adjustment is not required. In the presence of moderate hepatic impairment (class B on the Child-Pugh scale), treatment should be started with the minimum recommended dose. There is no experience of using the drug in patients with severe hepatic impairment (class C on the Child-Pugh scale).

In patients with mild to moderate renal insufficiency, dose adjustment is not required. There is no experience of using the drug in patients with severe renal failure.

For patients taking fluconazole (a CYP2C9 inhibitor), CelebrexЃ should be administered at the minimum recommended dose. The drug should be used with caution in conjunction with other inhibitors of the isoenzyme CYP2C9.

CelebrexЃ should be used with caution in patients who are slow metabolizers or with suspicion of such a condition, because this can lead to the accumulation of high plasma concentrations of celecoxib. In such patients, the initial recommended dose of the drug should be reduced by 2 times.

Hard gelatin capsules

1 caps.

celecoxib

Excipients: lactose monohydrate, sodium lauryl sulfate, povidone K30, croscarmellose sodium, magnesium stearate.

• Bronchial asthma, urticaria, or allergic reactions after taking acetylsalicylic acid or other NSAIDs, including other COX-2 inhibitors;

• condition after coronary artery bypass grafting;

• peptic ulcer in the acute phase;

• gastrointestinal bleeding;

• inflammatory bowel disease;

• heart failure (NYHA functional classes II-IV);

• clinically confirmed coronary artery disease;

• peripheral arterial disease and severe cerebrovascular disease;

• severe hepatic impairment (no experience with use);

• severe renal failure (no experience with use);

• pregnancy;

• lactation period (breastfeeding);

• children and adolescents up to 18 years of age (no experience of use);

• hypersensitivity to drug components;

• hypersensitivity to sulfonamides.

The drug should be used with caution in gastrointestinal diseases (peptic ulcer, history of bleeding), Helicobacter pylori infection, fluid retention and edema, moderate liver dysfunction, diseases of the cardiovascular system, cerebrovascular diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, with diseases of peripheral arteries, severe somatic diseases; simultaneously with anticoagulants (including with warfarin), with antiplatelet agents (including with acetylsalicylic acid, clopidogrel), oral corticosteroids (including with prednisolone), with selective serotonin reuptake inhibitors (citalopram , fluoxetine, paroxetine, sertraline), with inhibitors of the CYP2C9 isoenzyme; in patients receiving long-term NSAIDs; in patientswhich are slow metabolizers or there is a suspicion of such a condition.

pharmachologic effect

NSAIDs. Celecoxib has anti-inflammatory, analgesic and antipyretic effects, blocking the formation of inflammatory prostaglandins mainly by inhibiting COX-2. The induction of COX-2 occurs in response to the inflammatory process and leads to the synthesis and accumulation of prostaglandins, especially prostaglandin E2, with an increase in the manifestations of inflammation (edema 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, and also does not affect normal physiological processes associated with COX-1 and occurring in tissues, and above all in the tissues of the stomach, intestines and platelets.

Effects on renal function. Celecoxib reduces urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1 (prostacyclin metabolite), but does not affect serum thromboxane B2 and 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 patients with chronic renal failure, transiently reduces sodium excretion. In patients with arthritis, the observed incidence of peripheral edema, arterial hypertension and heart failure is comparable to that of non-selective COX inhibitors, which have inhibitory activity against COX-1 and COX-2. This effect was most pronounced in patients receiving diuretic therapy. Nonetheless,there was no increase in the incidence of increased blood pressure and the development of heart failure, and peripheral edema was mild and resolved on its own.

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, Cmax in plasma is 705 ng / ml. The 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 in higher doses, the degree of increase in Cmax and AUC is less proportional.

Effect of food intake: Taking celecoxib with fatty foods increases the time to reach Cmax by about 1-2 hours and increases total absorption by about 20%.

Distribution

Plasma protein binding is concentration-independent and is about 97%; celecoxib does not bind to red blood cells. Penetrates the BBB.

The mean steady state Vd is approximately 500 L / 70 kg in young healthy adult patients, indicating a wide tissue distribution of celecoxib.

Metabolism

Celecoxib is metabolized in the liver by hydroxylation, oxidation and, in part, glucuronization. Metabolism mainly occurs with the participation of the isoenzyme CYP2C9. The metabolites found in the blood are pharmacologically inactive against COX-1 and COX-2.

The activity of the isoenzyme CYP2C9 is reduced in individuals with genetic polymorphisms, such as polymorphisms homozygous for CYP2C9 * 3, which leads to a decrease in enzymatic activity.

Withdrawal

Celecoxib is metabolized in the liver, excreted in feces and urine as metabolites (57% and 27%, respectively), less than 3% of the dose taken - unchanged. With repeated use, T1 / 2 is 8-12 hours, and the clearance is about 500 ml / min. With repeated use of Css in plasma, it is reached by 5 days.

The variability of the main pharmacokinetic parameters (AUC, Cmax, T1 / 2) is about 30%.

Pharmacokinetics in special clinical situations

In patients over 65 years of age, there is an increase of 1.5-2 times in the average values ??of Cmax and AUC of celecoxib, which is largely due to changes in body weight, not age (elderly patients, as a rule, have a lower average body weight than individuals younger age, so they have, other things being equal, higher concentrations of celecoxib are achieved). 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 weighing less than 50 kg, treatment should be started at the lowest recommended dose.

In a representative Negroid race, the AUC of celecoxib is approximately 40% higher than that of Europeans. The reasons and clinical significance of this fact are not known, therefore, their treatment is recommended to start with the minimum recommended dose.

Liver dysfunction. Plasma concentrations of celecoxib in patients with mild hepatic impairment (class A on the Child-Pugh scale) do not change significantly. In patients with moderate hepatic impairment (class B on the Child-Pugh scale), the plasma concentration of celecoxib can be increased by almost 2 times.

Impaired renal function. In patients with chronic renal failure with a GFR> 65 ml / min / 1.73 m2 and in patients with a GFR of 35-60 ml / min / 1.73 m2, the pharmacokinetics of celecoxib does not change. No significant association was found between serum creatinine (or CC) 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 excretion is conversion into inactive metabolites in the liver.

Side effect

General reactions: exacerbation of allergic diseases, flu-like syndrome, accidental injuries.

From the side of the cardiovascular system: peripheral edema.

From the digestive system: abdominal pain, diarrhea, dyspepsia, flatulence, dental disease (postextraction alveolitis).

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

From the urinary system: urinary tract infection.

From the respiratory system: bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections.

On the part of the skin: itching, skin rash.

General reactions: swelling of the face.

From the hematopoietic system: anemia, ecchymosis, thrombocytopenia.

From the side of the cardiovascular system: aggravation of the course of arterial hypertension, increased blood pressure, arrhythmia, hot flashes, palpitations, tachycardia.

From the senses: tinnitus, blurred vision.

From the digestive system: vomiting.

From the nervous system: anxiety, drowsiness.

On the part of the skin: alopecia, urticaria.

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

From the digestive system: stomach and duodenal ulcers, ulceration of the esophagus, intestinal perforation, pancreatitis, increased activity of liver enzymes.

Allergic reactions: angioedema, bullous rash.

From the nervous system: confusion.

Adverse reactions identified during post-marketing observations

Allergic reactions: anaphylaxis.

From the nervous system: hallucinations, aseptic meningitis.

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

From the side of the cardiovascular system: vasculitis, cerebral hemorrhage.

From the digestive system: gastrointestinal bleeding, hepatitis, liver failure, fulminant hepatitis, liver necrosis, cholestasis, cholestatic hepatitis, jaundice.

From 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.

Reproductive system disorders: menstrual irregularities, decreased fertility in women.

From the respiratory system: pulmonary embolism.

Others: hyponatremia, chest pain.

Application during pregnancy and lactation

Clinical experience with celecoxib in pregnancy is limited. The potential risk of using CelebrexЃ during pregnancy has not been established, but cannot be excluded.

In accordance with the mechanism of action, with the use of NSAIDs, including celecoxib, some women may develop changes in the ovaries, which can cause complications during pregnancy. In women who are planning a pregnancy or undergoing testing for infertility, consideration should be given to discontinuing NSAIDs, including celecoxib.

Celecoxib, which belongs to the group of inhibitors of prostaglandin synthesis, when taken during pregnancy, especially in the third trimester, can cause weakness of uterine contractions and premature closure of the ductus arteriosus. The use of inhibitors of prostaglandin synthesis at an early stage of pregnancy can negatively 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. However, given the potential for side effects from celecoxib in a nursing infant, the feasibility of discontinuing either breastfeeding or celecoxib should be evaluated, given the importance of taking CelebrexЃ for the mother.

Application for violations of liver function

Contraindicated in severe liver dysfunction.

Application for impaired renal function

Contraindicated in severe renal impairment.

Application in children

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

special instructions

CelebrexЃ, given its antipyretic effect, can reduce the diagnostic significance of a symptom such as fever and affect the diagnosis of infection.

Effects on the cardiovascular system. Celecoxib (like all coxibs) can increase the risk of serious cardiovascular complications such as blood clots, myocardial infarction and stroke, which can lead to death. The risk of these reactions may increase with the duration of the drug intake, as well as in patients with diseases of the cardiovascular system. To reduce the risk of these reactions in patients taking CelebrexЃ, it should be prescribed in the lowest recommended doses and for the shortest possible periods. The attending physician and patient should be aware of the possibility of such complications even in the absence of previously known cardiovascular symptoms. Patients should be informed about the signs and symptoms of negative effects on the cardiovascular system and about the measuresto take if they occur.

When using NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass grafting for the treatment of pain in the first 10-14 days, an increase in the frequency 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 canceled in patients at risk of developing thromboembolic complications.

Like other NSAIDs, celecoxib can lead to an increase in blood pressure, which increases the risk of complications from the cardiovascular system. In patients with arterial hypertension, all NSAIDs, incl. and celecoxib should be used with caution. It is necessary to regularly monitor blood pressure at the beginning of therapy with celecoxib, as well as during the course of treatment.

Effect on the gastrointestinal tract. Very rare cases of perforation, ulceration, and bleeding from the gastrointestinal tract were observed in patients taking celecoxib. The risk of developing these complications in the treatment of NSAIDs is highest in elderly patients, patients with cardiovascular diseases, in patients simultaneously receiving acetylsalicylic acid, and in patients with ulcerative lesions of the gastrointestinal tract, inflammatory diseases in the acute phase and in history. Other risk factors for the development of bleeding from the gastrointestinal tract are the simultaneous use with oral corticosteroids and anticoagulants, a long period of NSAID therapy, smoking, alcohol consumption. Most of the spontaneous reports of serious gastrointestinal side effects were in elderly and debilitated patients.

Combined use with warfarin and other anticoagulants. Serious, and some fatal, bleeding has been reported in patients receiving concomitant treatment with warfarin or similar agents. Since an increase in prothrombin time has been reported, anticoagulant activity must be monitored after starting treatment with CelebrexЃ or changing its dose.

«адержка жидкости и отеки.  ак и при применении других лекарственных средств, ингибирующих синтез простагландинов, у р¤да пациентов, принимающих ?елебрексЃ, могут отмечатьс¤ задержка жидкости и отеки, поэтому следует соблюдать осторожность при назначении данного препарата пациентам с состо¤ни¤ми, предрасполагающими или ухудшающимис¤ из-за задержки жидкости. ѕациенты с сердечной недостаточностью в анамнезе или артериальной гипертензией должны находитьс¤ под тщательным наблюдением.

¬ли¤ние на функцию почек. Ќѕ¬—, в т.ч. и целекоксиб, могут оказывать токсическое действие на функцию почек. Ѕыло установлено, что целекоксиб не обладает большей токсичностью по сравнению с другими Ќѕ¬—. ?елебрексЃ следует примен¤ть с осторожностью у пациентов с нарушением функции почек, с сердечной недостаточностью, нарушением функции печени и у пациентов пожилого возраста. ‘ункцию почек у таких пациентов следует тщательно контролировать.

—ледует с осторожностью назначать ?елебрексЃ пациентам с дегидратацией. ¬ таких случа¤х целесообразно сначала провести регидратацию, а затем начинать терапию препаратом ?елебрексЃ.

¬ли¤ние на функцию печени. ?елебрексЃ следует примен¤ть с осторожностью при лечении пациентов с печеночной недостаточностью средней т¤жести и назначать в наименьшей рекомендованной дозе. ¬ некоторых случа¤х наблюдались т¤желые реакции со стороны печени, включа¤ фульминантный гепатит (иногда с летальным исходом), некроз печени (иногда с летальным исходом или необходимостью трансплантации печени). Ѕольшинство из этих реакций развивались через 1 мес¤ц после начала приема целекоксиба. ѕациентам с симптомами нарушени¤ функции печени, или в случае вы¤влени¤ нарушени¤ функции печени лабораторными методами, требуетс¤ тщательное наблюдение дл¤ своевременной диагностики более т¤желых реакций со стороны печени во врем¤ лечени¤ препаратом ?елебрексЃ.

јнафилактические реакции. ѕри приеме препарата ?елебрексЃ были зарегистрированы случаи анафилактических реакций.

—ерьезные реакции со стороны кожных покровов.  райне редко при приеме целекоксиба отмечались серьезные реакции со стороны кожных покровов, такие как эксфолиативный дерматит, синдром —тивенса-?жонсона и токсический эпидермальный некролиз, некоторые из них с летальным исходом. Ѕолее высок риск по¤влени¤ таких реакций у пациентов в начале терапии, в большинстве отмеченных случаев такие реакции начинались в первый мес¤ц терапии. —ледует прекратить прием препарата ?елебрексЃ при по¤влении кожной сыпи, изменений на слизистых оболочках или других признаков повышенной чувствительности.

“ерапи¤ v —. ?елебрексЃ не может заменить v — или примен¤тьс¤ в качестве терапии глюкокортикоидной недостаточности.

¬ли¤ние на способность к вождению автотранспорта и управлению механизмами

¬ли¤ние целекоксиба на способность к вождению транспортных средств и управлению механизмами не исследовалось. ќсновыва¤сь на фармакодинамических свойствах и общем профиле безопасности, представл¤етс¤ маловеро¤тным, что ?елебрексЃ оказывает такое вли¤ние.

ѕередозировка

 линический опыт передозировки ограничен. Ќе наблюдалось клинически значимых побочных эффектов при однократном приеме препарата в дозе до 1.2 г и многократном приеме в дозах до 1.2 мг/сут в 2 приема.

Ћечение: при подозрении на передозировку необходимо обеспечить проведение соответствующей поддерживающей терапии. ѕредположительно диализ не ¤вл¤етс¤ эффективным методом выведени¤ целекоксиба из крови, из-за высокой степени его св¤зывани¤ с белками плазмы.

Ћекарственное взаимодействие

»сследовани¤ in vitro показали, что целекоксиб хот¤ и не ¤вл¤етс¤ субстратом CYP2D6, но ингибирует его активность. ѕоэтому существует веро¤тность лекарственного взаимодействи¤ in vivo с препаратами, метаболизм которых св¤зан с цитохромом CYP2D6.

ѕри одновременном приеме с варфарином и другими антикоагул¤нтами возможно увеличение протромбинового времени.

ѕри одновременном применении флуконазола в дозе 200 мг 1 раз/сут отмечаетс¤ увеличение концентрации целекоксиба в плазме крови в 2 раза. “акой эффект св¤зан с угнетением метаболизма целекоксиба флуконазолом через изофермент CYP2C9. ѕациентам, принимающим флуконазол (ингибитор CYP2C9), целекоксиб следует назначать в наименьшей рекомендованной дозе.  етоконазол (ингибитор изофермента CYP3A4) не оказывает клинически значимого эффекта на метаболизм целекоксиба.

»нгибирование синтеза простагландинов может уменьшить эффект ингибиторов јѕ‘ и антагонистов ангиотензина II. Ёто взаимодействие следует принимать во внимание при назначении целекоксиба совместно с ингибиторами јѕ‘/антагонистами ангиотензина II. ќднако не отмечалось значительного фармакодинамического взаимодействи¤ с лизиноприлом в отношении вли¤ни¤ на ј?.

” пациентов пожилого возраста, у пациентов с обезвоживанием (в т.ч. получающих терапию диуретиками) или у пациентов с нарушением функции почек одновременное применение Ќѕ¬—, включа¤ селективные ингибиторы ?ќv-2, с ингибиторами јѕ‘ может приводить к ухудшению функции почек, включа¤ возможную острую почечную недостаточность. ќбычно данные эффекты обратимы.

»звестные ранее Ќѕ¬— у некоторых пациентов могут снижать натрийуретический эффект фуросемида и тиазидов за счет ингибировани¤ почечного синтеза простагландинов, это следует иметь в виду при назначении целекоксиба.

Ќе отмечалось клинически значимого вли¤ни¤ целекоксиба на фармакокинетику комбинированных контрацептивных препаратов, содержащих 1 мг норэтистерона/35 мкг этинилэстрадиола.

ќтмечалось повышение концентрации лити¤ в плазме примерно на 17% при совместном приеме лити¤ и целекоксиба. ѕациенты, получающие терапию литием, должны быть под тщательным наблюдением при назначении или отмене целекоксиба.

Ќе отмечалось клинически значимого взаимодействи¤ между целекоксибом и антацидами (алюминий- и магнийсодержащие препараты), омепразолом, метотрексатом, глибенкламидом, фенитоином или толбутамидом.

Celecoxib does not affect the antiplatelet effect of acetylsalicylic acid taken in low doses. Celecoxib has a weak effect on platelet function, therefore, it cannot be considered as a substitute for acetylsalicylic acid, which is prescribed for the prevention of cardiovascular diseases.

Avoid the simultaneous use of celecoxib with other NSAIDs (not containing acetylsalicylic acid).