Celebrex capsules 200 mg blister No. 20

Instructions Celebrex capsules 200 mg blister No. 20

Composition

active ingredient: celecoxib;

1 capsule contains 200 mg of celecoxib;

Excipients: lactose monohydrate; sodium lauryl sulfate; povidone; croscarmellose sodium; magnesium stearate; gelatin; titanium dioxide (E 171); shellac; anhydrous ethanol; isopropyl alcohol; butyl alcohol; propylene glycol; concentrated ammonia solution; iron oxide yellow (E 172).

Dosage form

Capsules.

Main physicochemical properties: hard gelatin capsules (containing white to off-white granules). White opaque body with a gold stripe containing white “200”; white opaque cap with a gold stripe containing white “7767”. Each gold stripe almost, but not completely outlines the capsule.

Pharmacotherapeutic group

Anti-inflammatory and antirheumatic agents. Coxibs. ATX code M01A H01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action. Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Celebrex® is thought to be related to inhibition of prostaglandin synthesis, primarily through inhibition of cyclooxygenase-2 (COX2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations achieved during therapy produced effects in vivo.

Prostaglandins increase the sensitivity of afferent nerves and enhance the action of bradykinin, stimulating pain, in animal models. Prostaglandins are mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mechanism of action may be due to a decrease in prostaglandin levels in peripheral tissues.

Pharmacodynamic properties.

- Platelets. In clinical studies in healthy volunteers, single doses of Celebrex® up to 800 mg and multiple doses of Celebrex® up to 600 mg twice daily for up to 7 days (which exceeds the recommended therapeutic doses) did not reduce platelet aggregation or prolong clotting time. Due to the lack of effect on platelets, Celebrex® cannot be used as a substitute for aspirin for the prevention of cardiovascular diseases. It is not known whether Celebrex® affects platelets in terms of increasing the risk of serious cardiovascular thrombotic adverse reactions associated with Celebrex®.

- Fluid retention. Inhibition of prostaglandin E2 (PGE2) synthesis may lead to sodium and water retention by increasing reabsorption in the thick ascending limb of the loop of Henle in the renal medulla and possibly in other segments of the distal nephron. PGE2 is thought to inhibit water reabsorption in the collecting tubules by interfering with the action of antidiuretic hormone.

Pharmacokinetics.

Celecoxib exposure increases approximately dose-proportionally after administration of 200 mg twice daily; at higher doses, a less proportional increase is observed. The drug is widely distributed and highly protein bound. Celecoxib is metabolized primarily by CYP2C9 with a half-life of approximately 11 hours.

Absorption. Peak plasma levels of celecoxib are achieved approximately 3 hours after oral administration. When administered in the fasted state at doses up to 200 mg twice daily, both maximum plasma levels (Cmax) and area under the pharmacokinetic curve (AUC) are approximately dose-proportional; at higher doses, Cmax and AUC increase sublinearly (see below, “Effect of food intake”). Absolute bioavailability studies have not been conducted. Steady state is reached on or before the fifth day of multiple dosing. The pharmacokinetic parameters of celecoxib in healthy volunteers are shown in Table 1.

Table 1.

Distribution kinetics of a single dose (200 mg) of celecoxib in healthy volunteers1.

Vss/F – volume of distribution at steady state.

CL/F – plasma clearance.

- Effect of food. When Celebrex® capsules are administered with a high-fat meal, peak plasma levels are delayed by approximately 1–2 hours with an increase in total absorption (AUC) of 10% to 20%. When administered in the fasted state at doses above 200 mg, there is a sublinear increase in Cmax and AUC, which is associated with the low solubility of the drug in aqueous media.

In healthy adult volunteers, the total systemic exposure (AUC) of celecoxib was not different between oral administration of the capsule and dilution of the capsule contents in applesauce. No significant changes in Cmax, Tmax, or t1/2 were observed after administration of the capsule contents with applesauce (see Dosage and Administration).

Distribution: Celecoxib is almost completely protein bound (approximately 97%) in healthy volunteers at the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and to a lesser extent to α1-acid glycoprotein. The apparent volume of distribution at steady state is approximately 400 L, indicating extensive tissue distribution. Celecoxib does not show preferential binding to erythrocytes.

Breeding.

- Metabolism. Celecoxib is primarily metabolized by CYP2C9. Three metabolites have been identified in human plasma: the primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate. These metabolites have no activity against COX-1 or COX-2.

- Excretion. Celecoxib is eliminated primarily by hepatic metabolism, with only a small amount (less than 3%) of unchanged drug excreted in the urine and feces. After a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% in the urine. The major metabolite in the urine and feces was the carboxylic acid (73% of the dose), with a small amount of the glucuronide also being recovered in the urine. The low solubility of the drug is thought to prolong the absorption process, making the elimination half-life (t1/2) more variable. The effective elimination half-life is approximately 11 hours under fasting conditions. Plasma clearance is approximately 500 mL/min.

Certain groups of patients.

- Elderly patients. In elderly patients (over 65 years of age), steady-state Cmax was 40% higher and AUC was 50% higher compared to younger patients. In elderly women, Cmax and AUC of celecoxib are higher than in elderly men, but this increase is mainly due to the lower body weight of women. In general, no dose adjustment is required in elderly patients. However, in patients weighing less than 50 kg, treatment should be initiated at the lowest recommended dose (see section 4.2).

- Children. In a clinical study, the steady-state pharmacokinetics of celecoxib in an experimental oral suspension formulation were evaluated in 152 patients with juvenile rheumatoid arthritis aged 2 to 17 years and weighing ≥ 10 kg with single or multiple joint involvement or systemic manifestations of juvenile rheumatoid arthritis. A population pharmacokinetic analysis showed that oral clearance (not adjusted for body weight) of celecoxib increased less than proportionally with increasing body weight, with clearance predicted to be 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared to an adult patient with rheumatoid arthritis weighing 70 kg.

Administration of celecoxib capsules 50 mg twice daily to patients with juvenile rheumatoid arthritis weighing ≥ 12 and ≤ 25 kg and 100 mg capsules to patients with juvenile rheumatoid arthritis weighing > 25 kg should provide similar plasma celecoxib concentrations to those observed in a clinical trial that demonstrated non-inferiority of celecoxib to naproxen 7.5 mg/kg twice daily (see Dosage and Administration). Celecoxib has not been studied in patients with juvenile rheumatoid arthritis younger than 2 years of age or weighing less than 10 kg, and no studies longer than 24 weeks in duration have been conducted.

- Race. A meta-analysis of pharmacokinetic studies suggested that the AUC of celecoxib in blacks was 40% higher than in whites. The explanation and clinical significance of these findings are unknown.

- Hepatic impairment. A pharmacokinetic study in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment showed that the AUC of celecoxib at steady state was increased by approximately 40% and 180%, respectively, compared to that in healthy control subjects. Therefore, the recommended daily dose of Celebrex® capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment.

- Renal impairment. In a cross-sectional study, the AUC of celecoxib in patients with chronic renal failure (glomerular filtration rate 35-60 mL/min) was approximately 40% lower than in patients with normal renal function. There was no significant relationship between glomerular filtration rate and celecoxib clearance.

Drug interaction studies.

- Aspirin. When NSAIDs were used with aspirin, the degree of their protein binding was reduced, although the clearance of the unbound form of the NSAID was not changed. The clinical significance of this interaction is unknown. For clinically significant interactions of NSAIDs with aspirin, see section "Interaction with other medicinal products and other forms of interaction".

- Lithium: In a study in healthy volunteers, mean steady-state plasma lithium levels were increased by approximately 17% in patients receiving 450 mg of lithium twice daily in combination with Celebrex 200 mg twice daily compared to lithium alone (see Interactions).

- Fluconazole. Concomitant administration of fluconazole 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentrations. This increase is due to inhibition of celecoxib metabolism by fluconazole, which is mediated by the P450 2C9 isoenzyme (see section 4.5).

- Other medicinal products. In vivo studies have been conducted to investigate the effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate (see section 4.5), phenytoin and tolbutamide, but no clinically significant interactions have been identified.

Pharmacogenomics: In selected patients with genetic polymorphisms (CYP2C9*2 homozygosity and CYP2C9*3 polymorphism), there is a decrease in CYP2C9 activity, resulting in reduced enzymatic activity. Limited data published in four reports, which included a total of 8 patients homozygous for CYP2C9*3/*3, showed that in these patients systemic levels of celecoxib were 3-7 times higher compared to patients with the CYP2C9*1/*1 and *I/*3 genotypes. The pharmacokinetics of celecoxib in patients with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11, have not been evaluated. The frequency of homozygous *3/*3 genotype is estimated to be 0.3% to 1.0% across ethnic groups (see section 4.2).

A double-blind, randomized, controlled trial (PRECISION; NCT00346216) of comprehensive cardiovascular safety in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) with or at high risk of cardiovascular disease compared celecoxib with naproxen and ibuprofen. Patients were randomized to receive a starting dose of 100 mg celecoxib twice daily, 600 mg ibuprofen three times daily, or 375 mg naproxen twice daily, with the option to increase the dose as needed for pain management.

To assess non-inferiority (80%) by the Antiplatelet Trialists' Collaboration (APTC), a primary composite endpoint was defined by the Antiplatelet Trialists' Collaboration (APTC) as the composite endpoint of cardiovascular death (including bleeding), nonfatal myocardial infarction, and nonfatal stroke. All patients received open-label esomeprazole (20–40 mg) as a gastroprotector. Randomization to treatment groups was stratified by baseline low-dose aspirin use.

An additional 4-month study (PRECISION-ABPM) was conducted to evaluate the effects of the three above-mentioned drugs on blood pressure measured during ambulatory monitoring.

Celecoxib 100 mg twice daily compared with naproxen or ibuprofen at the respective doses met the prespecified criteria for non-inferiority (p < 0.001 for non-inferiority in both comparisons) for the above composite endpoint as defined by the APTC.

In the analysis of the patient population with assigned treatment for 30 months, all-cause mortality was 1.6% in the celecoxib group, 1.8% in the ibuprofen group, and 2.0% in the naproxen group.

Because the increase in the dose of celecoxib to 200 mg twice daily occurred in a relatively small proportion of the total number of patients taking celecoxib (5.8%), the results of the PRECISION study are not suitable for determining the relative cardiovascular safety of celecoxib 200 mg twice daily compared with ibuprofen and naproxen at corresponding doses.

In the additional PRECISION-ABPM study in 444 patients, celecoxib 100 mg twice daily reduced mean daily systolic blood pressure by 0.3 mmHg at month 4, whereas ibuprofen and naproxen at the corresponding doses increased mean daily systolic blood pressure by 3.7 and 1.6 mmHg, respectively. These changes demonstrated a statistically and clinically significant difference of 3.9 mmHg (p = 0.0009) between celecoxib and ibuprofen and a statistically insignificant difference of 1.8 (p = 0.119) mmHg between celecoxib and naproxen.

Indication

For the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis (see section "Special instructions").

For the treatment of acute pain in adult patients (see section "Special instructions").

For the treatment of primary dysmenorrhea (see section "Special instructions").

Contraindication

- with known hypersensitivity (e.g. anaphylactic reactions and serious skin reactions) to celecoxib or to any of the components of the medicinal product (see section "Special warnings and precautions for use");

- with a history of bronchial asthma, urticaria or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see section "Special warnings and precautions for use");

- after coronary artery bypass graft surgery (see section "Special instructions for use");

- in whom allergic-type reactions to sulfonamide drugs have been recorded (see section "Special instructions for use");

- with established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease;

- with active peptic ulcer or gastrointestinal bleeding;

- with estimated creatinine clearance < 30 ml/min;

- with congestive heart failure (class II–IV according to the NYHA classification);

- with severe liver dysfunction (serum albumin < 25 g/l or Child-Pugh score ≥ 10).

Interaction with other medicinal products and other types of interactions

Medicinal products affecting haemostasis. Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. Concomitant use of celecoxib and anticoagulants increases the risk of serious bleeding compared to the use of either drug alone.

Serotonin, released by platelets, plays an important role in hemostasis. Case-control and cohort epidemiological studies have shown that the concomitant use of serotonin reuptake inhibitors and NSAIDs increases the risk of bleeding more than the use of NSAIDs alone.

Patients taking Celebrex and anticoagulants (e.g. warfarin), antiplatelet agents (e.g. aspirin), selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors should be monitored for bleeding (see section 4.4).

Aspirin: Controlled clinical trials have shown that concomitant use of NSAIDs and aspirin at an analgesic dose does not provide any greater therapeutic benefit than the use of the NSAIDs alone. In a clinical trial, concomitant use of NSAIDs and aspirin was associated with a significantly increased incidence of gastrointestinal adverse reactions compared with the use of the NSAIDs alone (see section 4.4).

In two studies involving healthy volunteers and patients with osteoarthritis and chronic heart disease, respectively, it was demonstrated that celecoxib (at a dose of 200–400 mg/day) did not affect the cardioprotective antiplatelet effect of aspirin (at a dose of 100–325 mg).

Celebrex® and aspirin at analgesic doses are generally not recommended together due to the increased risk of bleeding (see section "Special warnings and precautions for use"). Celebrex® should not be used in place of low-dose aspirin for the prevention of cardiovascular disease.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and β-blockers: NSAIDs may reduce the hypotensive effect of ACE inhibitors, angiotensin receptor blockers or β-blockers (including propranolol).

Concomitant use of NSAIDs with ACE inhibitors or angiotensin receptor blockers in elderly patients, in patients who are dehydrated (including those treated with diuretics), or in patients with impaired renal function may lead to worsening of renal function, including acute renal failure. These effects are usually reversible.

When Celebrex® is used concomitantly with ACE inhibitors, angiotensin receptor blockers, or β-blockers, blood pressure should be monitored to ensure that the desired blood pressure level is achieved.

When Celebrex® is used concomitantly with ACE inhibitors or angiotensin receptor blockers in elderly patients and in those with dehydration or impaired renal function, monitoring for signs of worsening renal function should be performed (see section "Special warnings and precautions for use").

Patients should be adequately hydrated during concomitant use of these drugs. Renal function should be assessed at the beginning of concomitant use of these drugs and periodically thereafter.

Diuretics: Clinical studies and post-marketing experience have shown that NSAIDs may reduce the natriuretic effect of loop diuretics (e.g. furosemide) and thiazide diuretics in some patients. This effect is due to the inhibition of prostaglandin synthesis in the kidney by NSAIDs.

Digoxin: Concomitant use of celecoxib with digoxin has been reported to increase serum digoxin concentrations and prolong its half-life.

In case of simultaneous use of Celebrex® with digoxin, serum digoxin levels should be monitored.

Lithium: NSAIDs have been shown to increase plasma lithium levels and decrease renal lithium clearance. Mean trough lithium concentrations were increased by 15% and renal clearance was decreased by approximately 20%. This effect is thought to be due to inhibition of prostaglandin synthesis in the kidney by NSAIDs.

When Celebrex® is used concomitantly with lithium preparations, patients should be monitored for signs of lithium toxicity.

Methotrexate: Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g. neutropenia, thrombocytopenia, renal impairment).

Celebrex® does not affect the pharmacokinetics of methotrexate.

During concomitant use of Celebrex® with methotrexate, patients should be monitored for methotrexate toxicity.

Cyclosporine. Concomitant use of Celebrex® with cyclosporine may increase the nephrotoxicity of the latter.

During concomitant use of Celebrex® with cyclosporine, patients should be monitored for signs of worsening renal function.

NSAIDs and salicylates: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g. diflunisal and salsalate) increases the risk of gastrointestinal toxicity with little or no increase in efficacy (see section 4.4).

Concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.

Pemetrexed: Concomitant use of Celebrex® and pemetrexed may increase the risk of pemetrexed-related myelosuppression and renal and gastrointestinal toxicity (see pemetrexed Summary of Product Characteristics).

When Celebrex® and pemetrexed are used concomitantly in patients with renal impairment with creatinine clearance ranging from 45 to 79 mL/min, they should be monitored for signs of myelosuppression and renal and gastrointestinal toxicity.

NSAIDs with a short half-life (such as diclofenac and indomethacin) should be avoided for two days before and after, and on the day of pemetrexed administration.

In the absence of data on the potential interaction between pemetrexed and NSAIDs with a longer half-life (such as meloxicam and nabumetone), patients taking these NSAIDs should discontinue their use at least 5 days before, on the day of, and for 2 days after pemetrexed administration.

CYP2C9 inhibitors or inducers: Celecoxib metabolism is mediated primarily by the cytochrome P450 isoenzyme CYP2C9 in the liver. Concomitant use of celecoxib with drugs that are known inhibitors of CYP2C9 (e.g., fluconazole) may increase the exposure and toxicity of celecoxib, while concomitant use with CYP2C9 inducers (e.g., rifampin) may result in decreased efficacy of celecoxib.

When considering the use of celecoxib, the patient's medical history should be assessed. When celecoxib is used in combination with inhibitors or inducers of cytochrome CYP2C9, dose adjustment of this drug is justified (see section "Pharmacokinetics").

CYP2D6 Substrates: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for in vivo drug interactions with drugs metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may increase the exposure and toxicity of these drugs.

When considering the use of celecoxib, the patient's medical history should be assessed. When celecoxib is used in combination with CYP2D6 substrates, dose adjustment of this drug is warranted (see Pharmacokinetics).

Corticosteroids: Concomitant use of corticosteroids with Celebrex® may increase the risk of gastrointestinal ulcers or bleeding.

Patients receiving Celebrex and corticosteroids concomitantly should be monitored for signs of bleeding (see Precautions).

Application features

Cardiovascular thrombotic events. Clinical trials of several selective and non-selective COX-2 inhibitors of the NSAID class of drugs of up to 3 years duration have shown an increased risk of serious thrombotic adverse events, including myocardial infarction and stroke, which can be fatal. It is not possible to determine from the available data whether the risk of thrombotic cardiovascular events is similar for all NSAIDs. The relative increase in the incidence of serious thrombotic cardiovascular events compared to baseline, which is associated with the use of NSAIDs, occurs both in patients with known cardiovascular disease and risk factors for it and in patients without such diseases and factors. However, patients with known cardiovascular disease or risk factors for cardiovascular disease had an even higher absolute incidence of serious thrombotic cardiovascular events due to the increased incidence of these factors and conditions at baseline. In some observational studies, this increased risk of serious thrombotic cardiovascular events was found to be apparent as early as the first weeks of treatment. The increased risk of thrombotic cardiovascular events was most consistently observed at higher doses.

In the APC (celecoxib Adenoma Prevention) trial, an approximately three-fold increased risk of the composite endpoint (cardiovascular death, myocardial infarction, or stroke) was observed in the Celebrex® 400 mg twice daily and Celebrex® 200 mg twice daily treatment groups compared to placebo. This increased risk in both celecoxib treatment groups compared to placebo was primarily due to an increased incidence of myocardial infarction.

A randomized controlled clinical trial, “Prospective Randomized Comprehensive Safety Evaluation of Celecoxib versus Ibuprofen or Naproxen (PRECISION),” was conducted to compare the relative risk of cardiovascular thrombotic events associated with the COX-2 inhibitor celecoxib with that associated with the nonselective NSAIDs naproxen and ibuprofen. Celecoxib was non-inferior to naproxen and ibuprofen (see Pharmacodynamics).

To minimize the potential risk of cardiovascular adverse reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. Physicians and patients should be closely monitored for the development of such reactions throughout the course of treatment, even in the absence of a history of cardiovascular symptoms. Patients should be informed of the symptoms of serious cardiovascular adverse reactions and the measures to be taken if they occur.

There is no direct evidence that concomitant use of aspirin reduces the increased risk of serious thrombotic cardiovascular events associated with NSAID use. Concomitant use of aspirin and NSAIDs such as celecoxib increases the risk of serious gastrointestinal reactions (see section 4.4, sub-section Gastrointestinal bleeding, ulceration and perforation).

In the CLASS study, the Kaplan-Meier pooled estimates of peripheral edema at 9 months in patients treated with Celebrex® 400 mg twice daily (4 and 2 times the recommended doses for OA and RA, respectively), ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily were 4.5%, 6.9%, and 4.7%, respectively. In the CLASS study, the incidence of hypertension in patients treated with Celebrex®, ibuprofen, and diclofenac was 2.4%, 4.2%, and 2.5%, respectively.

Post-coronary artery bypass graft surgery: Two large controlled clinical trials of COX-2 selective NSAIDs for pain control in the first 10-14 days after coronary artery bypass grafting showed an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in coronary artery bypass grafting (see section 4.3).

Gastrointestinal bleeding, ulceration, and perforation. NSAIDs, including celecoxib, have been associated with serious gastrointestinal adverse reactions, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, and large intestine, which can be fatal. These serious adverse reactions, with or without prior symptoms, can occur at any time in patients taking Celebrex®. Only about 1 in 5 patients develop a serious upper gastrointestinal adverse reaction during NSAID treatment with a clinical presentation. Approximately 1% of patients treated for 3 to 6 months and approximately 2 to 4% of patients treated for 1 year experience upper gastrointestinal ulcers, serious bleeding, or perforation associated with NSAID use. However, even short-term NSAID therapy is associated with risk.

Risk factors for gastrointestinal bleeding, ulceration, and perforation. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who were taking NSAIDs had a more than 10-fold increased risk of gastrointestinal bleeding compared with patients without such risk factors. Other factors that increase the risk of gastrointestinal bleeding in patients taking NSAIDs include longer duration of NSAID treatment, concomitant use of oral corticosteroids, antiplatelet agents (e.g., aspirin), anticoagulants, or selective serotonin reuptake inhibitors, tobacco smoking, alcohol consumption, advanced age, and poor general health. Most post-marketing reports of fatal gastrointestinal adverse reactions have occurred in elderly or debilitated patients. In addition, patients with progressive liver disease and/or coagulopathy are at increased risk of developing gastrointestinal bleeding.

In the CLASS study, the incidence of complicated and symptomatic ulcers in all patients at 9 months was 0.78% and in the subgroup of patients taking low-dose acetylsalicylic acid it was 2.19%. In patients aged 65 years and older, the incidence was 1.40% at 9 months and 3.06% with concomitant acetylsalicylic acid.

Strategy to minimize gastrointestinal risks in patients taking NSAIDs:

- use the lowest effective dose of the drug for the shortest possible period;

- avoid using more than one NSAID at the same time;

- avoid use in high-risk patients unless the benefit is expected to outweigh the increased risk of bleeding. In such patients, as well as in patients with active gastrointestinal bleeding, alternative drugs to NSAIDs should be considered;

- constantly monitor for signs and symptoms of gastrointestinal ulceration and/or bleeding during NSAID therapy;

- if a serious gastrointestinal adverse reaction is suspected, immediate investigation and treatment should be initiated and Celebrex® should be discontinued until a serious gastrointestinal adverse reaction has been ruled out;

- when concomitantly using low-dose aspirin for the prevention of cardiovascular complications, patients should be monitored more closely for signs of gastrointestinal bleeding (see section "Interaction with other medicinal products and other types of interactions").

Hepatotoxicity: Elevations in alanine aminotransferase or aspartate aminotransferase (3 times or more above the upper limit of normal) have been reported in approximately 1% of patients treated with NSAIDs in clinical trials. In addition, rare, sometimes fatal cases of severe hepatic impairment, including fulminant hepatitis, hepatic necrosis, and hepatic failure, have been reported.

Elevations in alanine aminotransferase or aspartate aminotransferase (less than 3 times the upper limit of normal) may occur in up to 15% of patients taking NSAIDs, including celecoxib.

In controlled clinical trials of Celebrex®, the incidence of mild elevations (1.2 to less than 3 times the upper limit of normal) in liver enzyme levels was 6% in patients treated with Celebrex® and 5% in patients treated with placebo, compared with approximately 0.2% in patients treated with placebo.