Celebrex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CELEBREX® (CELEBREX®)

Composition:

Active substance: celecoxib;

1 capsule contains 200 mg of celecoxib;

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

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules (containing granules from white to almost white). Opaque white body with a golden band containing white "200"; opaque white cap with a golden band containing white "7767". Each golden band almost, but not completely, encircles the capsule.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Celebrex® is believed to be related to inhibition of prostaglandin synthesis, primarily by selective inhibition of cyclooxygenase-2 (COX-2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of celecoxib achieved during therapy have produced effects in vivo.

Prostaglandins increase the sensitivity of afferent nerves and enhance the action of bradykinin, thereby promoting pain in animal models. Prostaglandins are mediators of inflammation. Since celecoxib inhibits prostaglandin synthesis, its mechanism of action may be attributed to reduced prostaglandin levels in peripheral tissues.

Pharmacodynamic properties.

• Platelets. In clinical studies involving healthy volunteers, administration of Celebrex® at single doses up to 800 mg and multiple doses up to 600 mg twice daily for up to 7 days (doses exceeding the recommended therapeutic doses) did not affect platelet aggregation or prolong bleeding 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 unknown whether Celebrex® affects platelets with regard to increasing the risk of serious cardiovascular thrombotic adverse reactions associated with the use of Celebrex®.
• Fluid retention. Inhibition of prostaglandin E2 (PGE2) synthesis may lead to sodium and water retention due to increased reabsorption in the ascending thick limb of the loop of Henle in the renal medulla and possibly in other segments of the distal nephron. PGE2 is believed to inhibit water reabsorption in the collecting ducts by counteracting the action of antidiuretic hormone.

Pharmacokinetics.

Exposure to celecoxib increases approximately dose-proportionally after administration of 200 mg twice daily; at higher doses, exposure increases less than proportionally. The drug is characterized by extensive distribution and high plasma protein binding. Celecoxib is primarily metabolized by CYP2C9 with an elimination half-life of approximately 11 hours.

Absorption. Peak plasma concentrations of celecoxib are reached approximately 3 hours after oral administration. When administered on an empty stomach at doses up to 200 mg twice daily, both maximum plasma concentrations (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. With repeated administration, steady state is achieved by day 5 or earlier. Pharmacokinetic parameters of celecoxib in healthy volunteers are presented in Table 1.

Table 1.

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

Mean (coefficient of variation, %) values of pharmacokinetic parameters
Cmax, ng/mL	Tmax, h	Effective t1/2, h	Vss/F, L	CL/F, L/h
705 (38)	2.8 (37)	11.2 (31)	429 (34)	27.7 (28)
1 – volunteers after administration of the drug on an empty stomach (n=36, 19– 52 years)

Vss/F – volume of distribution at steady state.

CL/F – plasma clearance.

• Effect of food intake. When Celebrex® capsules were administered with a high-fat meal, peak plasma concentrations of the drug were delayed by approximately 1–2 hours, with an increase in total absorption (AUC) by 10% to 20%. When the drug was administered in fasting conditions at doses exceeding 200 mg, sublinear increases in Cmax and AUC were observed, which is attributed to the low aqueous solubility of the drug.

Concomitant administration of Celebrex® with antacids containing aluminum and magnesium resulted in reduced plasma concentrations of celecoxib, with a 37% decrease in Cmax and a 10% decrease in AUC. Celebrex® at doses up to 200 mg twice daily may be taken independently of food intake. For improved absorption, higher doses (400 mg twice daily) should be taken with food.

In healthy adult volunteers, the overall systemic exposure (AUC) to celecoxib did not differ between swallowing the capsule whole and dispersing its contents in applesauce. After administration of the capsule contents mixed with applesauce, no significant changes in Cmax, Tmax, or t1/2 were observed (see section "Dosage and administration").

Distribution. In healthy volunteers, following administration within the clinical dose range, celecoxib is almost completely bound to plasma proteins (approximately 97%). In vitro studies demonstrate 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 exhibit preferential binding to erythrocytes.

Elimination.

• Metabolism. Celecoxib is primarily metabolized via CYP2C9. Three metabolites have been identified in human plasma: the primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate. These metabolites do not exhibit inhibitory activity against COX-1 or COX-2.
• Excretion. Celecoxib is primarily eliminated through hepatic metabolism, with only a small amount (less than 3%) of unchanged drug excreted in urine and feces. After a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in feces and 27% in urine. The main metabolite in both urine and feces was the carboxylic acid (73% of dose), with a small amount of glucuronide also detected in urine. The low solubility of the drug is believed to prolong the absorption process, resulting in a more variable elimination half-life (t1/2). The effective elimination half-life is approximately 11 hours under fasting conditions. Plasma clearance is about 500 mL/min.

Special patient populations.

• 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 primarily due to lower body weight in women. Overall, dose adjustment in elderly patients is not generally required. However, in patients with body weight less than 50 kg, treatment should be initiated at the lowest recommended dose (see section "Dosage and administration").
• Children. A clinical study in 152 patients aged 2 to 17 years with juvenile rheumatoid arthritis, body weight ≥ 10 kg, and involvement of one or more joints or systemic manifestations of juvenile rheumatoid arthritis evaluated steady-state pharmacokinetics after administration of celecoxib in an experimental oral suspension formulation. Population pharmacokinetic analysis showed that oral clearance (not corrected for body weight) of celecoxib increases less than proportionally with increasing body weight. It was predicted that clearance in patients with body weights of 10 kg and 25 kg would be 40% and 24% lower, respectively, compared to that in an adult rheumatoid arthritis patient weighing 70 kg.

Administration of 50 mg celecoxib capsules twice daily to juvenile rheumatoid arthritis patients with body weight ≥ 12 to ≤ 25 kg, and 100 mg capsules to patients with body weight > 25 kg, is expected to achieve plasma celecoxib concentrations similar to those observed in a clinical study demonstrating non-inferior efficacy of celecoxib compared to naproxen at 7.5 mg/kg twice daily (see section "Dosage and administration"). Studies of celecoxib use in juvenile rheumatoid arthritis patients under 2 years of age or with body weight less than 10 kg have not been conducted, nor have studies longer than 24 weeks.

• Racial differences. Based on a meta-analysis of pharmacokinetic studies, it was hypothesized that AUC of celecoxib in Black individuals is approximately 40% higher than in Caucasian individuals. 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 steady-state AUC of celecoxib increased by approximately 40% and 180%, respectively, compared to healthy control volunteers. Therefore, the recommended daily dose of Celebrex® capsules should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh class B).
• Renal impairment. Cross-study comparisons indicate that AUC of celecoxib in patients with chronic renal insufficiency (glomerular filtration rate 35–60 mL/min) was approximately 40% lower than in patients with normal renal function. No significant correlation between glomerular filtration rate and celecoxib clearance was observed.

Drug interaction studies.

In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19, or 3A4. In vivo studies have shown:

• Aspirin. When NSAIDs are co-administered with aspirin, the degree of protein binding of NSAIDs decreases, although the clearance of the unbound form of NSAIDs remains unchanged. The clinical significance of this interaction is unknown. For clinically significant NSAID-aspirin interactions, see section "Interactions with other medicinal products and other forms of interactions".
• Lithium-containing medications. In a study involving healthy volunteers, mean steady-state plasma lithium levels increased by approximately 17% in patients receiving 450 mg lithium twice daily in combination with Celebrex® 200 mg twice daily, compared to those receiving lithium alone (see section "Interactions with other medicinal products and other forms of interactions").
• Fluconazole. Concomitant administration of fluconazole 200 mg once daily resulted in a doubling of celecoxib plasma concentration. This increase is due to fluconazole's inhibition of celecoxib metabolism mediated by the CYP2C9 isoenzyme (see section "Interactions with other medicinal products and other forms of interactions").
• Other medicinal products. In vivo studies have been conducted on the effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate (see section "Interactions with other medicinal products and other forms of interactions"), phenytoin, and tolbutamide, but no clinically significant interactions were observed.

Pharmacogenomics. In some patients with genetic polymorphisms (homozygosity for CYP2C9*2 and CYP2C9*3 polymorphism), reduced CYP2C9 activity and enzymatic activity are observed. Limited data from four reports, including a total of 8 patients homozygous for CYP2C9*3/*3, showed that systemic celecoxib levels in these patients were 3–7 times higher than in patients with CYP2C9*1/*1 and *1/*3 genotypes. The pharmacokinetics of celecoxib in patients with other CYP2C9 polymorphisms such as *2, *5, *6, *9, and *11 have not been evaluated. It is estimated that the frequency of the homozygous *3/*3 genotype ranges from 0.3% to 1.0% across different ethnic groups (see section "Dosage and administration").

In a double-blind, randomized, controlled cardiovascular safety trial (PRECISION; NCT00346216) in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) with established cardiovascular disease or at high cardiovascular risk, celecoxib was compared with naproxen and ibuprofen. Patients were randomized to receive an initial dose of celecoxib 100 mg twice daily, ibuprofen 600 mg three times daily, or naproxen 375 mg twice daily, with the possibility of dose escalation as needed for pain control.

To assess non-inferiority (80%), the primary composite endpoint was defined by the Antiplatelet Trialists’ Collaboration (APTC) as cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke. All patients received open-label esomeprazole (20–40 mg) as a gastroprotective agent. 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 aforementioned drugs on blood pressure measured by ambulatory monitoring.

Celecoxib 100 mg twice daily met pre-specified non-inferiority criteria (p < 0.001 for non-inferiority in both comparisons) compared to naproxen or ibuprofen at the corresponding doses for the aforementioned APTC-defined composite endpoint.

In the per-protocol population analysis over 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.

Since dose escalation of celecoxib to 200 mg twice daily occurred in a relatively small proportion of the total number of patients receiving celecoxib (5.8%), the results of the PRECISION trial are not considered adequate to determine the relative cardiovascular safety of celecoxib 200 mg twice daily compared to ibuprofen and naproxen at corresponding doses.

In the supplementary PRECISION-ABPM study involving 444 patients, by the fourth month of treatment, celecoxib 100 mg twice daily reduced mean 24-hour systolic blood pressure by 0.3 mm Hg, whereas ibuprofen and naproxen at corresponding doses increased mean 24-hour systolic blood pressure by 3.7 mm Hg and 1.6 mm Hg, respectively. These changes demonstrated a statistically and clinically significant difference of 3.9 mm Hg (p = 0.0009) between celecoxib and ibuprofen, and a statistically non-significant difference of 1.8 mm Hg (p = 0.119) between celecoxib and naproxen.

Clinical characteristics.

Indications.

For symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (see section "Special precautions for use").

For treatment of acute pain in adult patients (see section "Special precautions for use").

For treatment of primary dysmenorrhea (see section "Special precautions for use").

Contraindications.

Celebrex® is contraindicated in patients:

• with known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib or to any component of the medicinal product (see section "Special 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 precautions for use");
• following coronary artery bypass graft (CABG) surgery (see section "Special precautions for use");
• who have experienced allergic-type reactions to sulfonamide drugs (see section "Special precautions for use");
• with established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease;
• with active peptic ulceration or gastrointestinal bleeding;
• with a calculated creatinine clearance < 30 mL/min;
• with congestive heart failure (NYHA class II–IV);
• with severe hepatic impairment (serum albumin < 25 g/L or Child–Pugh score ≥ 10).

Interaction with other medicinal products and other forms of interaction.

Medicinal products affecting hemostasis. Celecoxib and anticoagulants such as warfarin exert a synergistic effect on bleeding. Concomitant use of celecoxib and anticoagulants increases the risk of serious bleeding compared to use of each of these drugs alone.

Serotonin released by platelets plays an important role in hemostasis. Case-control studies and cohort epidemiological studies have shown that concomitant use of medicinal products that inhibit serotonin reuptake with NSAIDs increases the risk of bleeding more than NSAID monotherapy.

Patients receiving concomitant treatment with Celebrex® and anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) should be monitored for bleeding (see section "Special precautions for use").

Aspirin. Controlled clinical trials have shown that concomitant use of NSAIDs and analgesic doses of aspirin does not provide any additional therapeutic benefit compared to NSAID use alone. In a clinical trial, concomitant use of NSAIDs and aspirin was associated with a significantly increased incidence of gastrointestinal adverse reactions compared to NSAID use alone (see section "Special precautions for use").

In two studies involving healthy volunteers and patients with osteoarthritis and chronic heart disease, respectively, celecoxib (at doses of 200–400 mg/day) was shown not to interfere with the cardioprotective antiplatelet effect of aspirin (at doses of 100–325 mg).

Concomitant use of Celebrex® and aspirin at analgesic doses is generally not recommended due to increased risk of bleeding (see section "Special precautions for use"). Celebrex® should not be used as a substitute for low-dose aspirin for prevention of cardiovascular diseases.

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

Concomitant use of NSAIDs with ACE inhibitors or angiotensin receptor blockers in elderly patients, dehydrated patients (including those on diuretic therapy), and 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-adrenergic blockers, blood pressure should be monitored to ensure achievement of the desired blood pressure level.

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

Patients should maintain adequate fluid intake during concomitant use of these medicinal products. Renal function should be assessed at initiation of concomitant therapy and periodically thereafter.

Diuretics. Clinical trials and post-marketing observations have shown that in some patients, NSAIDs may reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics. This effect is explained by NSAID inhibition of renal prostaglandin synthesis.

When Celebrex® is used concomitantly with diuretics, patients should be monitored for signs of worsening renal function, and the effectiveness of the diuretic, including its antihypertensive effect, should be reassessed (see section "Special precautions for use").

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

Serum digoxin levels should be monitored when Celebrex® is used concomitantly with digoxin.

Lithium preparations. NSAIDs have been associated with increased plasma lithium levels and decreased renal clearance of lithium. The mean minimum lithium concentration increased by 15%, and renal clearance decreased by approximately 20%. This effect is explained by NSAID inhibition of renal prostaglandin synthesis.

Patients receiving concomitant treatment with Celebrex® and lithium preparations 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.

Patients should be monitored for signs of methotrexate toxicity during concomitant use of Celebrex® and methotrexate.

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

Patients should be monitored for signs of worsening renal function during concomitant use of Celebrex® and cyclosporine.

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

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-associated myelosuppression and renal and gastrointestinal toxicity (see the pemetrexed product information).

When Celebrex® is used concomitantly with pemetrexed in patients with impaired renal function (creatinine clearance between 45 and 79 mL/min), signs of myelosuppression and renal and gastrointestinal toxicity should be monitored.

NSAIDs with short elimination half-lives (e.g., diclofenac and indomethacin) should be avoided for two days before and after, as well as on the day of, pemetrexed administration.

In the absence of data on potential interactions between pemetrexed and NSAIDs with longer elimination half-lives (e.g., meloxicam and nabumetone), patients receiving these NSAIDs should discontinue their use at least five days before, on the day of, and for two days after pemetrexed administration.

Inhibitors or inducers of CYP2C9. Celecoxib metabolism is primarily mediated by the hepatic cytochrome P450 isoenzyme CYP2C9. Concomitant use of celecoxib with medicinal products known to be CYP2C9 inhibitors (e.g., fluconazole) may increase the effects and toxicity of celecoxib, whereas concomitant use with CYP2C9 inducers (e.g., rifampicin) may reduce celecoxib efficacy.

When considering celecoxib administration, the medical history of each patient should be evaluated. Dose adjustment of celecoxib is justified when used in combination with CYP2C9 inhibitors or inducers (see section "Pharmacokinetics").

Substrates of CYP2D6. In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, potential in vivo interactions with medicinal products metabolized by CYP2D6 (e.g., atomoxetine) are possible, and celecoxib may increase the effects and toxicity of these medicinal products.

When considering celecoxib administration, the medical history of each patient should be evaluated. Dose adjustment of celecoxib is justified when used in combination with CYP2D6 substrates (see section "Pharmacokinetics").

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

Patients receiving concomitant treatment with Celebrex® and corticosteroids should be monitored for signs of bleeding (see section "Special precautions for use").

Special precautions for use.

Cardiovascular thrombotic events. Clinical studies of several selective and non-selective COX-2 inhibitor NSAIDs with durations up to 3 years have demonstrated an increased risk of serious thrombotic adverse events, including myocardial infarction and stroke, which may be fatal. Available data do not allow determination whether the risk of thrombotic cardiovascular complications is similar for all NSAIDs. The relative increase in frequency of serious cardiovascular thrombotic complications compared to baseline frequency associated with NSAID use occurs both in patients with known cardiovascular diseases and risk factors for their development, and in patients without such diseases and risk factors. However, patients with known cardiovascular disease or cardiovascular risk factors had a higher absolute frequency of serious cardiovascular thrombotic complications due to the higher baseline frequency of these factors and diseases. In some observational studies, this increased risk of serious cardiovascular thrombotic complications appeared as early as the first weeks of treatment. The increased risk of cardiovascular thrombotic complications is most consistently observed with higher doses of the drug.

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

A randomized, controlled clinical trial "Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION)" was conducted to assess the relative risk of cardiovascular thrombotic events associated with the COX-2 inhibitor celecoxib compared to non-selective NSAIDs naproxen and ibuprofen. Celecoxib demonstrated non-inferior efficacy compared to naproxen and ibuprofen (see section "Pharmacodynamics").

To minimize the potential risk of cardiovascular adverse reactions in patients using NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. Physicians and patients should carefully monitor for the development of such reactions throughout the entire treatment course, even in the absence of prior cardiovascular symptoms. Patients should be informed about symptoms of serious cardiovascular adverse reactions and measures to be taken if they occur.

There is no direct evidence that concomitant use of aspirin reduces the increased risk of serious cardiovascular thrombotic complications associated with NSAID use. Concomitant use of aspirin and NSAIDs, such as celecoxib, increases the risk of serious gastrointestinal adverse reactions (see section "Special precautions for use", subsection "Gastrointestinal bleeding, ulceration, and perforation").

In the CLASS study, Kaplan-Meier cumulative incidence rates at 9 months for peripheral edema in patients receiving Celebrex® at 400 mg twice daily (4 and 2 times higher than 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. According to the CLASS study, the incidence of hypertension in patients receiving Celebrex®, ibuprofen, and diclofenac was 2.4%, 4.2%, and 2.5%, respectively.

Post-CABG state. In two large controlled clinical trials, use of selective COX-2 inhibitor NSAIDs for pain control in the first 10–14 days after coronary artery bypass graft (CABG) surgery was associated with an increased incidence of myocardial infarction and stroke. Use of NSAIDs after CABG surgery is contraindicated (see section "Contraindications").

Patients after myocardial infarction. Observational studies conducted by the Danish National Registry demonstrated that patients using NSAIDs after myocardial infarction have an increased risk of recurrent myocardial infarction, cardiovascular death, and all-cause mortality, starting from the first week of treatment. In the same cohort, the mortality rate in the first year after myocardial infarction was 20 cases per 100 patient-years in patients using NSAIDs compared to 12 cases per 100 patient-years in patients not using NSAIDs. Although the absolute number of deaths decreases after the first year following myocardial infarction, analysis of results from at least four subsequent years of follow-up demonstrated that the elevated relative risk of mortality in patients using NSAIDs persists.

Gastrointestinal bleeding, ulceration, and perforation. NSAIDs, including celecoxib, can cause serious gastrointestinal adverse reactions, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, and large intestine, which may be fatal. These serious adverse reactions, with or without preceding symptoms, may occur at any time in patients treated with Celebrex®. Only one in five patients develops clinical symptoms of serious upper gastrointestinal adverse reactions during NSAID therapy. Approximately 1% of patients treated with the drug for 3–6 months and approximately 2–4% of patients treated for one year experience upper gastrointestinal ulcers, serious bleeding, or perforation due to NSAID use. However, even short-term NSAID therapy is associated with risk.

Gastrointestinal bleeding, ulceration, and perforation risk factors. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who take NSAIDs have more than a 10-fold higher risk of gastrointestinal bleeding compared to patients without such risk factors. Other factors increasing the risk of gastrointestinal bleeding in patients using NSAIDs include longer duration of NSAID therapy, concomitant oral use of corticosteroids, antiplatelet agents (e.g., aspirin), anticoagulants, or selective serotonin reuptake inhibitors, tobacco smoking, alcohol consumption, advanced age, and poor general health. Most reports of fatal gastrointestinal adverse reactions reported after drug marketing occurred in elderly patients or debilitated patients. Additionally, patients with progressive liver disease and/or coagulopathy are prone to an increased risk of 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 use.

Strategies for minimizing gastrointestinal risks in patients using NSAIDs:

• Use the lowest effective dose for the shortest possible duration;
• Avoid using more than one NSAID simultaneously;
• Avoid use in high-risk patients except when benefit is expected to outweigh the increased risk of bleeding. For such patients, as well as for patients with active gastrointestinal bleeding, consider alternative medications instead of NSAIDs;
• Continuously monitor for signs and symptoms of gastrointestinal ulceration and/or bleeding during NSAID therapy;
• If a serious gastrointestinal adverse reaction is suspected, immediately initiate evaluation and treatment and discontinue Celebrex® until the serious gastrointestinal adverse reaction is ruled out;
• When concomitantly using low-dose aspirin for cardiovascular event prevention, conduct more careful monitoring for signs of gastrointestinal bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Hepatotoxicity. Elevations in alanine aminotransferase or aspartate aminotransferase levels (3 times or more above the upper limit of normal) were observed in approximately 1% of patients treated with NSAIDs in clinical studies. Additionally, rare, sometimes fatal cases of severe liver function impairment, including fulminant hepatitis, liver necrosis, and liver failure, have been reported.

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

In controlled clinical trials of Celebrex®, the incidence of mild elevations (exceeding the upper limit of normal by 1.2 to less than 3 times) in liver function-related enzymes was 6% in patients treated with Celebrex® and 5% in patients receiving placebo, while approximately 0.2% of patients treated with Celebrex® and 0.3% of patients receiving placebo experienced significant elevations in alanine aminotransferase and aspartate aminotransferase levels.

Patients should be informed about symptoms of hepatotoxicity (e.g., nausea, increased fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant pain, and flu-like symptoms). If clinical signs and symptoms suggesting liver disease or systemic manifestations (e.g., eosinophilia, rash, etc.) occur, Celebrex® should be discontinued immediately and the patient should undergo clinical evaluation.

Arterial hypertension. Use of NSAIDs, including Celebrex®, may lead to the development of arterial hypertension or worsening of pre-existing arterial hypertension, and in each case may increase the frequency of cardiovascular adverse reactions. In patients taking ACE inhibitors, thiazide diuretics, or loop diuretics, impaired response to these drugs may occur during NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

Blood pressure should be monitored at the start of NSAID therapy and throughout the treatment course.

Heart failure and edema. Results from a combined meta-analysis by the Antithrombotic Trialists’ Collaboration of randomized controlled trials of coxibs and traditional NSAIDs demonstrated approximately a twofold increase in hospitalization rates for heart failure in patients receiving selective and non-selective COX-2 inhibitors and in patients using non-selective NSAIDs compared to patients receiving placebo. In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of myocardial infarction, hospitalization for heart failure, and mortality.

Additionally, fluid retention and edema have been observed in some patients using NSAIDs. Use of celecoxib may attenuate cardiovascular effects of several drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers) (see section "Interaction with other medicinal products and other forms of interaction").

In the CLASS study, the cumulative incidence of peripheral edema calculated by the Kaplan-Meier method after 9 months of treatment with Celebrex® 400 mg twice daily (4 and 2 times higher than the recommended dose for osteoarthritis and rheumatoid arthritis, respectively), ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily was 4.5%, 6.9%, and 4.7%, respectively.

Nephrotoxicity. Prolonged use of NSAIDs has led to renal papillary necrosis and other kidney damage.

Nephrotoxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In such patients, NSAID use may cause dose-dependent reduction in prostaglandin production and, consequently, decreased renal blood flow, potentially leading to significant renal decompensation. Patients at increased risk of these reactions include those with impaired renal function, dehydration, hypovolemia, heart failure, hepatic dysfunction, patients taking diuretics, ACE inhibitors, angiotensin receptor blockers, and elderly patients. Discontinuation of NSAID therapy usually results in return to the pre-treatment state.

There is no information from controlled clinical trials on the use of Celebrex® in patients with progressive kidney disease. The effect of Celebrex® on the kidneys may accelerate the progression of pre-existing renal impairment.

Before initiating treatment with Celebrex®, dehydration or hypovolemia, if present, should be corrected. In patients with impaired renal or hepatic function, heart failure, dehydration, or hypovolemia, renal function should be monitored during Celebrex® use (see section "Interaction with other medicinal products and other forms of interaction"). Use of Celebrex® should be avoided in patients with progressive kidney disease except when benefit is expected to outweigh the risk of worsening renal function. If Celebrex® is used in patients with progressive kidney disease, patients should be monitored for signs of worsening renal function.

Hyperkalemia. Cases of increased serum potassium concentration, including hyperkalemia, have been reported with NSAID use, even in some patients without impaired renal function. In patients with normal renal function, these effects were associated with a hyporeninemic-hypoaldosteronism state.

Anaphylactic reactions. Use of celecoxib has been associated with anaphylactic reactions in patients with known hypersensitivity to celecoxib or without it, as well as in patients with aspirin-induced asthma. Celebrex® is a sulfonamide-containing drug, and both NSAIDs and sulfonamide-containing drugs can cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe episodes of bronchial asthma in some sensitive individuals (see section "Contraindications").

In case of an anaphylactic reaction, immediate medical assistance is required.

Exacerbation of bronchial asthma associated with aspirin sensitivity. Some patients with bronchial asthma may have aspirin-induced asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and intolerance to aspirin and other NSAIDs. Since cross-reactivity between aspirin and other NSAIDs has been documented in such aspirin-sensitive patients, use of Celebrex® is contraindicated in patients with this form of aspirin sensitivity (see section "Contraindications"). When using Celebrex® in patients with pre-existing bronchial asthma (without known aspirin sensitivity), their condition should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions. Celebrex® may cause serious skin adverse reactions such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These serious reactions may develop without warning symptoms and may be fatal.

Patients should be informed about signs and symptoms of serious skin reactions and the need to discontinue Celebrex® at the first appearance of skin rash or any other signs of hypersensitivity. Celebrex® is contraindicated in patients with a history of serious skin reactions to NSAIDs (see section "Contraindications").

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported in patients using NSAIDs such as Celebrex®. Some of these cases were fatal or life-threatening. DRESS syndrome typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS syndrome may resemble acute viral infection. Eosinophilia is often present. Since this syndrome has diverse manifestations, other organ systems may also be involved. It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may occur even without visible rash. If such signs or symptoms are observed, Celebrex® should be discontinued and the patient should be evaluated immediately.

Fetal toxicity.

Premature closure of ductus arteriosus in the fetus. Use of NSAIDs, including Celebrex®, should be avoided in pregnant women from approximately the 30th week of pregnancy. NSAIDs, including Celebrex®, increase the risk of premature closure of the ductus arteriosus in the fetus around this gestational period.

Oligohydramnios/renal failure in newborns. Use of NSAIDs, including Celebrex®, from approximately the 20th week of pregnancy may cause impaired renal function in the fetus, leading to oligohydramnios and, in some cases, renal failure in newborns. These adverse outcomes are observed on average after several days or weeks of treatment, although rare reports of oligohydramnios have occurred as early as 48 hours after starting NSAID use. Oligohydramnios is often, but not always, reversible after discontinuation of treatment. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some post-marketing cases, impaired renal function in newborns required invasive procedures such as exchange transfusion or dialysis.

If NSAID treatment is necessary between approximately the 20th and 30th weeks of pregnancy, use of Celebrex® should be limited to the lowest effective dose and shortest possible duration. Consideration should be given to ultrasound monitoring of amniotic fluid if treatment with Celebrex® lasts more than 48 hours. Use of Celebrex® should be discontinued if oligohydramnios develops, and monitoring should continue according to clinical practice (see section "Use during pregnancy or lactation").

Hematological toxicity. Cases of anemia have been reported in patients using NSAIDs. This may be due to occult or significant blood loss, fluid retention, or effects on erythropoiesis, which are not fully characterized. If a patient exhibits any signs or symptoms of anemia during treatment with Celebrex®, hemoglobin or hematocrit levels should be monitored.

In controlled clinical trials, the incidence of anemia was 0.6% with Celebrex® and 0.4% with placebo. In patients undergoing prolonged treatment with Celebrex®, hemoglobin or hematocrit levels should be monitored if any signs or symptoms of anemia or blood loss are present.

NSAIDs, including Celebrex®, may increase the risk of bleeding. Contributing factors such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors may increase this risk. Such patients should be monitored for signs of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Masking of inflammation and fever. The pharmacological activity of Celebrex® in reducing inflammation and possibly lowering elevated temperature may reduce the diagnostic value of clinical signs in detecting infections.

Monitoring of laboratory test results. Since serious gastrointestinal bleeding, hepatotoxicity, and renal damage may occur without warning signs or symptoms, consideration should be given to monitoring patients using NSAIDs for prolonged periods. Monitoring includes periodic performance of complete blood count and biochemical blood tests (see section "Special precautions for use").

In controlled clinical trials, increased blood urea nitrogen levels occurred more frequently in patients taking Celebrex® than in those receiving placebo. This laboratory abnormality was also observed in patients receiving comparator NSAIDs in these trials. The clinical significance of this laboratory abnormality has not been established.

Disseminated intravascular coagulation. Since there is a risk of disseminated intravascular coagulation during use of Celebrex® in children with systemic manifestations of juvenile rheumatoid arthritis, patients should be monitored for signs and symptoms of coagulation disorders or bleeding, and patients and their caregivers should be informed about the need to report such symptoms as soon as possible.

Fertility. Since the mechanism of action of NSAIDs (including Celebrex®) is mediated through prostaglandins, use of these drugs may delay or prevent follicular rupture, which may be associated with temporary infertility in some women. Published animal studies have shown that use of prostaglandin synthesis inhibitors may potentially disrupt prostaglandin-mediated follicular rupture necessary for ovulation. Small studies in women using NSAIDs have also demonstrated reversible ovulation delay. Consideration should be given to discontinuing NSAIDs, including Celebrex®, in women experiencing difficulties conceiving or undergoing infertility evaluation.

Use during pregnancy or lactation.

Pregnancy. Use of NSAIDs, including Celebrex®, may cause premature closure of the ductus arteriosus in the fetus and impaired fetal renal function leading to oligohydramnios and, in some cases, renal failure in newborns. Due to these risks, dose and duration of Celebrex® use should be limited between approximately the 20th and 30th weeks of pregnancy, and use of Celebrex® should be avoided from approximately the 30th week of pregnancy.

Premature closure of ductus arteriosus in the fetus. Use of NSAIDs, including Celebrex®, from approximately the 30th week of pregnancy increases the risk of premature closure of the ductus arteriosus in the fetus.

Oligohydramnios/renal failure in newborns. Use of NSAIDs from approximately the 20th week of pregnancy has been associated with impaired fetal renal function leading to oligohydramnios and, in some cases, renal failure in newborns.

Based on data from observational studies, no definitive conclusions can be drawn regarding other potential embryofetal risks of NSAID use in women during the first or second trimesters of pregnancy. In reproductive animal studies, embryofetal lethality and increased incidence of diaphragmatic hernia were observed in rats given daily oral celecoxib during organogenesis at doses approximately 6 times the maximum recommended human dose of 200 mg twice daily. Additionally, structural abnormalities (e.g., septal defects, rib fusions, sternal segment fusions, and sternal segment deformities) were observed in rabbits given oral celecoxib during organogenesis at doses approximately 2 times the maximum recommended human dose. Data from animal studies demonstrate the important role of prostaglandins in regulating endometrial vascular permeability, blastocyst implantation, and decidualization. Animal studies have shown that administration of prostaglandin synthesis inhibitors, such as celecoxib, increases the frequency of pre- and post-implantation losses. Prostaglandins are also known to play an important role in fetal kidney development. Published animal studies have reported that prostaglandin synthesis inhibitors impair kidney development when used at clinically relevant doses.

The estimated background risk of major congenital defects and miscarriages in the specified population is unknown. All pregnancies are associated with a background risk of congenital malformations, miscarriages, or other adverse outcomes. In the general US population, the estimated background risk of serious congenital malformations and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Adverse effects in fetus/newborn.

Premature closure of ductus arteriosus in the fetus

NSAID use should be avoided in women from approximately the 30th week of pregnancy, as NSAIDs, including Celebrex®, may cause premature closure of the ductus arteriosus in the fetus.

Oligohydramnios/renal failure in newborns

If NSAID use is necessary from approximately the 20th week of pregnancy, use should be limited to the lowest effective dose and shortest possible duration. If treatment with Celebrex® lasts more than 48 hours, consideration should be given to ultrasound monitoring for oligohydramnios. If oligohydramnios is observed, use of Celebrex® should be discontinued and treatment continued according to clinical practice (see below "Human data").

Labour and delivery. Studies on the effect of Celebrex® on labour or delivery have not been conducted. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, causing delayed delivery and increased frequency of stillbirth.

Human data. Available data do not allow assessment of the presence or absence of embryofetal toxicity associated with use of Celebrex®.

The effect of Celebrex® on the course of labour and delivery in pregnant women is unknown.

Premature closure of ductus arteriosus in the fetus

Publications report that use of NSAIDs around the 30th week of pregnancy and later may cause premature closure of the ductus arteriosus in the fetus.

Oligohydramnios/renal failure in newborns

Published studies and post-marketing reports describe use of NSAIDs in women around the 20th week of pregnancy or later, associated with impaired fetal renal function leading to oligohydramnios and, in some cases, renal failure in newborns. These adverse outcomes are observed on average after several days or weeks of treatment, although rare reports of oligohydramnios have occurred as early as 48 hours after starting NSAID use. In many cases, but not always, reduction in amniotic fluid volume was temporary and resolved after discontinuation of the drug. There is a limited number of reports on NSAID use in women and impaired renal function in newborns without oligohydramnios, some of which were irreversible. Some cases of impaired renal function in newborns required treatment with invasive procedures such as exchange transfusion or dialysis.

Methodological limitations of these post-marketing studies and reports include lack of a control group; limited information on dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations prevent reliable assessment of the risk of adverse outcomes for the fetus and newborns when NSAIDs are used by their mothers. Since published safety data for newborns primarily concern preterm infants, generalization of certain reported risks to term infants exposed to NSAIDs through maternal use is uncertain.

Lactation. Limited data from three published reports involving a total of 12 breastfeeding women indicate low levels of Celebrex® in breast milk. The calculated average daily infant dose was 10–40 µg/kg/day, which is less than 1% of the therapeutic dose for a two-year-old child adjusted for body weight. In a report on two breastfed infants aged 17 and 22 months, no adverse reactions were reported.

Celebrex® should be used with caution in women who are breastfeeding. The benefit of breastfeeding for the child's health and development should be weighed against the mother's clinical need for Celebrex® and any potential adverse effects of Celebrex® or the impact of the mother's underlying condition on the infant.

Ability to affect reaction speed when driving vehicles or operating machinery.

If adverse reactions such as dizziness, vertigo, or somnolence occur during use of celecoxib, driving vehicles and operating machinery should be avoided.

Method of Administration and Dosage

General Dosing Instructions. Before deciding to use this medicinal product, the expected potential benefits and risks of using Celebrex® should be carefully weighed, and the appropriateness of other treatment options should be considered. The lowest effective dose should be used for the shortest duration consistent with the individual patient's treatment goals (see section "Special Instructions").

This medicine can be taken independently of food intake.

Osteoarthritis. For the treatment of osteoarthritis, the daily dose is 200 mg administered once daily or 100 mg twice daily.

Rheumatoid Arthritis. For the treatment of rheumatoid arthritis, the dose is 100–200 mg twice daily.

Ankylosing Spondylitis. For the treatment of ankylosing spondylitis, the daily dose of Celebrex® is 200 mg, which may be taken as a single dose (once daily) or divided (twice daily). If no positive effect is observed within 6 weeks, the dose may be increased to 400 mg daily. If there is no response after 6 weeks of treatment at 400 mg daily, a therapeutic response is unlikely, and alternative treatment options should be considered.

Management of Acute Pain and Treatment of Primary Dysmenorrhea. For the management of acute pain and treatment of primary dysmenorrhea, the initial dose is 400 mg, followed by an additional 200 mg dose on the first day if needed. On subsequent days, the recommended dose is 200 mg twice daily, as needed.

Special Patient Groups.

Hepatic Impairment. In patients with moderate hepatic impairment (Child–Pugh Class B), the dose should be reduced by 50%. Patients with Slow Metabolism of CYP2C9 Substrates. In adult patients with known or suspected slow metabolism of CYP2C9 substrates based on genotype or previous experience with other CYP2C9 substrates (e.g., warfarin, phenytoin), celecoxib should be initiated at half the minimum recommended dose.

For patients with juvenile rheumatoid arthritis and known or suspected slow metabolism of CYP2C9 substrates, consideration should be given to alternative treatments (see section "Pharmacological Properties. Pharmacogenomics").

Elderly Patients. Elderly patients have a higher risk compared to younger patients of developing serious adverse reactions associated with NSAID use, such as cardiovascular, gastrointestinal, and/or renal adverse reactions.

If the anticipated benefit outweighs the potential risks in elderly patients, treatment should be initiated at the lowest dose, with careful monitoring for adverse reactions (see section "Special Instructions").

In the overall population of patients who received Celebrex® in clinical trials prior to marketing, more than 3300 patients were aged 65–74 years, and approximately 1300 additional patients were aged 75 years or older. No significant differences in efficacy were observed between this patient group and younger patients. In clinical studies comparing renal function (assessed by glomerular filtration rate, blood urea nitrogen, and creatinine) and platelet function (assessed by bleeding time and platelet aggregation), no differences were observed between elderly and younger volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal gastrointestinal events and acute renal failure in elderly patients compared to younger patients (see section "Special Instructions").

Children. Celebrex® 200 mg capsules are not indicated for use in children.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric abdominal pain, and are generally reversible with supportive treatment. Cases of gastrointestinal bleeding have been reported. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma have been reported (see section "Special Instructions").

There were no cases of overdose with Celebrex® reported during clinical trials. No serious intoxication was observed in 12 patients who received doses up to 2400 mg/day for up to 10 days. Information on the possibility of eliminating celecoxib by hemodialysis is lacking; however, due to its high plasma protein binding (> 97%), dialysis is likely to be ineffective in overdose.

Following NSAID overdose, symptomatic and supportive treatment should be administered. There are no specific antidotes. Inducing vomiting and/or administering activated charcoal (60–100 g for adults, 1–2 g per kg body weight for children) and/or an osmotic laxative should be considered in patients who develop overdose symptoms within four hours after ingestion, as well as in patients with severe overdose (doses 5–10 times higher than the recommended dose).

Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion are not recommended due to high protein binding.

For additional information on overdose management, contact a poison control center.

Adverse Reactions

Since clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of one drug cannot be directly compared with the frequency in the clinical trials of another drug, and the incidence rates observed in clinical trials may not reflect those observed in clinical practice. However, information on adverse reactions observed during clinical trials provides a basis for identifying reactions that may be related to drug use and for estimating their approximate frequency.

Among all participants in the premarketing controlled clinical trials of CELEBREX®, approximately 4,250 patients had osteoarthritis, about 2,100 had rheumatoid arthritis, and about 1,050 had postoperative pain. More than 8,500 patients received CELEBREX® at total daily doses of 200 mg (100 mg twice daily or 200 mg once daily) or higher, including over 400 patients who received 800 mg (400 mg twice daily). Approximately 3,900 patients received CELEBREX® at these doses for 6 months or longer; about 2,300 of these patients received the drug for 1 year or longer, and 124 of these patients received it for 2 years or longer.

Pre-marketing controlled trials of the drug in the treatment of arthritis.

Table 2 lists all adverse reactions, regardless of causal relationship, that occurred in ≥ 2% of patients during 12 controlled trials of CELEBREX® in patients with osteoarthritis or rheumatoid arthritis, which included placebo and/or active control groups. Because these 12 trials varied in duration and patient exposure time, the percentages shown in Table 2 do not represent cumulative incidence rates of adverse reactions.

Table 2.

Adverse reactions occurring in more than 2% of patients treated with CELEBREX® during pre-marketing controlled trials of the drug in the treatment of arthritis.

Adverse reaction	CBS N=4146	Placebo N=1864	NSAID N=1366	DCF N=387	IBU N=345
Gastrointestinal disorders Stomach pain Diarrhea Dyspepsia Flatulence Nausea	4.1% 5.6% 8.8% 2.2% 3.5%	2.8% 3.8% 6.2% 1.0% 4.2%	7.7% 5.3% 12.2% 3.6% 6.0%	9.0% 9.3% 10.9% 4.1% 3.4%	9.0% 5.8% 12.8% 3.5% 6.7%
General disorders Back pain Peripheral edema Accidental injury	2.8% 2.1% 2.9%	3.6% 1.1% 2.3%	2.2% 2.1% 3.0%	2.6% 1.0% 2.6%	0.9% 3.5% 3.2%
Nervous system disorders Dizziness Headache	2.0% 15.8%	1.7% 20.2%	2.6% 14.5%	1.3% 15.5%	2.3% 15.4%
Psychiatric disorders Insomnia	2.3%	2.3%	2.9%	1.3%	1.4%
Respiratory system disorders Pharyngitis Rhinitis Sinusitis Upper respiratory tract infection	2.3% 2.0% 5.0% 8.1%	1.1% 1.3% 4.3% 6.7%	1.7% 2.4% 4.0% 9.9%	1.6% 2.3% 5.4% 9.8%	2.6% 0.6% 5.8% 9.9%
Skin disorders Rash	2.2%	2.1%	2.1%	1.3%	1.2%

CBS – Celebrex® at a dose of 100–200 mg twice daily or 200 mg once daily;
NSAID – naproxen at a dose of 500 mg twice daily;
DCF – diclofenac at a dose of 75 mg twice daily;
IBU – ibuprofen at a dose of 800 mg three times daily.

In placebo-controlled clinical trials or active-controlled studies, the proportion of patients who discontinued treatment due to adverse reactions was 7.1% in the Celebrex® group and 6.1% in the placebo group. The most common reasons for discontinuation due to adverse reactions in patients receiving Celebrex® were dyspepsia and abdominal pain (0.8% and 0.7%, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% due to abdominal pain.

The following adverse reactions were observed in 0.1–1.9% of patients treated with Celebrex® (100–200 mg twice daily or 200 mg once daily).

Gastrointestinal disorders: constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting.

Cardiovascular system disorders: worsening of arterial hypertension, angina pectoris, ischemic heart disease, myocardial infarction, heart failure.

General disorders: hypersensitivity reactions, allergic reactions, chest pain, cyst (unspecified), generalized edema, facial swelling, increased fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain, peripheral edema/fluid retention.

Central and peripheral nervous system disorders: leg cramps, hypertension, hypesthesia, migraine, paresthesia, vertigo.

Ear and labyrinth disorders: deafness, tinnitus.

Heart rate and rhythm disorders: palpitations, tachycardia.

Hepatobiliary disorders: increased liver enzyme levels (including increased aspartate aminotransferase and alanine aminotransferase levels).

Metabolism and nutrition disorders: increased blood urea nitrogen, increased blood creatine phosphokinase, hypercholesterolemia, hyperglycemia, hypokalemia, increased non-protein nitrogen, increased blood creatinine, increased blood urea, increased alkaline phosphatase, weight gain.

Musculoskeletal system disorders: arthralgia, arthritis, myalgia, synovitis, tendinitis.

Platelet disorders (bleeding or coagulation): ecchymosis, epistaxis, thrombocytosis.

Psychiatric disorders: anorexia, anxiety, increased appetite, depression, nervousness, somnolence.

Blood disorders: anemia.

Respiratory system disorders: bronchitis, bronchospasm, worsening of bronchospasm, cough, dyspnea, laryngitis, pneumonia.

Skin and subcutaneous tissue disorders: alopecia, dermatitis, photosensitivity reactions, pruritus, erythematous rash, maculopapular rash, skin disorders, dry skin, increased sweating, urticaria.

Application site disorders: panniculitis, contact dermatitis.

Renal and urinary system disorders: albuminuria, cystitis, dysuria, hematuria, frequent urination, urolithiasis.

The following serious adverse reactions (causal relationship not assessed) were reported in < 0.1% of patients.

Cardiovascular system disorders: syncope, congestive heart failure, ventricular fibrillation, pulmonary artery thromboembolism, acute cerebrovascular accident, peripheral gangrene, thrombophlebitis.

Gastrointestinal disorders: gastrointestinal hemorrhage, duodenal ulcer, gastric ulcer, esophageal ulcer, intestinal ulcer, colonic ulcer, intestinal obstruction, intestinal perforation, gastrointestinal bleeding, hemorrhagic colitis, esophageal perforation, pancreatitis, intestinal obstruction.

General disorders: sepsis, sudden death.

Hepatobiliary disorders: cholelithiasis.

Blood and lymphatic system disorders: thrombocytopenia.

Nervous system disorders: ataxia, suicide (see section "Interaction with other medicinal products and other forms of interaction").

Renal disorders: acute renal failure.

Long-term safety study of celecoxib for the treatment of arthritis.

Hematological disorders. The incidence of clinically significant hemoglobin decrease (> 2 g/dL) was lower in patients treated with Celebrex® 400 mg twice daily (0.5%) compared to those treated with diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily (1.9%). This lower incidence with Celebrex® was maintained both with and without concomitant aspirin use (see section "Pharmacodynamics").

Discontinuation of treatment / serious adverse reactions. The cumulative incidence of treatment discontinuation due to adverse reactions over 9 months, calculated using the Kaplan-Meier method, was 24%, 29%, and 26% for Celebrex®, diclofenac, and ibuprofen, respectively. The incidence of serious adverse reactions (i.e., those leading to hospitalization, life-threatening, or otherwise medically significant), regardless of causal relationship, did not differ significantly among the treatment groups (8%, 7%, and 8%, respectively).

Study of celecoxib use in the treatment of juvenile rheumatoid arthritis.

In a 12-week double-blind, active-controlled study, 242 patients with juvenile rheumatoid arthritis aged 2 to 17 years received either celecoxib or naproxen; 77 patients received celecoxib at 3 mg/kg twice daily, 82 patients received celecoxib at 6 mg/kg twice daily, and 83 patients received naproxen at 7.5 mg/kg twice daily. The most common adverse reactions (≥ 5%) observed in patients treated with celecoxib were headache, increased temperature (hyperthermia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting. The most common adverse reactions (≥ 5%) observed in patients treated with naproxen were headache, nausea, vomiting, increased temperature, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 3). During this 12-week double-blind study, no harmful effects on growth and development were observed with celecoxib at doses of 3 and 6 mg/kg twice daily compared to naproxen. There were no significant differences between treatment groups in the number of clinical uveitis flares or systemic signs of juvenile rheumatoid arthritis.

In the 12-week open-label extension phase of the above double-blind study, 202 patients with juvenile rheumatoid arthritis received celecoxib at 6 mg/kg twice daily. The frequency of adverse reactions was similar to that observed during the double-blind phase; no unexpected clinically significant adverse reactions were observed.

Table 3.
Adverse reactions occurring in ≥ 5% of patients with juvenile rheumatoid arthritis in any treatment group, categorized by system organ class (% of patients with adverse reactions).

System organ classes	All doses twice daily
	Celecoxib 3 mg/kg N=77	Celecoxib 6 mg/kg N=82	Naproxen 7.5 mg/kg N=83
Any reaction	64	70	72
Eye disorders	5	5	5
Gastrointestinal disorders	26	24	36
Abdominal pain, unspecified	4	7	7
Upper abdominal pain	8	6	10
Vomiting, unspecified	3	6	11
Diarrhea, unspecified	5	4	8
Nausea	7	4	11
General disorders	13	11	18
Pyrexia	8	9	11
Infections	25	20	27
Nasopharyngitis	5	6	5
Injury and poisoning	4	6	5
Investigations*	3	11	7
Musculoskeletal system disorders	8	10	17
Arthralgia	3	7	4
Nervous system disorders	17	11	21
Headache, unspecified	13	10	16
Dizziness (excluding vertigo)	1	1	7
Respiratory system disorders	8	15	15
Cough	7	7	8
Skin and subcutaneous tissue disorders	10	7	18

* Abnormal laboratory test results, which include: prolonged activated partial thromboplastin time, bacteriuria (unspecified), increased blood creatine phosphokinase, positive blood culture, increased blood glucose, increased blood pressure, increased blood uric acid, decreased hematocrit, presence of hematuria, decreased hemoglobin, abnormal liver function biochemical tests (unspecified), presence of proteinuria, increased transaminases (unspecified), abnormal urine analysis findings (unspecified).

Other studies conducted prior to market release of the drug.

• Adverse reactions observed in studies on the treatment of ankylosing spondylitis. Overall, 378 patients received Celebrex® in placebo-controlled and active-controlled studies for the treatment of ankylosing spondylitis. The drug was studied at doses up to 400 mg once daily. The types of adverse reactions reported in the ankylosing spondylitis treatment studies were similar to those reported in the osteoarthritis/rheumatoid arthritis treatment studies.
• Adverse reactions observed in analgesic and dysmenorrhea treatment studies. Approximately 1700 patients received Celebrex® in analgesic and dysmenorrhea treatment studies. In studies involving patients with postoperative oral surgery pain, all participants received a single dose of the investigational drug. In studies on the treatment of primary dysmenorrhea and post-orthopedic surgical pain, Celebrex® was studied at doses up to 600 mg/day. The types of adverse reactions reported in the analgesic and dysmenorrhea treatment studies were the same as those reported in arthritis studies. The only additional adverse reaction recorded in the post-orthopedic surgical pain studies was alveolar osteitis following tooth extraction (post-extraction alveolar socket alveolitis).

PreSAP study and the adenoma prevention celecoxib study.

Adverse reactions in long-term placebo-controlled polyp prevention studies. The exposure of Celebrex® in the adenoma prevention celecoxib study and the PreSAP study was 400–800 mg daily over a period of up to 3 years.

Some adverse reactions occurred in a higher percentage of patients than in the arthritis treatment studies conducted prior to market release of the drug (treatment duration up to 12 weeks). Table 4 lists adverse reactions that occurred more frequently in patients receiving Celebrex® compared to patients in the pre-market arthritis treatment studies.

Table 4

Adverse reactions	Celebrex® (400 to 800 mg daily), N=2285	Placebo N=1303
Diarrhea	10.5 %	7.0 %
Gastroesophageal reflux disease	4.7 %	3.1 %
Nausea	6.8 %	5.3 %
Vomiting	3.2 %	2.1 %
Dyspnea	2.8 %	1.6 %
Arterial hypertension	12.5 %	9.8 %
Nephrolithiasis	2.1 %	0.8 %

The following additional adverse reactions were observed in ≥ 0.1% and < 1% of patients treated with Celebrex® at a frequency higher than that in the placebo group in long-term polyp prevention studies. These adverse reactions were either not reported during controlled clinical trials of the drug for arthritis treatment conducted prior to marketing or were observed more frequently in long-term placebo-controlled polyp prevention studies:

Nervous system disorders: Ischemic stroke.

Eye disorders: Vitreous opacity, conjunctival haemorrhage.

Ear and labyrinth disorders: Labyrinthitis.

Cardiac disorders: Unstable angina, aortic valve dysfunction, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy.

Vascular disorders: Deep vein thrombosis.

Reproductive system and breast disorders: Ovarian cyst.

Investigations: Increased blood potassium, increased blood sodium, increased blood testosterone.

Injury, poisoning and procedural complications: Epicondylitis, tendon rupture.

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of Celebrex®. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular disorders: Vasculitis, deep vein thrombosis.

General disorders: Anaphylactoid reaction, angioneurotic oedema.

Hepatobiliary disorders: Liver necrosis, hepatitis, jaundice, liver failure (sometimes resulting in death or requiring liver transplantation), fulminant hepatitis (sometimes fatal), hepatic necrosis, cholestasis, cholestatic hepatitis.

Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, pancytopenia, leucopenia.

Metabolic and nutritional disorders: Hypoglycaemia, hyponatraemia.

Nervous system disorders: Aseptic meningitis, ageusia, anosmia, intracranial haemorrhage (including fatal intracranial haemorrhage).

Renal and urinary disorders: Interstitial nephritis, tubulointerstitial nephritis, nephrotic syndrome, minimal change glomerulonephritis.

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 30 °C.

Packaging. 10 capsules in a blister pack, 1, 2, or 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Pfizer Manufacturing Deutschland GmbH /

Pfizer Manufacturing Deutschland GmbH.

Manufacturer's address.

Mooswaldallee 1, 79108 Freiburg im Breisgau, Germany /
Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany.