Remoxib

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT REVMOKSIB (REVMOXIB)

Composition:

Active substance: celecoxib;

1 capsule contains celecoxib calculated as 100 % substance – 200 mg;

Excipients: lactose monohydrate (Granulac-70); povidone; sodium lauryl sulfate; calcium stearate;

Capsule shell composition: gelatin, titanium dioxide (E 171), azorubine (E 122).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size 0, body white, cap pink. The capsule contents are a white or almost white powder.

Pharmacotherapeutic group. Anti-inflammatory and antirheumatic agents. Coxibs.

ATC code M01AH01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of celecoxib is believed to be related to inhibition of prostaglandin synthesis, primarily by inhibiting cyclooxygenase-2 (COX-2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of celecoxib achieved during therapy 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 celecoxib at single doses up to 800 mg and multiple doses up to 600 mg twice daily for up to 7 days (exceeding recommended therapeutic doses) did not affect platelet aggregation or prolong blood clotting time. Due to the lack of effect on platelets, celecoxib cannot be used as a substitute for aspirin in the prevention of cardiovascular diseases. It is unknown whether celecoxib affects platelets in terms of increasing the risk of serious cardiovascular thrombotic adverse reactions associated with celecoxib use.

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.

The pharmacokinetic parameters of celecoxib increase approximately in proportion to the dose following administration of 200 mg twice daily; at higher doses, the increase in parameters is less than proportional. 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 the maximum plasma concentration (Cmax) and the area under the pharmacokinetic curve (AUC) are approximately dose-proportional; at higher doses, Cmax and AUC increase sublinearly (see section «Effect of food intake» below). Absolute bioavailability studies of the drug have not been conducted. At steady state, equilibrium 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 under fasting conditions (n = 36, 19– 52 years).

Vss/F – apparent volume of distribution at steady state.

CL/F – plasma clearance.

Effect of food. When celecoxib capsules were administered with a high-fat meal, peak plasma levels of the drug were observed with a delay of 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 celecoxib 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. Celecoxib at doses up to 200 mg twice daily can be taken regardless 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) of celecoxib did not differ when the capsule was swallowed whole compared to when its contents were mixed with applesauce. After administration of the capsule contents 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 entirely 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 show preferential binding to red blood cells.

Elimination.

Metabolism. Celecoxib metabolism is primarily mediated by 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 via hepatic metabolism, with only a small amount (<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 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 for 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 required. However, in patients with body weight less than 50 kg, treatment should be initiated with the lowest recommended dose (see section "Dosage and administration").

Children. In a clinical study involving 152 patients with juvenile rheumatoid arthritis aged 2 to 17 years and body weight ≥10 kg, with involvement of one or more joints or systemic manifestations of juvenile rheumatoid arthritis, the steady-state pharmacokinetics of celecoxib were evaluated after administration of an experimental oral suspension formulation. Population pharmacokinetic analysis showed that oral clearance (not adjusted for body weight) of celecoxib increases less than proportionally with increasing body weight, with predicted clearance values 40% and 24% lower in patients weighing 10 kg and 25 kg, respectively, compared to 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 concentrations of celecoxib similar to those observed in a clinical study demonstrating non-inferior efficacy of celecoxib compared to naproxen at a dose of 7.5 mg/kg twice daily (see section "Dosage and administration"). Studies in patients with juvenile rheumatoid arthritis younger than 2 years of age or with body weight less than 10 kg have not been conducted, nor have studies longer than 24 weeks.

Race. Based on results from a meta-analysis of pharmacokinetic studies, it was hypothesized that AUC values of celecoxib in Black individuals are 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 celecoxib capsules should be reduced by approximately 50% when administered to patients with moderate hepatic impairment (Child-Pugh class B).

Renal impairment. According to results from cross-study comparisons, 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 the following.

Aspirin. When nonsteroidal anti-inflammatory drugs (NSAIDs) are co-administered with aspirin, their protein binding decreases, although the clearance of the unbound form of NSAIDs remains unchanged. The clinical significance of this interaction is unknown.

Clinically significant NSAID-aspirin interactions are described in the section "Interaction with other medicinal products and other forms of interaction."

Lithium-containing drugs. In a study conducted in healthy volunteers, mean steady-state plasma lithium levels increased by approximately 17% in patients receiving 450 mg lithium twice daily in combination with celecoxib 200 mg twice daily, compared to those receiving lithium alone (see section "Interaction with other medicinal products and other forms of interaction").

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 "Interaction with other medicinal products and other forms of interaction").

Other medicinal products. In vivo studies have been conducted to evaluate the effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate (see section "Interaction with other medicinal products and other forms of interaction"), phenytoin, and tolbutamide, but no clinically significant interactions were identified.

Pharmacogenomics. In some patients with genetic polymorphisms (homozygosity for CYP2C9*2 and CYP2C9*3 polymorphism), reduced CYP2C9 activity and enzymatic activity have been 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 compared to 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. The estimated 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 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 dose escalation permitted as needed for pain control.

To assess non-inferiority (80%), the primary composite endpoint, defined by the Antiplatelet Trialists’ Collaboration (APTC), included cardiovascular death (including death due to hemorrhage), non-fatal myocardial infarction, and non-fatal stroke. All patients received open-label esomeprazole (20–40 mg) as gastroprotection. 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 ambulatory blood pressure 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 respective doses for the 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 only a relatively small proportion of the total number of patients receiving celecoxib (5.8%), the results of the PRECISION trial are not applicable for determining the relative cardiovascular safety of celecoxib 200 mg twice daily compared to ibuprofen and naproxen at the respective doses.

In the supplementary PRECISION-ABPM study involving 444 patients, at four months of treatment, celecoxib 100 mg twice daily reduced mean 24-hour systolic blood pressure by 0.3 mm Hg, whereas ibuprofen and naproxen at the respective doses increased mean 24-hour systolic blood pressure by 3.7 and 1.6 mm Hg, respectively. These changes led to 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 instructions").

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

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

Contraindications.

Rheumoxyb is contraindicated in patients:

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

Interaction with other medicinal products and other types of interactions.

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 using each of these drugs separately.

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 Rheumoxyb 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 "Special instructions").

Aspirin. Controlled clinical studies have shown that concomitant use of NSAIDs and analgesic-dose aspirin does not provide any additional therapeutic benefit compared to NSAID monotherapy. In a clinical study, concomitant use of NSAIDs and aspirin was associated with a significantly increased incidence of gastrointestinal adverse reactions compared to NSAID monotherapy (see section "Special instructions").

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 Rheumoxyb and analgesic-dose aspirin is generally not recommended due to increased risk of bleeding (see section "Special instructions"). Rheumoxyb must 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 receiving 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 Rheumoxyb 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 Rheumoxyb is used concomitantly with ACE inhibitors or angiotensin receptor blockers in elderly patients or in patients with dehydration or impaired renal function, patients should be monitored for signs of worsening renal function (see section "Special instructions").

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

Diuretics. Clinical studies 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 inhibition of prostaglandin synthesis in the kidneys by NSAIDs.

When Rheumoxyb is used concomitantly with diuretics, patients should be monitored for signs of worsening renal function, and the effectiveness of the diuretic, including antihypertensive effect, should be confirmed (see section "Special instructions").

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 Rheumoxyb is used concomitantly with digoxin.

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

Patients receiving concomitant treatment with Rheumoxyb 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 dysfunction).

Rheumoxyb does not affect the pharmacokinetics of methotrexate.

Patients should be monitored for methotrexate toxicity during concomitant use of Rheumoxyb and methotrexate.

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

Patients should be monitored for signs of worsening renal function during concomitant use of Rheumoxyb 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 instructions").

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

Pemetrexed. Concomitant use of Rheumoxyb and pemetrexed may increase the risk of pemetrexed-associated myelosuppression and renal and gastrointestinal toxicity (see the pemetrexed product information).

When Rheumoxyb is used concomitantly with pemetrexed, patients with renal impairment (creatinine clearance between 45 and 79 mL/min) should be monitored for signs of myelosuppression and renal and gastrointestinal toxicity.

Avoid using NSAIDs with short elimination half-lives (e.g., diclofenac and indomethacin) 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 taking these NSAIDs should discontinue their use at least 5 days before pemetrexed administration, on the day of pemetrexed administration, and for the following 2 days after 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 exposure and toxicity of celecoxib, whereas concomitant use with CYP2C9 inducers (e.g., rifampicin) may reduce celecoxib efficacy.

When considering celecoxib administration, each patient's medical history should be evaluated. Dose adjustment of celecoxib may be warranted when used concomitantly 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, a potential in vivo interaction with medicinal products metabolized by CYP2D6 (e.g., atomoxetine) is possible, and celecoxib may increase the exposure and toxicity of these medicinal products.

Corticosteroids. Concomitant use of corticosteroids with Rheumoxyb may increase the risk of gastrointestinal ulcers or bleeding.

Patients receiving concomitant treatment with Rheumoxyb and corticosteroids should be monitored for signs of bleeding (see section "Special instructions").

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 events, including myocardial infarction and stroke, which may be fatal. Based on available data, it is unclear whether the risk of developing thrombotic cardiovascular complications is similar for all NSAIDs. The relative increase in the frequency of serious thrombotic cardiovascular complications compared to baseline rates 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 even higher absolute frequencies of serious thrombotic cardiovascular complications due to the increased baseline prevalence of these factors and diseases. In some observational studies, this increased risk of serious thrombotic cardiovascular complications appeared as early as the first weeks of treatment. The increased risk of thrombotic cardiovascular complications was 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 combined endpoint (death due to cardiovascular disease, myocardial infarction, or stroke) in the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment groups compared to placebo. This increased risk in both celecoxib 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 Study Comparing Celecoxib and 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 adverse cardiovascular reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. Physicians and patients should remain vigilant for the development of such reactions throughout the entire course of treatment, even in the absence of prior cardiovascular symptoms. Patients should be informed about 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 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, the cumulative Kaplan-Meier incidence rates at 9 months for peripheral edema in patients receiving celecoxib 400 mg twice daily (4 and 2 times higher than 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. According to the CLASS study, the incidence of hypertension in patients receiving celecoxib, ibuprofen, and diclofenac was 2.4%, 4.2%, and 2.5%, respectively.

Post-CABG state. In two large controlled clinical trials, the use of selective COX-2 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. The use of NSAIDs after CABG surgery is contraindicated (see section "Contraindications").

Post-myocardial infarction patients. Observational studies conducted by the Danish National Registry demonstrated that patients using NSAIDs in the period following myocardial infarction were at increased risk of recurrent myocardial infarction, cardiovascular death, and all-cause mortality, starting from the first week of treatment. In the same cohort, the rate of mortality in the first year after myocardial infarction was 20 cases per 100 person-years among patients using NSAIDs, compared to 12 cases per 100 person-years among 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 and large intestine, which may be fatal. These serious adverse reactions may occur at any time, with or without preceding symptoms, in patients receiving celecoxib. Only one in five patients develops clinical symptoms of serious upper gastrointestinal adverse reactions during NSAID treatment. Approximately 1% of patients treated with the drug for 3–6 months and approximately 2–4% of patients treated for one year experienced upper gastrointestinal ulcers, severe 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 taking 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 after the drug's market release were recorded in elderly 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 use of acetylsalicylic acid.

Strategies to minimize gastrointestinal risks in patients taking 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 the expected benefit outweighs the increased risk of bleeding. For such patients, as well as for patients with active gastrointestinal bleeding, consider using 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 diagnostic evaluation and treatment, and discontinue use of the drug Revmoxyb until the serious gastrointestinal adverse reaction is ruled out;
• When using low-dose aspirin concomitantly 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. Elevated levels of alanine aminotransferase or aspartate aminotransferase (3 times or more above the upper limit of normal) were observed in approximately 1% of patients taking NSAIDs in clinical trials. Additionally, rare, sometimes fatal, cases of severe liver function impairment, including fulminant hepatitis, liver necrosis, and liver failure, have been reported.

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

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

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 indicating liver disease or systemic manifestations (e.g., eosinophilia, rash, etc.) occur, use of celecoxib should be immediately discontinued and a clinical evaluation of the patient should be conducted.

Arterial hypertension. The use of NSAIDs, including celecoxib, may lead to the development of arterial hypertension or worsening of 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 with NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

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

Heart failure and edema. Results from a meta-analysis by the Antiplatelet Trialists’ Collaboration of randomized controlled trials of coxibs and traditional NSAIDs demonstrated approximately a twofold increase in hospitalization rates due to 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 due to heart failure, and mortality.

Additionally, fluid retention and edema have been observed in some patients taking NSAIDs. The use of celecoxib may attenuate the 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 celecoxib 400 mg twice daily (4 and 2 times higher than the recommended doses 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 decompensation of renal function. Patients at increased risk of these reactions include those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, patients taking diuretics, ACE inhibitors, angiotensin receptor blockers, and elderly patients. Discontinuation of NSAID treatment usually results in return to the pre-treatment state.

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

Before initiating celecoxib treatment, 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 celecoxib use (see section "Interaction with other medicinal products and other forms of interaction"). Celecoxib use should be avoided in patients with progressive kidney disease, except when the expected benefit outweighs the risk of worsening renal function. If celecoxib 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-hypoaldosteronemic state.

Anaphylactic reactions. The use of celecoxib has been associated with the development of anaphylactic reactions in patients with known hypersensitivity to celecoxib or without it, as well as in patients with aspirin-induced asthma. Revmoxyb 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 attention 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, the use of celecoxib is contraindicated in patients with this form of aspirin sensitivity (see section "Contraindications"). When using celecoxib in patients with pre-existing bronchial asthma (without known aspirin sensitivity), patients should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions. Celecoxib may cause serious skin adverse reactions such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash 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 the signs and symptoms of serious skin reactions and the need to discontinue celecoxib at the first appearance of skin rash or any other signs of hypersensitivity. Celecoxib 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 taking NSAIDs, such as Revmoxyb. 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 affected. 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, use of the medicinal product Revmoxyb should be discontinued immediately and the patient should be evaluated promptly.

Fetal toxicity.

Premature closure of the fetal ductus arteriosus. Celecoxib may cause premature closure of the fetal ductus arteriosus. The use of NSAIDs, including celecoxib, should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester).

Oligohydramnios/renal failure in newborns. The use of NSAIDs, including Revmoxyb, 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 within several days or weeks of treatment, although rare reports of oligohydramnios have been documented 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 Revmoxyb 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 Revmoxyb lasts more than 48 hours. If oligohydramnios develops, use of the medicinal product Revmoxyb should be discontinued 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 taking NSAIDs. This may be due to occult or significant blood loss, fluid retention, or an effect on erythropoiesis that is not fully characterized. If a patient exhibits any signs or symptoms of anemia while taking celecoxib, hemoglobin or hematocrit levels should be monitored.

In controlled clinical trials, the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. In patients undergoing long-term treatment with celecoxib, hemoglobin or hematocrit levels should be monitored if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs, including celecoxib, may increase the risk of bleeding. Concomitant factors such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), selective 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 celecoxib, which reduces inflammation and possibly fever, may diminish the diagnostic utility 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 taking 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 celecoxib than in those receiving placebo. This laboratory test abnormality was also observed in patients receiving comparator NSAID drugs during these trials. The clinical significance of this abnormality has not been established.

Disseminated intravascular coagulation. Since there is a risk of disseminated intravascular coagulation in children with systemic juvenile rheumatoid arthritis during celecoxib use, 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 symptoms as soon as possible.

Revmoxyb contains azorubine (E 122), which may cause allergic reactions.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or lactation.

Fertility. Since the mechanism of action of NSAIDs (including celecoxib) is mediated through prostaglandins, their use may delay or prevent ovarian follicle rupture, which may be associated with temporary infertility in some women. Published animal studies have shown that the 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 celecoxib, in women experiencing difficulties with conception or undergoing infertility evaluation.

Pregnancy. The use of NSAIDs, including celecoxib, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus and impaired fetal renal function, leading to oligohydramnios and, in some cases, renal failure in newborns. Due to these risks, the dose and duration of celecoxib use should be limited between approximately the 20th and 30th weeks of pregnancy, and use of the medicinal product Revmoxyb should be avoided from approximately the 30th week of pregnancy.

Premature closure of the fetal ductus arteriosus. The use of NSAIDs, including Revmoxyb, from approximately the 30th week of pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/renal failure in newborns. The 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 regarding potential embryofetal risks of NSAID use in women during the first or second trimester of pregnancy, definitive conclusions could not be drawn. In reproductive animal studies, cases of embryofetal lethality and increased incidence of diaphragmatic hernia were observed in rats given celecoxib orally daily during the organogenesis period at doses approximately 6 times higher than 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 celecoxib orally during the organogenesis period at doses approximately 2 times higher than the maximum recommended human dose. Based on animal data, prostaglandins play an important role in regulating endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as celecoxib, led to increased pre- and post-implantation losses. Prostaglandins are also known to play an important role in fetal kidney development. According to published animal studies, prostaglandin synthesis inhibitors impair kidney development when used at clinically relevant doses.

All pregnancies are associated with a background risk of birth defects, miscarriage, or other adverse outcomes. In the general US population, regardless of drug exposure, all clinically recognized pregnancies have a background incidence of 2–4% major birth defects and 15–20% miscarriage. The estimated background risk of major birth defects and miscarriage for this population is unknown.

Adverse effects in fetus/newborn.

Premature closure of the fetal ductus arteriosus

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

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 Revmoxyb lasts more than 48 hours, consider ultrasound monitoring for oligohydramnios. If oligohydramnios is observed, use of the medicinal product Revmoxyb should be discontinued and management continued according to clinical practice (see below "Human data").

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

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

The effects of celecoxib on the course of labour and delivery in pregnant women are unknown.

Premature closure of the fetal ductus arteriosus

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

Oligohydramnios/renal failure in newborns

Published studies and post-marketing reports describe NSAID use 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 within several days or weeks of treatment, although rare reports of oligohydramnios have been documented as early as 48 hours after starting NSAID use. In many cases, but not always, the reduction in amniotic fluid volume was temporary and resolved after discontinuation of the drug. There is a limited number of reports of 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 the absence of a control group; limited information on dose, duration, and timing of drug exposure; and concomitant use of other medicinal products. These limitations hinder reliable assessment of the risk of adverse outcomes in fetuses and newborns exposed to NSAIDs via maternal use. Since published data on neonatal safety 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 celecoxib in breast milk. The calculated average daily dose for the infant 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 of two breastfed infants aged 17 and 22 months, no adverse reactions were reported.

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

Ability to affect reaction speed when driving vehicles or operating machinery. If dizziness, vertigo, or drowsiness occur during celecoxib use, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage.

General Dosing Instructions. Before deciding to use this medicinal product, the expected potential benefits and risks of celecoxib therapy should be carefully considered, and the appropriateness of alternative treatment options should be evaluated. The lowest effective dose should be used for the shortest duration consistent with the individual treatment goals (see section "Special Warnings and Precautions for Use").

This medicinal product may be taken independently of food intake.

Osteoarthritis. For the treatment of osteoarthritis, the recommended dose is 200 mg 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 celecoxib 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 no response is observed 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 Primary Dysmenorrhea. For the management of acute pain and 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 Populations.

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.

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

Elderly Patients. Elderly patients have a greater risk compared to younger patients of developing serious adverse reactions associated with NSAID use, including 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, and patients should be monitored for the development of adverse reactions (see section "Special Warnings and Precautions for Use").

In the overall population of patients who received celecoxib in pre-marketing clinical trials, 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 selectively inhibiting COX-2, post-marketing surveillance has reported a higher number of spontaneous reports of fatal gastrointestinal events and acute renal failure in elderly patients compared to younger patients (see section "Special Warnings and Precautions for Use").

Pediatric Population. Remoxib, 200 mg capsules, is 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 care. Cases of gastrointestinal bleeding have been reported. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma have been observed (see section "Special Warnings and Precautions for Use").

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

Following NSAID overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. Induction of emesis and/or administration of 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 symptoms within 4 hours after oral ingestion, as well as in patients with severe overdose (dose 5–10 times 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

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of one drug cannot be directly compared with the rate observed in the clinical trials of another drug, and may not reflect the incidence rates observed in practice. However, adverse reaction information from clinical trials provides a basis for identifying reactions potentially associated with drug use and for estimating their frequency.

Among patients who received celecoxib in controlled clinical trials conducted prior to marketing approval, approximately 4250 patients had osteoarthritis, approximately 2100 patients had rheumatoid arthritis, and approximately 1050 patients had postoperative pain. More than 8500 patients received celecoxib 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 3900 patients received celecoxib at these doses for 6 months or longer; about 2300 of these patients received the drug for 1 year or more, and 124 of these patients received the drug for 2 years or longer.

Controlled pre-marketing studies of celecoxib for the treatment of arthritis.

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

Table 2.

Adverse reactions occurring in more than 2% of patients receiving celecoxib during controlled pre-marketing studies of celecoxib for the treatment of arthritis.

	PBO N=4146	Placebo N=1864	NSAID N=1366	DMARD N=387	IBU N=345
Gastrointestinal disorders Abdominal 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 and administration site conditions 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 and subcutaneous tissue disorders Rash	2.2%	2.1%	2.1%	1.3%	1.2%

CBS — celecoxib at a dose of 100**–**200 mg twice daily or 200 mg once daily.

NSAIDs — 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% among patients receiving celecoxib and 6.1% among those receiving placebo. The most common reasons for discontinuation due to adverse reactions in the celecoxib groups 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 reported in 0.1**–1.9% of patients treated with celecoxib (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 edema, increased fatigue, fever, hot flushes, flu-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 levels of liver enzymes (including increased levels of aspartate aminotransferase and alanine aminotransferase).

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

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

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

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

Blood disorders: anemia.

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

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

Application site disorders: panniculitis, contact dermatitis.

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: intestinal perforation, gastrointestinal hemorrhage, hemorrhagic colitis, esophageal perforation, pancreatitis, intestinal obstruction, duodenal ulcer, gastric ulcer, esophageal ulcer, intestinal ulcer, ulcer of the large intestine.

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 types of interactions").

Renal disorders: acute renal failure.

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

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

Discontinuation of treatment / serious adverse reactions. The cumulative incidence of discontinuation of celecoxib, diclofenac, and ibuprofen due to adverse reactions over 9 months, calculated using the Kaplan-Meier method, was 24%, 29%, and 26%, respectively. The incidence of serious adverse reactions (i.e., those leading to hospitalization or life-threatening conditions, or otherwise representing important medical events), 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%) reported in patients treated with celecoxib were headache, fever (hyperthermia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting. The most common adverse reactions (≥ 5%) reported in patients treated with naproxen were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). During this 12-week double-blind study, no adverse 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 flares of uveitis or systemic manifestations 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
Laboratory test results*	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 biochemistry (unspecified), presence of proteinuria, increased transaminase levels (unspecified), abnormal urine analysis findings (unspecified).

Other studies conducted prior to the market release of celecoxib.

Adverse reactions observed in ankylosing spondylitis treatment studies. A total of 378 patients received celecoxib in placebo-controlled and active-controlled studies of ankylosing spondylitis treatment. The studies evaluated celecoxib 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 osteoarthritis/rheumatoid arthritis treatment studies.

Adverse reactions observed in analgesic and dysmenorrhea treatment studies. Approximately 1700 patients received celecoxib in analgesic and dysmenorrhea studies. In studies involving patients with postoperative oral surgery pain, all participants received a single dose of the investigational drug. In studies of primary dysmenorrhea and post-orthopedic surgical pain treatment, celecoxib was evaluated at doses up to 600 mg/day. The types of adverse reactions reported in analgesic and dysmenorrhea studies were the same as those reported in arthritis studies. The only additional adverse reaction reported in post-orthopedic surgery pain studies was alveolar osteitis after tooth extraction (post-extraction socket alveolitis).

PreSAP study and celecoxib adenoma prevention study.

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

Some adverse reactions occurred at a higher frequency compared to those observed in arthritis treatment studies conducted prior to market release (treatment duration up to 12 weeks). The table below lists adverse reactions that occurred more frequently in patients receiving celecoxib compared to patients in pre-marketing arthritis treatment studies.

Adverse reactions	Celecoxib (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 celecoxib, and occurred more frequently than with placebo in long-term polyp prevention trials. These were either not reported during pre-marketing controlled trials of the drug for the treatment of arthritis 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 pectoris, 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 with celecoxib.

The following adverse reactions have been identified during post-marketing use of celecoxib. 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 system: vasculitis, deep vein thrombosis.

General disorders: anaphylactoid reaction, angioneurotic oedema.

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

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

Metabolism and nutrition 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 in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 capsules in a blister, 1 blister in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.