Lekoxa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEKOXA (LEKOXA)

Composition:

active substance: celecoxib;

1 hard capsule contains celecoxib 100 mg or 200 mg;

excipients: lactose monohydrate; sodium lauryl sulfate; sodium croscarmellose; povidone; isopropyl alcohol; magnesium stearate;

capsules of 100 mg: capsule (iron oxide red (E 172), titanium dioxide (E 171), gelatin);

capsules of 200 mg: capsule (titanium dioxide (E 171), gelatin).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

capsules of 100 mg – hard gelatin capsules, size № 2, opaque, beige cap and body, containing white or almost white powder;

capsules of 200 mg – hard gelatin capsules, size № 0, opaque, white cap and body, containing white or almost white powder.

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. Its mechanism of action is believed to be related to inhibition of prostaglandin synthesis, primarily by inhibition of 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 effect 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

Effect on 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 bleeding time. Due to the lack of effect on platelets, celecoxib cannot be used as a substitute for acetylsalicylic acid for 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

Celecoxib exposure increases approximately dose-proportionally after administration of 200 mg twice daily; at higher doses, exposure increases less than proportionally. Celecoxib 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

After oral administration, peak plasma concentrations of celecoxib are reached in approximately 3 hours. 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"). Studies on absolute bioavailability of celecoxib have not been conducted. At steady state, equilibrium is achieved by day 5 or earlier with multiple dosing. Pharmacokinetic parameters of celecoxib in healthy volunteers are presented in Table 1.

Table 1

Pharmacokinetic parameters after 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)
In healthy volunteers after administration of celecoxib under fasting conditions (n=36, 19–52 years)

Vss/F – volume of distribution at steady state.

CL/F – plasma clearance.

Effect of food intake

When celecoxib was administered with a high-fat meal, Cmax was delayed by approximately 1–2 hours, with an increase in total absorption (AUC) of 10% to 20%. When celecoxib was administered in fasting conditions at doses exceeding 200 mg, sublinear increases in Cmax and AUC were observed, which is attributed to its low solubility in aqueous media.

Concomitant administration of celecoxib with antacids containing aluminium 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 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) of celecoxib was not different when the capsule was swallowed whole or when its contents were mixed with applesauce. After administration of the capsule contents mixed with applesauce, no significant changes were observed in Cmax, time to maximum concentration (Tmax), or elimination half-life (t1/2) (see section "Dosage and administration").

Distribution

In healthy volunteers, following administration within the clinical dose range, celecoxib is highly 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 distribution of celecoxib into tissues. Celecoxib does not show preferential binding to erythrocytes.

Metabolism

Celecoxib is primarily metabolized by CYP2C9. Three metabolites have been identified in human plasma: the primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate. These metabolites are inactive with respect to inhibition of 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 celecoxib, 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 celecoxib is believed to prolong the absorption process, resulting in a more variable t1/2. The effective t1/2 is approximately 11 hours under fasting conditions. Plasma clearance is approximately 500 mL/min.

Special patient populations

Elderly patients

In elderly patients (aged 65 years and older), 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, treatment should be initiated with the lowest recommended dose in patients with body weight below 50 kg (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 following administration of an experimental oral suspension formulation. Population pharmacokinetic analysis showed that oral clearance (unadjusted 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 adult patients with rheumatoid arthritis weighing 70 kg.

Administration of 50 mg celecoxib capsules twice daily to patients with juvenile rheumatoid arthritis 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 7.5 mg/kg twice daily (see section "Dosage and administration"). Studies of celecoxib in patients with juvenile rheumatoid arthritis under 2 years of age or with body weight <10 kg have not been conducted, nor have studies longer than 24 weeks.

Patients of different races

Based on the results of a meta-analysis of pharmacokinetic studies, it was hypothesized that AUC values of celecoxib in Black/African individuals are 40% higher than in Caucasian individuals. The explanation and clinical significance of these findings are unknown.

Hepatic impairment

In patients with mild hepatic impairment, mean increases in Cmax and AUC of celecoxib were 53% and 26%, respectively, compared to patients with normal liver function. In patients with moderate hepatic impairment, corresponding increases were 41% and 146%, respectively. The rate of celecoxib metabolism in patients with mild and moderate hepatic impairment correlated with serum albumin levels. Treatment in patients with moderate hepatic impairment (serum albumin level 25–35 g/L) should be initiated with half the recommended dose. Patients with severe hepatic impairment (serum albumin <25 g/L) have not been studied; celecoxib is contraindicated in these patients.

Renal impairment

Experience with celecoxib in patients with renal impairment is limited. The pharmacokinetics of celecoxib in this patient group has not been specifically studied, but no significant changes are expected. Nevertheless, caution should be exercised when treating patients with renal impairment. Celecoxib is contraindicated in patients with severe renal impairment.

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.

Acetylsalicylic acid

When NSAIDs are co-administered with acetylsalicylic acid, their plasma protein binding is reduced, although the clearance of the unbound form of NSAIDs remains unchanged. The clinical significance of this interaction is unknown. Clinically relevant interactions between NSAIDs and acetylsalicylic acid are described in the section "Interaction with other medicinal products and other forms of interaction".

Lithium preparations

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 inhibition by fluconazole 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 investigate 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 observed.

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 levels of celecoxib were 3–7 times higher in these patients compared to those with CYP2C9*1/*1 and *I/*3 genotypes. The pharmacokinetics of celecoxib in patients with other CYP2C9 polymorphisms, such as *2, *5, *6, *9, and *11, have not been evaluated. 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 management.

To assess non-inferiority (80%), the primary composite endpoint was defined by the Antiplatelet Trialists’ Collaboration (APTC) as a combination of cardiovascular death (including fatal bleeds), non-fatal myocardial infarction, and non-fatal stroke. All patients received open-label esomeprazole (20–40 mg) as gastroprotection. Randomization into treatment groups was stratified by baseline use of low-dose acetylsalicylic acid.

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 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 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, by the fourth month, mean 24-hour systolic blood pressure decreased by 0.3 mm Hg in the celecoxib 100 mg twice daily group, whereas in the ibuprofen and naproxen groups at the respective doses, mean 24-hour systolic blood pressure increased by 3.7 mm Hg 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

• Symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (see section "Special Considerations").
• Treatment of acute pain in adult patients (see section "Special Considerations").
• Treatment of primary dysmenorrhea (see section "Special Considerations").

Contraindications

• Hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib and/or to any of the components of the medicinal product (see section "Special Considerations").
• History of bronchial asthma, urticaria, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic-type reactions after taking acetylsalicylic acid or other NSAIDs, including COX-2 inhibitors. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see section "Special Considerations").
• History of allergic-type reactions to sulfonamide drugs.
• Following coronary artery bypass graft (CABG) surgery (see section "Special Considerations").
• Active peptic ulcer or gastrointestinal bleeding.
• Inflammatory bowel disease.
• Congestive heart failure (NYHA Class II–IV).
• Established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.
• Severe hepatic impairment (plasma albumin <25 g/L or Child–Pugh score ≥10).
• Use in patients with a calculated creatinine clearance <30 mL/min.
• Pregnancy and use in women of childbearing potential who are not using effective contraception.
• Breastfeeding period.

Interaction with Other Medicinal Products and Other Forms of Interaction

Medicinal Products Affecting Hemostasis

Concomitant use of celecoxib and anticoagulants increases the risk of serious bleeding compared to use of either agent alone. Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. Therefore, in patients receiving oral anticoagulants, prothrombin time and international normalized ratio (INR) should be closely monitored, especially during the first few days after initiating celecoxib therapy or changing the dose of celecoxib. Cases of bleeding associated with increased prothrombin time have been reported, predominantly in elderly patients receiving celecoxib and warfarin concurrently; some of these cases were fatal.

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

When celecoxib is used concomitantly with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs), patients should be monitored for signs of bleeding (see section "Special Considerations").

Acetylsalicylic Acid

Controlled clinical studies have shown that concomitant use of NSAIDs and acetylsalicylic acid at analgesic doses does not provide any additional therapeutic benefit compared to NSAID use alone. In a clinical study, concomitant use of NSAIDs and acetylsalicylic acid was associated with a significantly higher incidence of gastrointestinal adverse reactions compared to NSAID use alone (see section "Special Considerations").

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

Concomitant use of celecoxib and acetylsalicylic acid at analgesic doses is generally not recommended due to increased risk of bleeding (see section "Special Considerations"). Celecoxib should not be used as a substitute for low-dose acetylsalicylic acid for prevention of cardiovascular disease.

Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers, and β-Blockers

Concomitant use with NSAIDs may reduce the antihypertensive effect of ACE inhibitors, angiotensin receptor blockers, diuretics, or β-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 deterioration in renal function, including acute renal failure. These effects are usually reversible.

When celecoxib is used concomitantly with ACE inhibitors, angiotensin receptor blockers, or β-blockers, blood pressure should be monitored to ensure achievement of the desired blood pressure level.

When celecoxib 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 renal impairment should be performed (see section "Special Considerations").

Patients receiving concomitant therapy should maintain adequate fluid intake. Renal function should be assessed at the start of treatment and periodically thereafter.

In a 28-day clinical study in patients with stage I and II hypertension controlled by lisinopril, administration of celecoxib 200 mg twice daily did not result in clinically significant increases in mean 24-hour systolic or diastolic blood pressure compared to placebo, as determined by 24-hour ambulatory blood pressure monitoring. Among patients receiving celecoxib 200 mg twice daily, 48% were considered non-responsive to lisinopril at the final clinic visit, compared to 27% in the placebo group; this difference was statistically significant.

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 NSAID inhibition of renal prostaglandin synthesis.

When these medicinal products are used concomitantly, patients should be monitored for signs of renal impairment, and diuretic efficacy, including antihypertensive effect, should be confirmed (see section "Special Considerations").

Digoxin

Concomitant use of celecoxib with digoxin has been shown to increase plasma digoxin concentrations and prolong its t1/2. When these medicinal products are used concomitantly, plasma digoxin levels should be monitored.

Lithium

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

In healthy subjects, concomitant administration of celecoxib 200 mg twice daily with lithium 450 mg twice daily resulted in an average increase in Cmax of lithium by 16% and AUC by 18%. Therefore, patients taking lithium should be closely monitored at the start of treatment and during discontinuation of celecoxib.

When these medicinal products are used concomitantly, patients should be monitored for signs of lithium toxicity.

Methotrexate

Concomitant use with NSAIDs may increase methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal impairment). Celecoxib does not affect the pharmacokinetics of methotrexate. When used concomitantly, patients should be monitored for signs of methotrexate toxicity.

Cyclosporine and Tacrolimus

Concomitant use of celecoxib with cyclosporine or tacrolimus may increase the nephrotoxicity of cyclosporine or tacrolimus. When these medicinal products are used concomitantly, patients should be monitored for signs of renal impairment.

Other NSAIDs, 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 Considerations").

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

Pemetrexed

In patients with impaired renal function, concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression and renal and gastrointestinal toxicity (see the pemetrexed product information).

When these medicinal products are used concomitantly in patients with renal impairment (creatinine clearance between 45 mL/min and 79 mL/min), monitoring for signs of myelosuppression and renal and gastrointestinal toxicity is recommended.

NSAIDs with short t1/2 (e.g., diclofenac, indomethacin) should be avoided for 2 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 t1/2 (e.g., meloxicam, nabumetone), patients taking these NSAIDs should discontinue their use at least 5 days before pemetrexed administration, on the day of pemetrexed administration, and for 2 days thereafter.

Inhibition of CYP2C19

In vitro studies have shown celecoxib has the potential to inhibit CYP2C19-mediated metabolism. The clinical significance of this in vitro finding is unknown. Examples of medicinal products metabolized by CYP2C19 include diazepam, citalopram, and imipramine.

Inhibitors or Inducers of CYP2C9

Celecoxib metabolism is primarily mediated by the hepatic cytochrome P450 isoenzyme CYP2C9. Concomitant use of celecoxib with known CYP2C9 inhibitors (e.g., fluconazole) may increase the effect and toxicity of celecoxib, whereas concomitant use with CYP2C9 inducers (e.g., rifampicin, carbamazepine, barbiturates) may reduce celecoxib efficacy. Concomitant administration of single-dose celecoxib 200 mg and fluconazole 200 mg once daily resulted in an average increase in Cmax of celecoxib by 60% and AUC by 130%.

When considering celecoxib administration, each patient's history should be evaluated. Dose adjustment of celecoxib may be warranted when used concomitantly with CYP2C9 inhibitors or inducers (see section "Pharmacokinetics").

Celecoxib does not have a clinically significant effect on the pharmacokinetics of tolbutamide (a CYP2C9 substrate) or glyburide.

Substrates of CYP2D6

In vitro study results indicate that celecoxib, while not a substrate, is an inhibitor of CYP2D6. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when used concomitantly with celecoxib. Examples include antidepressants (tricyclics and SSRIs), neuroleptics, antiarrhythmics, etc. The dose of individually titrated CYP2D6 substrates may need to be reduced at the start of celecoxib therapy or with dose escalation, and increased accordingly upon discontinuation of celecoxib.

Concomitant administration of celecoxib 200 mg twice daily increased plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates) by 2.6-fold and 1.5-fold, respectively. This increase is due to inhibition of CYP2D6 substrate metabolism by celecoxib.

Thus, potential in vivo drug interactions with medicinal products metabolized by CYP2D6 (e.g., atomoxetine) are possible, and celecoxib may increase the effect and toxicity of these medicinal products.

When considering celecoxib administration, each patient's history should be evaluated. Dose adjustment may be warranted when celecoxib is used concomitantly with CYP2D6 substrates (see section "Pharmacokinetics").

Corticosteroids

Concomitant use of celecoxib with corticosteroids may increase the risk of gastrointestinal ulcers or bleeding. When these medicinal products are used concomitantly, patients should be monitored for signs of bleeding (see section "Special Considerations").

Oral Contraceptives

In a drug interaction study, celecoxib had no clinically significant effect on the pharmacokinetics of oral contraceptives (1 mg norethisterone / 35 µg ethinylestradiol).

Ketoconazole and Antacids

No effect of ketoconazole or antacids on the pharmacokinetics of celecoxib has been observed.

Special precautions for use

Cardiovascular thrombotic events risk

Clinical trials of several selective and non-selective COX-2 inhibitors from the NSAID class, with durations of up to 3 years, have demonstrated an increased risk of serious thrombotic adverse 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 incidence of serious thrombotic cardiovascular complications associated with NSAID use occurs both in patients with known cardiovascular diseases and risk factors for their development, and in patients without such conditions and risk factors. However, patients with known cardiovascular disease or cardiovascular risk factors had an even higher absolute incidence of serious thrombotic cardiovascular complications due to the higher baseline prevalence of these factors and diseases. Patients with significant risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should be treated with celecoxib only after careful assessment of the benefit-risk ratio (see section "Pharmacological properties"). 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 the use of celecoxib at higher doses.

In a long-term placebo-controlled study, in which patients with sporadic adenomatous polyps received celecoxib at a dose of 200 mg or 400 mg twice daily, an increased incidence of serious cardiovascular events (including myocardial infarction) was observed compared to the placebo group.

A randomized, controlled clinical trial, "Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION)," was conducted to evaluate 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 using NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. The exact magnitude of risk associated with single-dose use, as well as the treatment duration at which the risk of cardiovascular complications increases, has not been established. Physicians and patients should remain vigilant 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 the measures to be taken if they occur.

There is no direct evidence that concomitant use of acetylsalicylic acid reduces the increased risk of serious thrombotic cardiovascular complications associated with NSAID use. Concomitant use of acetylsalicylic acid 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 of peripheral edema at 9 months 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 was 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.

Use in coronary artery bypass graft (CABG) surgery

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 grafting was associated with an increased incidence of myocardial infarction and stroke. The use of NSAIDs in CABG surgery is contraindicated (see section "Contraindications").

Use in patients after myocardial infarction

Observational studies conducted by the Danish National Registry demonstrated that patients using NSAIDs after myocardial infarction were at increased risk of recurrent myocardial infarction, cardiovascular death, and death from any cause, starting from the first week of treatment. In the same cohort, the incidence of death within the first year after myocardial infarction was 20 cases per 100 patient-years among NSAID users compared to 12 cases per 100 patient-years among non-users. 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 death in NSAID users persists.

Gastrointestinal bleeding, ulceration, and perforation risk

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 may occur at any time, with or without preceding symptoms, in patients taking celecoxib. Only one in five patients develops clinical symptoms of serious upper gastrointestinal adverse reactions during NSAID treatment. Approximately 1% of patients treated with celecoxib 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

The risk of gastrointestinal adverse effects with celecoxib use (gastrointestinal ulcers or other gastrointestinal complications) increases further with concomitant use of acetylsalicylic acid (even at low doses). Long-term clinical studies have not demonstrated a statistically significant difference in gastrointestinal safety profile between selective COX-2 inhibitors + acetylsalicylic acid compared to non-selective NSAIDs + acetylsalicylic acid.

Patients with a history of peptic ulcer and/or gastrointestinal bleeding while taking NSAIDs had 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 treatment duration, concomitant oral corticosteroid use, antiplatelet agents (e.g., acetylsalicylic acid), anticoagulants or SSRIs, tobacco smoking, alcohol consumption, advanced age, and poor general health. Most reports of fatal gastrointestinal adverse reactions following celecoxib marketing 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 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 using the drug in high-risk patients, except when the expected benefit outweighs the increased risk of bleeding (in such patients, and in patients with active gastrointestinal bleeding, consider using alternative agents 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 the drug until the serious gastrointestinal adverse reaction is ruled out;
• When using low-dose acetylsalicylic acid concomitantly for cardiovascular event prevention, patients should be monitored more closely for signs of gastrointestinal bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Hepatotoxicity risk

Elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (3 times or more above the upper limit of normal (ULN)) 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.

Elevations in ALT or AST levels (less than 3 times above ULN) may occur in approximately 15% of patients taking NSAIDs, including celecoxib.

In controlled clinical trials of celecoxib, the incidence of mild elevations (exceeding ULN from 1.2 to less than 3 times) in liver function-related enzymes was 6% in patients taking celecoxib and 5% in placebo recipients, while significant elevations in ALT and AST levels were observed in approximately 0.2% of celecoxib users and 0.3% of placebo recipients.

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 of disease (e.g., eosinophilia, rash) occur, the drug should be discontinued immediately and the patient clinically evaluated.

Liver function abnormalities occur more frequently in elderly patients; therefore, appropriate medical monitoring should be ensured.

Isolated cases of severe hepatic reactions, including fulminant hepatitis (some fatal), liver necrosis, and liver failure (some cases fatal or requiring liver transplantation), have been reported with celecoxib use. Among cases with known onset time, most severe hepatic adverse reactions developed within one month of treatment initiation.

If liver function deteriorates during treatment, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered.

Arterial hypertension risk

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 beginning of treatment and throughout the treatment course.

Heart failure and edema risk

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 placebo recipients. In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of myocardial infarction, hospitalization for heart failure, and death.

Additionally, as with other drugs that inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking NSAIDs. Celecoxib use 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 celecoxib 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.

The drug should be used with caution in patients with a history of heart failure, left ventricular dysfunction, or hypertension, as well as in patients with existing edema from any cause, since prostaglandin inhibition may lead to worsening renal function and fluid retention. Caution is also required when using the drug in patients taking diuretics or at risk of hypovolemia.

Nephrotoxicity risk

NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials of celecoxib showed renal effects similar to those observed with comparative NSAIDs.

Long-term 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, reduced renal blood flow, potentially leading to significant renal function decompensation.

Renal function abnormalities occur more frequently in elderly patients; therefore, appropriate medical monitoring should be ensured.

Patients at increased risk of these reactions include those with renal impairment, dehydration, hypovolemia, heart failure, hepatic dysfunction, patients taking diuretics, ACE inhibitors, angiotensin receptor blockers, and elderly patients. Such patients should be closely monitored during celecoxib treatment. Discontinuation of NSAID treatment is usually followed by 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 function impairment.

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

Hyperkalemia risk

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

Anaphylactic reactions risk

Celecoxib use has been associated with hypersensitivity reactions (including anaphylaxis, angioedema) in patients with known hypersensitivity to celecoxib or without it, as well as in patients with aspirin-induced asthma. Celecoxib is a sulfonamide-containing drug, and both NSAIDs and sulfonamide-containing drugs may 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.

Bronchial asthma exacerbation risk associated with acetylsalicylic acid 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 acetylsalicylic acid and other NSAIDs. Since cross-reactivity between acetylsalicylic acid and other NSAIDs has been reported in such acetylsalicylic acid-sensitive patients, the use of the drug is contraindicated in patients with this form of acetylsalicylic acid sensitivity (see section "Contraindications"). When using the drug in patients with pre-existing bronchial asthma (without known acetylsalicylic acid sensitivity), patients should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions risk

Celecoxib may cause serious skin adverse reactions such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Drug rashes, which may manifest in more severe forms such as generalized exanthematous pustulosis, have also been reported. 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 necessity to discontinue the drug at the first appearance of skin rash or any other signs of hypersensitivity.

Patients with sulfonamide allergy or any drug allergy may have an increased risk of developing severe skin reactions or hypersensitivity reactions (see section "Contraindications"). The highest risk of these reactions occurs early in therapy: in most cases, the reaction occurred within the first month of treatment. The drug should be discontinued at the first signs of skin rash, mucosal lesions, or any other manifestations of hypersensitivity.

The drug 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 celecoxib. 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, DRESS syndrome symptoms 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, the drug should be discontinued immediately and the patient evaluated.

Fetal toxicity

Premature closure of the fetal ductus arteriosus risk

Celecoxib may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/renal failure in newborns

The use of NSAIDs, including celecoxib, from approximately the 20th week of pregnancy may cause 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 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.

Hematological toxicity risk

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 the drug, hemoglobin or hematocrit levels should be monitored.

In controlled clinical trials, the incidence of anemia was 0.6% with celecoxib use and 0.4% with placebo. In patients undergoing long-term treatment with the drug, 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. Contributing factors such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., acetylsalicylic acid), SSRIs, or SNRIs may increase this risk. Patients should be monitored for signs of bleeding during drug use (see section "Interaction with other medicinal products and other forms of interaction").

Masking of inflammation and fever

The pharmacological activity of celecoxib in reducing inflammation and possibly lowering elevated temperature may diminish the diagnostic value of signs in detecting infections.

Monitoring of laboratory test results

Since serious gastrointestinal bleeding, hepatotoxicity, and renal damage may occur without warning symptoms and signs, consideration should be given to monitoring patients taking NSAIDs, including celecoxib, over a prolonged period. 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 placebo recipients. This laboratory abnormality was also observed in patients receiving comparative NSAID drugs in these trials. The clinical significance of this laboratory abnormality has not been established.

Disseminated intravascular coagulation risk

Since there is a risk of disseminated intravascular coagulation during celecoxib use in children with systemic juvenile rheumatoid arthritis, patients should be monitored for signs and symptoms of coagulation disorders or bleeding during drug use, and patients and their caregivers should be informed to report symptoms as soon as possible.

Effect on fertility

Given that 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 prostaglandin synthesis inhibitors may potentially disrupt prostaglandin-mediated follicle rupture necessary for ovulation. Small studies in women taking NSAIDs have also demonstrated reversible ovulation delay. Consideration should be given to discontinuing NSAIDs, including celecoxib, in women experiencing difficulty conceiving or undergoing infertility evaluation.

CYP2D6 inhibition

Celecoxib inhibits the CYP2D6 enzyme. Although it is not a potent inhibitor of this enzyme, dose reduction of CYP2D6-metabolized drugs requiring individual dose titration may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Use in patients with reduced CYP2C9 activity

Patients with reduced CYP2C9 enzyme activity (so-called "poor metabolizers") should be treated with caution (see section "Pharmacokinetics").

General warnings

Celecoxib may mask fever and other signs of inflammation, which may complicate the diagnosis of infectious or inflammatory processes in patients.

Use with oral anticoagulants

Serious bleeding, some fatal, has been reported in patients receiving concomitant warfarin therapy. Increased prothrombin time has been reported with concomitant use. Therefore, this parameter should be carefully monitored in patients taking warfarin or other coumarin anticoagulants, especially at the beginning of celecoxib treatment or when changing its dose. Concomitant use of anticoagulants with NSAIDs may increase the risk of bleeding. Caution is required when combining celecoxib with warfarin or other oral anticoagulants, including newer agents (e.g., apixaban, dabigatran, rivaroxaban).

Warnings related to excipients

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

The drug contains less than 1 mmol of sodium (23 mg) per capsule, i.e., practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

The use of celecoxib during pregnancy is contraindicated. The use of celecoxib is also contraindicated in women of childbearing potential. If a woman becomes pregnant during treatment, celecoxib use should be discontinued (see also sections "Contraindications" and "Special precautions for use").

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 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 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.

It is known that prostaglandins also play an important role in fetal kidney development. Published animal studies have reported that prostaglandin synthesis inhibitors impair kidney development when used at clinically significant doses.

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

Premature closure of the fetal ductus arteriosus

The use of NSAIDs, including celecoxib, 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.

Published studies and post-marketing reports describe the use of NSAIDs in women from approximately 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 been documented as early as 48 hours after starting NSAID use. In many cases, but not always, reduced amniotic fluid volume was temporary and resolved after discontinuation of celecoxib. 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 lack of a control group; limited information on dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations prevent a reliable assessment of the risk of adverse outcomes in fetuses and newborns exposed to NSAIDs in utero. Since published safety data for newborns primarily concern preterm infants, generalizing certain reported risks to term infants exposed to NSAIDs via maternal use is uncertain.

Labor and delivery

Studies on the effect of celecoxib on labor or delivery have not been conducted. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, causing delayed labor 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 labor and delivery in pregnant women are unknown.

Breastfeeding period

Celecoxib penetrates into the milk of lactating rats at concentrations similar to plasma levels. Limited use of celecoxib in breastfeeding women has shown very low penetration of celecoxib into breast milk.

Women taking celecoxib should not breastfeed.

Fertility

Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent ovarian follicle rupture, which is associated with reversible infertility in some women (see section "Special precautions for use").

Ability to influence reaction speed when driving or operating machinery

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

Method of Administration and Dosage

The medicinal product is intended for oral administration. Capsules can be taken independently of food intake.

Before deciding to use this medicinal product, the potential benefits and risks of celecoxib therapy should be carefully weighed, and the appropriateness of other treatment options should be considered.

The lowest effective dose of the medicinal product should be used for the shortest duration consistent with the individual treatment goals (see section "Special Warnings and Precautions for Use").

Osteoarthritis

Administer the medicinal product at a dose of 200 mg once daily or 100 mg twice daily.

Rheumatoid Arthritis

Administer the medicinal product at a dose of 100–200 mg twice daily.

Ankylosing Spondylitis

Administer the medicinal product at a dose of 200 mg, taken once daily or divided into two doses (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 a dose of 400 mg daily, a therapeutic response is unlikely, and alternative treatment options should be considered.

Management of Acute Pain and Primary Dysmenorrhea

Administer the medicinal product at an initial dose of 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

Patients with Hepatic Impairment

Treatment of patients with clinically evident moderate hepatic impairment (serum albumin level 25–35 g/L) should be initiated at half the recommended dose.
Experience with celecoxib in such patients is limited, particularly in patients with liver cirrhosis (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Patients with Renal Impairment

Experience with celecoxib in patients with mild or moderate renal impairment is limited. Therefore, the medicinal product should be used with caution in these patients (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Patients with Slow Metabolism of CYP2C9 Substrates

In adult patients with known or suspected reduced metabolism of CYP2C9 substrates based on genotype or previous experience with other CYP2C9 substrates (such as 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 alternative treatments (see section "Pharmacological Properties. Pharmacogenomics").

Elderly Patients

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

If the anticipated benefit for elderly patients outweighs the potential risks, 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 category 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 more spontaneous cases of fatal gastrointestinal events and acute renal failure in elderly patients compared to younger patients (see section "Special Warnings and Precautions for Use").

Children

The medicinal product is not intended for use in children.

Overdose

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric abdominal pain, and are usually 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 Warnings and Precautions for Use").

No cases of celecoxib overdose were reported during clinical trials. No serious intoxication was observed in 12 patients who received doses up to 2400 mg daily for up to 10 days.

There is no information on the possibility of eliminating celecoxib by hemodialysis; however, due to its high plasma protein binding (>97%), dialysis is expected to be ineffective in overdose.

In cases of NSAID overdose, symptomatic and supportive treatment should be provided. 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 overdose symptoms within four hours of ingestion, as well as in patients with severe overdose (dose 5–10 times the recommended dose). Clinical monitoring and, if necessary, symptomatic treatment may be beneficial. Forced diuresis, alkalinization of urine, 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 medicinal product cannot be directly compared with the rate observed in the clinical trials of another medicinal product, and may not reflect the incidence rates observed in practice. However, adverse reaction data from clinical trials provide the basis for identifying reactions that may be related to the use of the medicinal product and for estimating their frequency.

Among patients treated with celecoxib in controlled clinical trials conducted prior to its marketing approval, approximately 4,250 patients had osteoarthritis, approximately 2,100 patients had rheumatoid arthritis, and approximately

1,050 patients had postoperative pain. More than 8,500 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 3,900 patients received celecoxib at these doses for

6 months or longer; approximately 2,300 of these patients received celecoxib for 1 year or longer, and 124 of these patients received it for 2 years or more.

Controlled clinical trials of celecoxib for the treatment of arthritis conducted prior to its marketing approval

Table 2 lists all adverse reactions, regardless of causal relationship, that occurred in ≥ 2% of patients in 12 controlled trials of celecoxib 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, these percentages do not represent cumulative incidence rates of adverse reactions.

Table 2

Adverse reactions occurring in more than 2% of patients treated with celecoxib during controlled clinical trials of celecoxib for the treatment of arthritis conducted prior to its marketing approval

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 and administration site conditions Back pain Peripheral edema Injury, accidental	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 infections	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 at a dose of 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% among patients receiving celecoxib and 6.1% among patients 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 treatment due to dyspepsia and 0.6% due to abdominal pain.

The adverse reactions listed below 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, 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.

Cardiac arrhythmias: palpitations, tachycardia.

Hepatobiliary disorders: increased levels of liver enzymes (including increased AST and ALT levels).

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

Musculoskeletal and connective tissue 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.

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.

Hepatic and biliary 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 studies of celecoxib in the treatment of arthritis

Hematological disorders

The incidence of clinically significant decreases in hemoglobin levels (> 2 g/dL) 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 use of acetylsalicylic acid (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 events, or otherwise representing medically significant events), regardless of causal relationship, did not differ significantly among the treatment groups (8%, 7%, and 8%, respectively).

Studies of celecoxib 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 commonly reported adverse reactions (≥5%) in patients treated with celecoxib were headache, increased temperature (hyperthermia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting. The most commonly reported adverse reactions (≥5%) in patients treated with naproxen were headache, nausea, vomiting, increased temperature, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (see 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 flares of uveitis 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 a dose of
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 findings, including prolonged activated partial thromboplastin time, bacteriuria (unspecified), elevated plasma creatine phosphokinase, positive blood culture, elevated plasma glucose, elevated blood pressure, elevated plasma uric acid, decreased hematocrit, presence of hematuria, decreased hemoglobin, abnormal liver function biochemical tests (unspecified), presence of proteinuria, increased transaminase levels (unspecified), abnormal urine analysis findings (unspecified).

Other studies conducted prior to the marketing of celecoxib

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

Adverse reactions observed in pain relief and dysmenorrhea treatment studies. Approximately 1700 patients received celecoxib in pain relief and dysmenorrhea studies. In studies involving patients with pain following oral surgery, all participants received a single dose of investigational celecoxib. In studies of primary dysmenorrhea treatment and post-orthopedic surgical pain, celecoxib was studied at doses up to 600 mg per day. The types of adverse reactions reported in pain relief and dysmenorrhea 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 patients to celecoxib in the adenoma prevention with celecoxib study and the PreSAP study was 400–800 mg daily for up to 3 years.

Some adverse reactions occurred at a higher frequency than in the pre-marketing arthritis treatment studies with celecoxib (treatment duration up to 12 weeks). Table 4 lists the adverse reactions that occurred more frequently in patients receiving celecoxib compared to patients in the pre-marketing celecoxib arthritis treatment studies.

Table 4

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 their incidence exceeded that in the placebo group in long-term polyp prevention trials. These reactions were either not reported during pre-marketing controlled trials of celecoxib for arthritis treatment or occurred more frequently in long-term placebo-controlled polyp prevention trials:

Nervous system disorders:
ischemic stroke.

Eye disorders:
vitreous opacity, conjunctival haemorrhage.

Ear and labyrinth disorders:
labyrinthitis.

Cardiac disorders:
unstable angina, aortic valve insufficiency, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy.

Vascular disorders:
deep vein thrombosis.

Reproductive system and breast disorders:
ovarian cyst.

Investigations:
increased plasma potassium, increased plasma sodium, increased plasma testosterone.

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

Post-marketing experience

The following adverse reactions have been identified during post-approval use of celecoxib. Because these reactions are reported voluntarily from an unknown number of patients, 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 and administration site conditions:
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.

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.

Additional data are available on the following adverse reactions with celecoxib use:

Immune system disorders:

Common: hypersensitivity;
Very rare: anaphylactic shock³, anaphylactic reaction³.

Metabolism and nutrition disorders:

Common: hyperkalaemia.

Psychiatric disorders:

Very rare: confusion, hallucinations³.

Nervous system disorders:

Uncommon: cerebral infarction¹;
Rare: dysgeusia;
Very rare: epilepsy (including exacerbation)³.

Eye disorders:

Uncommon: conjunctivitis³;
Rare: haemorrhage in eye³;
Very rare: retinal artery/vein occlusion³.

Ear and labyrinth disorders:

Common: hearing impaired¹.

Cardiac disorders:

Uncommon: cardiac failure;
Very rare: arrhythmia³.

Skin and subcutaneous tissue disorders:

Very rare: bullous dermatitis³.

Reproductive system and breast disorders:

Very rare: menstrual disorder³, female infertility (reduced fertility)³.

General disorders and administration site conditions:

Common: influenza-like illness.

¹ Adverse reactions observed in polyp prevention trials in patients receiving celecoxib 400 mg/day in two clinical trials of up to 3 years duration (APC and PreSAP). The adverse reactions listed above for polyp prevention trials include only those previously identified in post-marketing surveillance or those occurring more frequently than in arthritis trials.

² Women planning pregnancy were excluded from all trials, therefore the frequency of this event could not be determined from the trial database.

³ Frequencies calculated based on a pooled meta-analysis of clinical trial data including 38,102 patients.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging

Hard capsules, 100 mg: 10 capsules in a blister; 2 or 5 blisters in a cardboard box.

Hard capsules, 200 mg: 10 capsules in a blister; 3 or 5 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.