Celcole 200

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CELCOLE 200 (CELCOLE 200)

Composition:

Active substance: celecoxib;

1 capsule contains 200 mg of celecoxib;

Excipients: lactose monohydrate; sodium croscarmellose; sodium lauryl sulfate; povidone; magnesium stearate; purified water; titanium dioxide (E 171); gelatin; sodium lauryl sulfate.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of size "2", with an opaque white cap with a yellow band and an opaque white body with a yellow band, marked with "200", containing a white or almost white powder.

Pharmacotherapeutic group.

Non-steroidal 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 the drug is believed to be related to inhibition of prostaglandin synthesis, primarily through selective inhibition of cyclooxygenase-2 (COX-2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of celecoxib achieved during therapy produce 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 bleeding time. Due to the lack of effect on platelets, celecoxib cannot be used as a substitute for aspirin 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 fluid 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 effects of antidiuretic hormone.

Pharmacokinetics.

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

Absorption. Peak plasma concentrations of celecoxib are reached approximately 3 hours after oral administration. When administered fasting at doses up to 200 mg twice daily, both maximum plasma concentrations (Cmax) and area under the pharmacokinetic curve (AUC) are approximately dose-proportional; at higher doses, Cmax and AUC increase sublinearly (see below, "Effect of food intake"). Absolute bioavailability studies of the drug have not been conducted. At steady state with repeated administration, equilibrium is achieved by day 5 or earlier. Pharmacokinetic parameters of celecoxib in healthy volunteers are presented in Table 1.

Kinetics of single-dose (200 mg) celecoxib distribution in healthy volunteers¹.

Table 1

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

Vss/F – volume of distribution at steady state.

CL/F – plasma clearance.

• Effect of food intake. When administered with a high-fat meal, peak plasma concentrations of celecoxib were delayed by approximately 1–2 hours, with an increase in total absorption (AUC) by 10–20%. When administered on an empty stomach 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. The drug can be administered at doses up to 200 mg twice daily 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) to celecoxib after oral administration did not differ significantly between swallowing the capsule whole and administering its contents mixed with applesauce. After administration of the capsule contents with applesauce, no clinically significant changes in Cmax, Tmax, or t1/2 were observed (see section "Dosage and administration").

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

Elimination.

• 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 eliminated mainly 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 recovered in feces and 27% in urine. The major 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 aqueous solubility of celecoxib 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 when administered on an empty stomach. Plasma clearance is approximately 500 mL/min.

Special patient populations.

• Elderly patients. In elderly patients (over 65 years of age), steady-state Cmax was 40% higher and AUC was 50% higher compared to younger patients. In elderly women, Cmax and AUC of celecoxib are higher than in elderly men, but this increase is primarily due to lower body weight in women. Overall, dose adjustment in elderly patients is not 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. It was predicted that clearance in patients weighing 10 kg and 25 kg would be 40% and 24% lower, 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 weighing ≥12 kg and ≤25 kg, and 100 mg capsules to those weighing >25 kg, is expected to achieve plasma celecoxib concentrations similar to those observed in the clinical study that demonstrated non-inferior efficacy of celecoxib compared to naproxen at a dose of 7.5 mg/kg twice daily (see section "Dosage and administration"). Studies of celecoxib use in patients with juvenile rheumatoid arthritis under 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 a meta-analysis of pharmacokinetic studies, it was hypothesized that the AUC of celecoxib in Black individuals is approximately 40% higher than in Caucasian individuals. The explanation and clinical significance of these findings are unknown.
• Hepatic impairment. A pharmacokinetic study in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment showed that steady-state AUC of celecoxib increased by approximately 40% and 180%, respectively, compared to healthy control subjects. Therefore, the recommended daily dose of celecoxib capsules should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh class B).
• Renal impairment. According to results from cross-study comparisons, the 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 that:

• Aspirin. When NSAIDs are co-administered with aspirin, their degree of plasma protein binding decreases, although the clearance of the unbound form of the NSAID remains unchanged. The clinical significance of this interaction is unknown. For clinically significant interactions between NSAIDs and aspirin, see section "Interaction with other medicinal products and other forms of interaction".
• Lithium-containing medications. 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 concentrations. 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 observed.

Pharmacogenomics. In some patients with genetic polymorphisms (homozygosity for CYP2C9*2 and CYP2C9*3 polymorphisms), reduced CYP2C9 activity and enzymatic function have been observed. Limited data from four reports, including a total of eight patients homozygous for CYP2C9*3/*3, showed that systemic celecoxib levels in these patients were 3–7 times higher than in patients with CYP2C9*1/*1 and *1/*3 genotypes. The pharmacokinetics of celecoxib in patients with other CYP2C9 polymorphisms, such as *2, *5, *6, *9, and *11, have not been evaluated. 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 the possibility of dose escalation if needed for pain control.

To assess non-inferiority (80% margin), the primary composite endpoint was defined by the Antiplatelet Trialists’ Collaboration (APTC) and 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 into 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 the pre-specified criteria for non-inferiority (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 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 mm Hg and 1.6 mm Hg, respectively. These changes demonstrated a statistically and clinically significant difference of 3.9 mm Hg (p = 0.0009) between celecoxib and ibuprofen, and a statistically non-significant difference of 1.8 mm Hg (p = 0.119) between celecoxib and naproxen.

Clinical characteristics.

Indications.

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

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

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

Contraindications.

The drug is contraindicated in patients:

• with known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib or to any component of the medicinal product (see section "Special precautions");
• with a history of bronchial asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see section "Special precautions");
• following coronary artery bypass graft (CABG) surgery (see section "Special precautions");
• who have experienced allergic-type reactions to sulfonamide drugs (see section "Special precautions");
• 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 class II–IV);
• with severe hepatic impairment (serum albumin < 25 g/L or Child–Pugh score ≥ 10).

Interaction with other medicinal products and other forms of interaction.

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

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

Patients receiving concomitant celecoxib and anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors should be monitored for signs of bleeding (see section "Special precautions").

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

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

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

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

When 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, dehydrated patients, or patients with impaired renal function, monitoring for signs of worsening renal function should be performed (see section "Special precautions").

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

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

When celecoxib is used concomitantly with diuretics, patients should be monitored for signs of worsening renal function, and the effectiveness of the diuretic, particularly its antihypertensive effect, should be additionally evaluated (see section "Special precautions").

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 celecoxib is used concomitantly with digoxin.

Lithium 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 NSAID inhibition of renal prostaglandin synthesis.

Patients receiving concomitant celecoxib 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).

CELCOLE 200 does not affect methotrexate pharmacokinetics.

Patients receiving concomitant celecoxib and methotrexate should be monitored for signs of methotrexate toxicity.

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

Patients receiving concomitant celecoxib and cyclosporine should be monitored for signs of worsening renal function.

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

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

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

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

In the absence of data on potential interactions between pemetrexed and NSAIDs with longer elimination half-lives (e.g., meloxicam, nabumetone), patients receiving these NSAIDs should discontinue them 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 cytochrome P450 isoenzyme CYP2C9 in the liver. Concomitant use of celecoxib with medicinal products known to be CYP2C9 inhibitors (e.g., fluconazole) may increase the effects and toxicity of celecoxib, whereas concomitant use with CYP2C9 inducers (e.g., rifampicin) may reduce celecoxib's 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 drug interaction with medicinal products metabolized by CYP2D6 (e.g., atomoxetine) is possible, and celecoxib may increase the effects and toxicity of these medicinal products.

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

Corticosteroids. Concomitant use of corticosteroids with CELCOLE 200 may increase the risk of gastrointestinal ulcers or bleeding.

Patients receiving concomitant celecoxib and corticosteroids should be monitored for signs of bleeding (see section "Special precautions").

Special precautions for use.

Cardiovascular thrombotic events. Clinical studies of several selective and non-selective COX-2 inhibitor NSAIDs for up to 3 years have demonstrated an increased risk of serious thrombotic cardiovascular events, including myocardial infarction and stroke, which may be fatal. Available data do not allow determining 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 levels associated with the use of NSAIDs 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 risk factors for cardiovascular disease had even higher absolute frequencies of serious thrombotic cardiovascular complications due to the higher baseline frequency 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 (cardiovascular death, 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 treatment groups compared to the placebo group was primarily due to an increased frequency of myocardial infarction.

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

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

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

In the CLASS study, Kaplan-Meier cumulative rates at 9 months for peripheral edema in patients receiving celecoxib 400 mg twice daily (4 and 2 times higher than recommended doses for OA and RA, respectively), ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily were 4.5%, 6.9%, and 4.7%, respectively. According to the CLASS study, the incidence of hypertension in patients receiving 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 inhibitor NSAIDs for pain control in the first 10–14 days after coronary artery bypass graft (CABG) surgery was associated with an increased incidence of myocardial infarction and stroke. The use of NSAIDs in CABG surgery is contraindicated (see section "Contraindications").

Patients after myocardial infarction. Observational studies conducted by the Danish National Registry demonstrated that in patients using NSAIDs after myocardial infarction, the risk of recurrent myocardial infarction, cardiovascular death, and death from any cause increases starting from the first week of treatment. In the same cohort, the mortality rate in the first year after myocardial infarction was 20 cases per 100 person-years in patients using NSAIDs compared to 12 cases per 100 person-years in patients not using NSAIDs. Although the absolute number of deaths decreases after the first year following myocardial infarction, analysis of results from at least four subsequent years of follow-up showed that the elevated relative risk of death 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, with or without preceding symptoms, may occur at any time in patients treated with celecoxib. Only one in five patients develops serious adverse reactions in the upper gastrointestinal tract 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.

Risk factors for gastrointestinal bleeding, ulceration, and perforation. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who take NSAIDs have more than a 10-fold higher risk of gastrointestinal bleeding compared to patients without such risk factors. Other factors increasing the risk of gastrointestinal bleeding in patients using NSAIDs include longer duration of NSAID treatment, concomitant oral use of corticosteroids, antiplatelet agents (e.g., aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs), tobacco smoking, alcohol consumption, advanced age, and poor general health. Most reports of fatal gastrointestinal adverse reactions reported after the drug's market release were 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 for minimizing gastrointestinal risks in patients using NSAIDs:

• Use the lowest effective dose for the shortest possible duration;
• Avoid using more than one NSAID simultaneously;
• Avoid use in high-risk patients except when 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 evaluation and treatment and discontinue celecoxib until the serious gastrointestinal adverse reaction is ruled out;
• When using low-dose aspirin concomitantly for prevention of cardiovascular complications, conduct more careful monitoring of patients 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 treated with NSAIDs in clinical studies. Additionally, rare, sometimes fatal cases of severe liver function impairment, including fulminant hepatitis, liver necrosis, and liver failure, have been reported.

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 treated with NSAIDs, including celecoxib.

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

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 of disease (e.g., eosinophilia, rash, etc.) appear, celecoxib should be discontinued immediately, and the patient should undergo clinical evaluation.

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 during NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

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

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 for heart failure in patients receiving selective and non-selective COX-2 inhibitors and in patients using non-selective NSAIDs compared to patients receiving placebo. In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of myocardial infarction, hospitalization for heart failure, and death.

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

In the CLASS study, the cumulative incidence of peripheral edema calculated by the Kaplan-Meier method after 9 months of treatment with 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.

Nephrotoxicity. Prolonged use of NSAIDs has led to renal medullary 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 decompensation of kidney function. Patients at increased risk of these reactions include those with impaired kidney 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 existing kidney function impairment in patients.

Before starting celecoxib treatment, dehydration or hypovolemia, if present, should be corrected. In patients with impaired kidney or liver function, heart failure, dehydration, or hypovolemia, kidney 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 kidney function. If celecoxib is used in patients with progressive kidney disease, patients should be monitored for signs of worsening kidney function.

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

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

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

Exacerbation of bronchial asthma associated with aspirin sensitivity. Some patients with bronchial asthma may have aspirin-induced asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and intolerance to aspirin and other NSAIDs. Since cross-reactivity between aspirin and other NSAIDs has been reported 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), the condition of such patients should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions. The drug 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 the drug at the first appearance of a skin rash or any other signs of hypersensitivity. The drug is contraindicated for use in patients with a history of serious skin reactions to NSAIDs (see section "Contraindications").

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported in patients using NSAIDs such as CELCOLE 200. Some of these cases were fatal or life-threatening. DRESS syndrome usually, 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 various 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 and the patient should be evaluated immediately.

Fetal toxicity.

Premature closure of the ductus arteriosus in the fetus. NSAIDs, including CELCOLE 200, should be avoided in pregnant women from approximately the 30th week of pregnancy. NSAIDs, including CELCOLE 200, increase the risk of premature closure of the ductus arteriosus in the fetus at approximately this stage of pregnancy.

Oligohydramnios / renal failure in newborns. The use of NSAIDs, including CELCOLE 200, from approximately the 20th week of pregnancy may cause impaired kidney function in the fetus, leading to oligohydramnios and in some cases to renal failure in newborns. These adverse outcomes are observed on average after several days or several weeks of treatment, although oligohydramnios has been reported 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 kidney function in newborns required invasive procedures such as exchange transfusion or dialysis.

If NSAID treatment is necessary between approximately the 20th and 30th week of pregnancy, use should be limited to the lowest effective dose and shortest possible duration. Consider the possibility of ultrasound monitoring of amniotic fluid if treatment with CELCOLE 200 lasts more than 48 hours. Discontinue CELCOLE 200 if oligohydramnios develops and continue monitoring according to clinical practice (see section "Use during pregnancy or lactation").

Hematological toxicity. Cases of anemia have been reported in patients using NSAIDs. This may be due to occult or significant blood loss, fluid retention, or effects on erythropoiesis, which are not fully described. If a patient has any signs or symptoms of anemia while using CELCOLE 200, hemoglobin levels or hematocrit should be monitored.

In controlled clinical trials, the incidence of anemia was 0.6% with CELCOLE 200 and 0.4% with placebo. In patients undergoing long-term treatment with CELCOLE 200, hemoglobin or hematocrit levels should be monitored if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs, including CELCOLE 200, may increase the risk of bleeding. Such concomitant factors as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors may increase this risk. Patients should be monitored for signs of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Masking inflammation and fever. The pharmacological activity of CELCOLE 200, which includes reducing inflammation and possibly lowering elevated temperature, may reduce the practical value of diagnostic signs in detecting infections.

Monitoring laboratory test results. Since serious gastrointestinal bleeding, hepatotoxicity, and kidney damage may occur without warning symptoms and signs, consider monitoring patients using NSAIDs for prolonged periods. Monitoring includes periodic performance of complete 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 patients 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 manifestations of 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 such symptoms as soon as possible.

Fertility. Since the mechanism of action of NSAIDs (including CELCOLE 200) is mediated through prostaglandins, their use may delay or prevent follicular rupture in the ovary, 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. Consider discontinuing NSAIDs, including CELCOLE 200, in women experiencing difficulties with conception or undergoing infertility evaluation.

Lactose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or lactation.

Pregnancy. The use of NSAIDs, including CELCOLE 200, may cause premature closure of the ductus arteriosus in the fetus and impaired kidney function in the fetus, leading to oligohydramnios and in some cases to renal failure in newborns. Due to these risks, the dose and duration of use of CELCOLE 200 should be limited between approximately the 20th and 30th week of pregnancy, and use of CELCOLE 200 should be avoided from approximately the 30th week of pregnancy.

Premature closure of the ductus arteriosus in the fetus. The use of NSAIDs, including CELCOLE 200, from approximately the 30th week of pregnancy increases the risk of premature closure of the ductus arteriosus in the fetus.

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

Based on data from observational studies regarding other potential embryofetal risks of NSAID use in women during the first or second trimester of pregnancy, no definitive conclusions could be drawn. In reproductive animal studies, cases of embryofetal lethality and increased incidence of diaphragmatic hernia in rats given celecoxib orally daily during organogenesis at doses approximately 6 times the maximum recommended human dose of 200 mg twice daily were observed. Additionally, structural abnormalities (e.g., septal defects, rib fusions, sternal segment fusions, and sternal segment deformities) were observed in rabbits given celecoxib orally during organogenesis at doses approximately 2 times the maximum recommended human dose. Data from animal studies demonstrate the important role of prostaglandins in regulating vascular permeability of the endometrium, blastocyst implantation, and decidualization. Animal studies have shown that administration of prostaglandin synthesis inhibitors, such as celecoxib, leads to increased 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 relevant doses.

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

Fetal / neonatal adverse reactions.

Premature closure of the ductus arteriosus in the fetus

NSAID use should be avoided in women from approximately the 30th week of pregnancy, as NSAIDs, including CELCOLE 200, may cause premature closure of the ductus arteriosus in the fetus.

Oligohydramnios / renal failure in newborns

If NSAID use is necessary from approximately the 20th week of pregnancy, use should be limited to the lowest effective dose and shortest possible duration. If treatment with CELCOLE 200 lasts more than 48 hours, consider ultrasound monitoring for oligohydramnios. If oligohydramnios is observed, discontinue CELCOLE 200 and continue treatment 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 assessing the presence or absence of embryofetal toxicity associated with celecoxib use.

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

Premature closure of the ductus arteriosus in the fetus

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

Oligohydramnios / renal failure in newborns

Published studies and post-marketing reports describe the use of NSAIDs in women around the 20th week of pregnancy or later, associated with impaired kidney function in the fetus, leading to oligohydramnios, and in some cases to renal failure in newborns. These adverse outcomes are observed on average after several days or several weeks of treatment, although there are rare reports of oligohydramnios 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 on NSAID use in women and impaired kidney function in newborns without oligohydramnios, some of which were irreversible. Some cases of impaired kidney 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 for the fetus and newborns when NSAIDs are used by their mothers. Since published safety data for newborns primarily concern preterm infants, generalization of certain reported risks to term infants exposed to NSAIDs through maternal use is uncertain.

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

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

Ability to influence reaction rate when driving vehicles or operating machinery.

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

Dosage and Administration.

General dosing instructions. Before deciding to use this medicinal product, the expected potential benefits and risks of using CELECOLE 200 should be carefully weighed, and the appropriateness of alternative treatment options should be considered. The lowest effective dose should be used for the shortest duration consistent with the individual patient's treatment goals (see section "Special precautions for use").

This medicinal product may be taken independently of food intake.

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

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

Ankylosing spondylitis. For the treatment of ankylosing spondylitis, the daily dose of CELECOLE 200 is 200 mg, which can 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 effect is observed after 6 weeks of treatment at a dose of 400 mg daily, a response to therapy is unlikely, and alternative treatment options should be considered.

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

If a dosing regimen requires a single 100 mg dose, celecoxib medicinal products with appropriate dosage strengths should be used.

Special patient groups.

Hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be reduced by 50%.

Patients who are slow metabolizers of CYP2C9 substrates. In adult patients known or suspected to be slow metabolizers of CYP2C9 substrates based on genotype or previous experience with other CYP2C9 substrates (e.g., warfarin, phenytoin), celecoxib should be initiated at half the minimum recommended dose.

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

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

If the anticipated benefit outweighs the potential risks in elderly patients, treatment should be initiated at the lowest dose, and patients should be monitored for the development of adverse reactions (see section "Special precautions for use").

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

Children. CELECOLE 200, 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 treatment. Cases of gastrointestinal bleeding have been reported. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma have been reported (see section "Special precautions for use").

No cases of 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. Information on the possibility of removing celecoxib by hemodialysis is lacking; however, due to its high plasma protein binding (>97%), dialysis is likely to be ineffective in overdose.

After NSAID overdose, symptomatic and supportive treatment should be administered to patients. No specific antidotes are available. Inducing emesis and/or administering activated charcoal (60–100 g for adults, 1–2 g per kg body weight for children) and/or an osmotic laxative should be considered in patients who develop symptoms of overdose within 4 hours of ingestion, as well as in patients with severe overdose (dose 5–10 times the recommended dose).

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

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

Adverse reactions

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

Across all participants in controlled clinical trials, approximately 4,250 patients received celecoxib for osteoarthritis, about 2,100 patients for rheumatoid arthritis, and approximately 1,050 patients for 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 receiving 800 mg daily (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or longer; about 2,300 of these patients received celecoxib for 1 year or more, and 124 of these patients received celecoxib for 2 years or longer.

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

Adverse reactions occurring in more than 2% of patients treated with celecoxib in controlled trials of arthritis treatment

Table 2

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

CBP – Celebrex® 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 comparator-controlled studies, the proportion of patients who discontinued treatment due to adverse reactions was 7.1% in the celecoxib group and 6.1% in the placebo group. Among the most common reasons for discontinuation due to adverse reactions in patients receiving celecoxib 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 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 system: constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting.

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

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

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

Ear and labyrinth disorders: deafness, tinnitus.

Heart rate and rhythm disorders: palpitations, tachycardia.

Hepatobiliary system: increased levels of liver enzymes (including increased levels of aspartate aminotransferase and alanine aminotransferase).

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

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

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

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

Blood system: anemia.

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

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

Application site disorders: panniculitis, contact dermatitis.

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

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

General disorders: sepsis, sudden death.

Hepatobiliary system: cholelithiasis.

Blood and lymphatic system: thrombocytopenia.

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

Renal system: acute renal failure.

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

Hematological disorders. The incidence of clinically significant hemoglobin decrease (> 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 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).

Studies of the use of the drug 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 a dose of 3 mg/kg twice daily, 82 patients received celecoxib at a dose of 6 mg/kg twice daily, and 83 patients received naproxen at a dose of 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 3). During this 12-week double-blind study, celecoxib at doses of 3 and 6 mg/kg twice daily, compared to naproxen, showed no adverse effects on growth and development. There were no significant differences between treatment groups in the number of clinical uveitis flares 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 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.

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)

Table 3

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

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

Other studies conducted prior to drug marketing.

• 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. The drug was studied at doses up to 400 mg once daily. The types of adverse reactions reported in studies of ankylosing spondylitis treatment 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 treatment studies. In studies involving patients with pain following oral surgery, all participants received a single dose of the investigational drug. In studies of primary dysmenorrhea treatment and pain following orthopedic surgery, celecoxib was studied at doses up to 600 mg/day. The types of adverse reactions reported in analgesic and dysmenorrhea treatment studies were the same as those reported in arthritis studies. The only additional adverse reaction reported in orthopedic surgical pain studies was alveolar osteitis following tooth extraction (post-extraction post-surgical alveolitis).

PreSAP study and celecoxib polyp prevention study.

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

Certain adverse reactions occurred in a higher percentage of patients than in the arthritis treatment studies conducted prior to drug marketing (treatment duration up to 12 weeks). Table 4 lists adverse reactions that occurred more frequently in patients receiving celecoxib compared to patients in 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 at a frequency higher than that in the placebo group in long-term polyp prevention trials. These adverse reactions were either not reported during pre-marketing controlled trials of the drug for arthritis treatment or were observed more frequently in long-term placebo-controlled polyp prevention trials.

Nervous system disorders: ischaemic stroke.

Eye disorders: vitreous opacity, conjunctival haemorrhage.

Ear and labyrinth disorders: labyrinthitis.

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

Vascular disorders: deep vein thrombosis.

Reproductive system and breast disorders: ovarian cyst.

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

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

Cardiovascular system disorders: vasculitis, deep vein thrombosis.

General disorders: anaphylactoid reaction, angioneurotic oedema.

Hepatobiliary disorders: liver necrosis, hepatitis, jaundice, liver failure (sometimes fatal 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.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Store in a place protected from light.

Keep out of the reach of children.

Packaging.

10 capsules in a blister; 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pinnecle Life Science Private Limited, India / Pinnacle Life Science Private Limited, India.

Manufacturer's address and location of business operations.

Khasra No.: 1328-1330, Village-Manpura, Tehsil-Baddi, District-Solan, Himachal Pradesh - 174101, India /
Khasra No.: 1328-1330, Village-Manpura, Tehsil-Baddi, District-Solan, Himachal Pradesh - 174101, India.