Denoxib

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

Composition:

Active substance: celecoxib;

1 capsule contains 100 mg or 200 mg of celecoxib;

Excipients: lactose monohydrate; sodium croscarmellose; povidone (K-30); sodium lauryl sulfate; magnesium stearate; titanium dioxide (E 171); gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties:

For 100 mg capsules: white, opaque, hard gelatin capsules, size "3", with "M" engraved on the cap and "12" on the body, filled with white or almost white granular powder.

For 200 mg capsules: white, opaque, hard gelatin capsules, size "1", with "M" engraved on the cap and "13" on the body, filled with white or almost white granular powder.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01A H01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of DENOKSIB is believed to be related to inhibition of prostaglandin synthesis, primarily by selective inhibition of cyclooxygenase-2 (COX-2). Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of celecoxib achieved during therapy 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. Clinical studies in healthy volunteers have shown that administration of celecoxib at single doses up to 800 mg and multiple doses up to 600 mg twice daily for up to 7 days (doses exceeding recommended therapeutic regimens) did not affect platelet aggregation or prolong bleeding time. Due to its lack of effect on platelets, celecoxib cannot be used as a substitute for acetylsalicylic acid in the prevention of cardiovascular diseases. It is unknown whether celecoxib affects platelets with regard to increasing the risk of serious cardiovascular thrombotic adverse reactions.

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 effects of antidiuretic hormone.

Pharmacokinetics.

The pharmacokinetic parameters of celecoxib increase approximately in proportion to the dose following administration of 200 mg twice daily; at higher doses, the increase in parameters is less than proportional. The drug is characterized by extensive distribution and high plasma protein binding. Celecoxib is primarily metabolized by CYP2C9, with 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 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. Studies on absolute bioavailability of the drug have not been conducted. At steady state, achieved by the 5th day or earlier with repeated dosing. Pharmacokinetic parameters of celecoxib in healthy volunteers are presented in Table 1.

Table 1

Pharmacokinetics of a single dose (200 mg) of celecoxib in healthy volunteers1

Vss/F – volume of distribution at steady state.

CL/F – plasma clearance.

Effect of food intake. When DENOXIB was administered with a high-fat meal, Cmax was observed with a delay of approximately 1–2 hours, with an increase in AUC by 10% to 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 solubility of the drug in aqueous media.

Concomitant administration of DENOXIB 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. DENOXIB 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 did not differ between swallowing the capsule whole and administering its contents mixed with applesauce. After administration of the capsule contents with applesauce, no significant changes in Cmax, Tmax, or t1/2 (elimination half-life) were observed (see section "Dosage and administration").

Distribution. In healthy volunteers, celecoxib was nearly completely bound to plasma proteins (approximately 97%) within the clinical dose range. In vitro studies demonstrated 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.

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 do not exhibit inhibitory activity against COX-1 or COX-2.

Excretion. Celecoxib is primarily eliminated via hepatic metabolism; only a small amount (<3%) of unchanged drug is 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 the dose), with a small amount of glucuronide also detected in urine. The low solubility of the drug is believed to prolong the absorption process, resulting in more variable t1/2. The effective t1/2 is approximately 11 hours when administered fasting. 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 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 generally required. However, treatment should be initiated with the lowest recommended dose in patients with body weight less than 50 kg (see section "Dosage and administration").

Children. Pharmacokinetics at steady state were evaluated in 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, following administration of celecoxib in an experimental oral suspension formulation. Population pharmacokinetic analysis showed that oral clearance (unadjusted for body weight) 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 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 less than 10 kg have not been conducted. Studies of duration longer than 24 weeks have also not been performed.

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

Hepatic impairment. A pharmacokinetic study in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment showed that steady-state AUC of celecoxib increased by approximately 40% and 180%, respectively, compared to healthy control volunteers. Therefore, the recommended daily dose of DENOXIB capsules should be reduced by approximately 50% when administered to patients with moderate hepatic impairment (Child-Pugh class B). Studies in patients with severe hepatic impairment (Child-Pugh class C) have not been conducted. DENOXIB is not recommended for use in patients with severe hepatic impairment (see section "Dosage and administration").

Renal impairment. According to results from cross-study comparisons, AUC of celecoxib in patients with chronic renal insufficiency (glomerular filtration rate 35–60 mL/min) was approximately 40% lower than in patients with normal renal function. No significant correlation between glomerular filtration rate and celecoxib clearance was observed. Studies in patients with acute renal failure have not been conducted. Similar to other nonsteroidal anti-inflammatory drugs (NSAIDs), DENOXIB is not recommended for use in patients with severe renal impairment (see section "Adverse reactions").

Clinical characteristics.

Indications.

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

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

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

Contraindications.

DENOCXIB is contraindicated in patients:

• with known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib or to any component of the medicinal product (see section "Special precautions for use");
• with a history of bronchial asthma, urticaria, or other allergic-type reactions after taking acetylsalicylic acid or other NSAIDs; severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see section "Special precautions for use");
• following coronary artery bypass graft (CABG) surgery (see section "Special precautions for use");
• who have experienced allergic-type reactions to sulfonamide drugs.

Interaction with other medicinal products and other forms of interaction.

Medicinal products affecting hemostasis. Celecoxib and anticoagulants such as warfarin exhibit a synergistic effect on bleeding. Concomitant use of celecoxib and anticoagulants increases the risk of serious bleeding compared to using either of these agents 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 and NSAIDs increases the risk of bleeding more than NSAID use as monotherapy.

Patients receiving concomitant DENOCXIB and anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), selective serotonin reuptake inhibitors (SSRIs), or serotonin–norepinephrine reuptake inhibitors (SNRIs) should be monitored for bleeding (see section "Special precautions for use").

Acetylsalicylic acid. Controlled clinical trials 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 increased incidence of gastrointestinal adverse reactions compared to NSAID use alone (see section "Special precautions for use").

Data from two studies involving healthy volunteers and patients with osteoarthritis and chronic heart disease, respectively, showed that celecoxib (at doses of 200–400 mg/day) does not interfere with the cardioprotective antiplatelet effect of acetylsalicylic acid (at doses of 100–325 mg).

Concomitant use of DENOCXIB and acetylsalicylic acid at analgesic doses is generally not recommended due to an increased risk of bleeding (see section "Special precautions for use"). DENOCXIB must not be used as a substitute for low-dose acetylsalicylic acid 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 deterioration of kidney function, including acute renal failure. These effects are usually reversible.

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

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 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 attributed to NSAID inhibition of prostaglandin synthesis in the kidneys.

When DENOCXIB is used concomitantly with diuretics, patients should be monitored for signs of impaired renal function and the efficacy of the diuretic, including its antihypertensive effect, should be additionally verified (see section "Special precautions for use").

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

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

Lithium preparations. 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 attributed to NSAID inhibition of prostaglandin synthesis in the kidneys.

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

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

Celecoxib does not affect the pharmacokinetics of methotrexate.

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

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

Patients should be monitored for signs of impaired renal function during concomitant use of DENOCXIB and cyclosporine.

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

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

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

When DENOCXIB 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 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 half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should discontinue their use at least five days before pemetrexed administration, on the day of pemetrexed administration, and for the following two days after administration.

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

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

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

Before prescribing celecoxib, each patient's medical history should be evaluated. Dose adjustment of celecoxib is justified when used in combination with CYP2D6 substrates (see section "Pharmacokinetics").

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

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

Special precautions for use.

Cardiovascular thrombotic events. Clinical trials of several COX-2 selective and non-selective NSAIDs, lasting 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 thrombotic cardiovascular complications is similar for all NSAIDs. The relative increase in the incidence of serious thrombotic cardiovascular complications associated with NSAID use, compared to baseline incidence, occurs both in patients with known cardiovascular diseases and risk factors for their development, and in patients without such conditions or 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. In some observational studies, this increased risk of serious thrombotic cardiovascular complications was observed 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.

According to data from the APC clinical trial (Adenoma Prevention with Celecoxib), an approximately threefold increase in risk was observed for the composite 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 placebo was primarily due to an increased incidence of myocardial infarction.

To minimize the potential risk of cardiovascular adverse reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest possible duration. 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 celecoxib increases the risk of serious gastrointestinal adverse reactions (see section "Special precautions for use", subsection "Gastrointestinal bleeding, ulceration, and perforation").

According to data from the CLASS study, the 9-month Kaplan-Meier cumulative incidence rates for peripheral edema in patients receiving celecoxib 400 mg twice daily (4 and 2 times higher than the recommended doses for OA and RA, respectively), ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily were 4.5%, 6.9%, and 4.7%, respectively. The incidence of hypertension in patients receiving celecoxib, ibuprofen, and diclofenac was 2.4%, 4.2%, and 2.5%, respectively.

Post-aortic coronary bypass surgery state. Data from two large controlled clinical trials showed that the use of COX-2 selective NSAIDs for pain control in the first 10–14 days after aortic coronary bypass surgery was associated with an increased incidence of myocardial infarction and stroke. The use of NSAIDs after aortic coronary bypass surgery is contraindicated (see section "Contraindications").

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

The use of DENOXIB should be avoided in patients with recent myocardial infarction, except when the expected benefit of treatment outweighs the risk of recurrence of thrombotic cardiovascular complications. If DENOXIB is used in patients with recent myocardial infarction, patients should be monitored for signs of cardiac ischemia.

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

Gastrointestinal bleeding, ulceration, and perforation risk factors. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who take NSAIDs have more than a 10-fold higher risk of gastrointestinal bleeding compared to patients without these risk factors. Other factors increasing the risk of gastrointestinal bleeding in patients taking NSAIDs include longer duration of NSAID therapy, concomitant oral use of corticosteroids, acetylsalicylic acid, anticoagulants, or SSRIs, tobacco smoking, alcohol consumption, advanced age, and poor general health. Most post-marketing reports of fatal gastrointestinal adverse reactions 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 9-month incidence of complicated and symptomatic ulcers in all patients 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 taking NSAIDs:

• Use the lowest effective dose for the shortest possible duration;
• Avoid using more than one NSAID simultaneously;
• Avoid use in high-risk patients, except when the expected benefit outweighs the increased risk of bleeding; in such patients, as well as in 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, initiate immediate evaluation and treatment and discontinue DENOXIB until the serious gastrointestinal adverse reaction is ruled out;
• When low-dose acetylsalicylic acid is used concomitantly for cardiovascular risk 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. Elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three times or more above the upper limit of normal) were observed in approximately 1% of patients taking NSAIDs in clinical trials. Additionally, rare, sometimes fatal cases of severe liver function impairment, including fulminant hepatitis, liver necrosis, and liver failure, have been reported.

Up to 15% of patients taking NSAIDs may have borderline elevations in one or more liver enzymes, and significant elevations in ALT or AST (approximately three times or more above the upper limit of normal) were observed in approximately 1% of patients taking NSAIDs. 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 suggestive of liver disease or systemic manifestations of disease (e.g., eosinophilia, rash) occur, DENOXIB should be discontinued immediately, and the patient should undergo clinical evaluation.

Arterial hypertension. The use of NSAIDs, including DENOXIB, 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 medications may occur with NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

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

Heart failure and edema. Fluid retention and edema have been observed in some patients taking NSAIDs. The use of celecoxib may attenuate the cardiovascular effects of several medications 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").

The use of DENOXIB should be avoided in patients with severe heart failure, except when the expected benefit outweighs the risk of worsening heart failure. If DENOXIB is used in patients with severe heart failure, patients should be monitored for signs of worsening heart failure.

Nephrotoxicity. 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 decompensation. Patients at increased risk of these reactions include those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, patients taking diuretics, ACE inhibitors, angiotensin receptor blockers, and elderly patients. Discontinuation of NSAID treatment 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 DENOXIB on the kidneys may accelerate the progression of existing renal impairment.

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

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

Anaphylactic reactions. 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. DENOXIB 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 the event of an anaphylactic reaction, immediate medical assistance should be sought.

Exacerbation of bronchial asthma associated with sensitivity to acetylsalicylic acid. 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 observed in such patients sensitive to acetylsalicylic acid, the use of DENOXIB is contraindicated in patients with this form of sensitivity to acetylsalicylic acid (see section "Contraindications"). When DENOXIB is used in patients with existing bronchial asthma (without known sensitivity to acetylsalicylic acid), patients should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions. DENOXIB may cause serious skin adverse reactions, such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, 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 DENOXIB at the first appearance of a skin rash or any other signs of hypersensitivity. DENOXIB is contraindicated in patients with a history of serious skin reactions to NSAIDs (see section "Contraindications").

Premature closure of the fetal ductus arteriosus. Celecoxib may cause premature closure of the ductus arteriosus. The use of DENOXIB should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester) (see section "Use during pregnancy or breastfeeding").

Hematological toxicity. Cases of anemia have been reported in patients taking NSAIDs. This may be due to occult or significant blood loss, fluid retention, or an effect on erythropoiesis that is not fully characterized. If a patient exhibits any signs or symptoms of anemia while taking DENOXIB, hemoglobin or hematocrit levels should be monitored.

NSAIDs, including DENOXIB, 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. Such patients should be monitored for signs of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Masking of inflammation and fever. The pharmacological activity of DENOXIB, which includes reducing inflammation and possibly lowering elevated temperature, may reduce the diagnostic utility of clinical signs in detecting infections.

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

According to data from controlled clinical trials, increased blood urea nitrogen levels occurred more frequently in patients taking celecoxib than in those receiving placebo. This laboratory abnormality was also observed in patients receiving comparator NSAID drugs during these trials. The clinical significance of this laboratory abnormality has not been established.

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

Fertility. Since the mechanism of action of NSAIDs (including DENOXIB) is mediated through prostaglandins, their use may delay or prevent follicular rupture of 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 taking NSAIDs have also demonstrated reversible delay of ovulation. The possibility of discontinuing DENOXIB should be considered in women experiencing difficulties with conception or undergoing infertility evaluation.

The product contains lactose. If intolerance to certain sugars is diagnosed, consult a physician before taking this product.

Use during pregnancy or breastfeeding.

Pregnancy. The use of NSAIDs, including DENOXIB, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. The use of DENOXIB should be avoided in pregnant women starting from the 30th week of pregnancy.

No adequate controlled studies on the use of celecoxib in pregnant women have been conducted. Based on data from observational studies on potential embryofetal risks of NSAID use in women during the first or second trimester of pregnancy, definitive conclusions could not be drawn. In reproductive animal studies, cases of embryofetal lethality and increased incidence of diaphragmatic hernia were observed in rats given celecoxib orally daily during organogenesis at doses approximately 6 times higher than the maximum recommended human dose of 200 mg twice daily. Additionally, structural abnormalities (e.g., septal defects, rib fusions, sternal segment fusions, and sternal segment deformities) were observed in rabbits given celecoxib orally during organogenesis at doses approximately 2 times higher than the maximum recommended human dose. Based on animal data, prostaglandins have been shown to play an important role in regulating vascular permeability of the endometrium, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as celecoxib, led to increased pre- and post-implantation losses.

All pregnancies are associated with a background risk of congenital defects, fetal loss, or other adverse outcomes. In the general US patient population, regardless of drug exposure, all clinically recognized pregnancies have a background incidence of 2–4% major congenital defects and 15–20% fetal loss during pregnancy. The estimated background risk of major congenital defects and miscarriages in this population is unknown.

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, leading to delayed delivery and increased incidence of stillbirth.

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

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

Breastfeeding. 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 infant dose was 10–40 mcg/kg/day, which is less than 1% of the therapeutic dose for a two-year-old child adjusted for body weight. In reports of two breastfed infants aged 17 and 22 months, no adverse reactions were reported.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

General Dosing Instructions. Before deciding to use this medicinal product, the expected potential benefits and risks of its use 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 individual patient treatment goals (see section "Special Warnings and Precautions for Use").

This medicinal product may be taken regardless of food intake.

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

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

Ankylosing Spondylitis. For the treatment of ankylosing spondylitis, the daily dose of DENOXIB 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 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 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.

Special Patient Populations.

Hepatic Impairment. In patients with moderate hepatic impairment (Child-Pugh Class B), the dose of the drug should be reduced by 50%. DENOXIB is not recommended for patients with severe hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Patients with Slow Metabolism of CYP2C9 Substrates. In adult patients with known or suspected slow metabolism of CYP2C9 substrates based on genotype or prior experience with other CYP2C9 substrates (e.g., warfarin, phenytoin), celecoxib should be initiated at half the minimum recommended dose.

In patients with juvenile rheumatoid arthritis and known or suspected slow metabolism of CYP2C9 substrates, alternative treatment options should be considered (see section "Pharmacological Properties").

Renal Impairment. DENOXIB is not recommended for patients with severe renal impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

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 risk in elderly patients, treatment should be initiated at the lowest dose, with careful monitoring for adverse reactions (see section "Special Warnings and Precautions for Use").

In premarketing clinical studies, over 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 assessing renal function (measured by glomerular filtration rate, blood urea nitrogen, and creatinine) and platelet function (measured 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").

Pediatric Population.

DENOXIB is not indicated for use in children.

Overdose.

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

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

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

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

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

Adverse Reactions.

There is data regarding the potential occurrence of the following adverse reactions.

Gastrointestinal disorders: constipation, diverticulitis, dysphagia, belching, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting, intestinal perforation, gastrointestinal hemorrhage, hemorrhagic colitis, esophageal perforation, pancreatitis, intestinal obstruction.

Cardiovascular system disorders: worsening of arterial hypertension, angina pectoris, ischemic heart disease, myocardial infarction, syncope, congestive heart failure, ventricular fibrillation, pulmonary artery thromboembolism, acute cerebrovascular accident, peripheral gangrene, thrombophlebitis, unstable angina, functional aortic valve insufficiency, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy, deep vein thrombosis, vasculitis, palpitations, tachycardia.

General disorders: hypersensitivity reactions, allergic reactions, chest pain, cyst (unspecified), generalized edema, facial swelling, increased fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain, sepsis, sudden death, anaphylactoid reaction, angioneurotic edema.

Central and peripheral nervous system disorders: leg cramps, hypertension, hypesthesia, migraine, paresthesia, vertigo, ataxia, suicide (see section "Interaction with other medicinal products and other forms of interaction"), ischemic stroke, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage.

Ear and labyrinth disorders: deafness, tinnitus, labyrinthitis.

Eye disorders: vitreous opacity, conjunctival hemorrhage.

Hepatobiliary disorders: increased liver enzymes (including elevated AST and ALT levels), cholelithiasis, liver necrosis, hepatitis, jaundice, hepatic failure.

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

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

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

Blood and lymphatic system disorders: anemia, thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia, ecchymosis, epistaxis, thrombocytosis.

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

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

Application site disorders: cellulitis, contact dermatitis.

Renal and urinary system disorders: albuminuria, cystitis, dysuria, hematuria, frequent urination, urolithiasis, acute renal failure, interstitial nephritis.

Reproductive system and breast disorders: ovarian cyst.

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

Shelf life. 2 years.

Storage conditions. No special storage conditions are required for this medicinal product. Keep out of the reach of children.

Packaging. 10 capsules in a blister; 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

MICRO LABS LIMITED.

Address of manufacturer and location of its operations.

Plot No. S.155 to S.159 & N1, Verna Industrial Estate, Phase III & Phase IV, Verna Salcette, IN-403 722, India.