Celebrex^® (Capsules) Instructions for Use

Marketing Authorization Holder

Upjohn US 1, LLC (USA)

Or

VIATRIS SPECIALTY, LLC (USA)

Manufactured By

Pfizer Pharmaceuticals, LLC (Puerto Rico)

Quality Control Release

PFIZER MANUFACTURING DEUTSCHLAND, GmbH (Germany)

ATC Code

M01AH01 (Celecoxib)

Active Substance

Celecoxib (Rec.INN registered by WHO)

Dosage Forms

	Celebrex®	Capsules 100 mg: 10, 20, 30, 40, 50 or 100 pcs.
		Capsules 200 mg: 10, 20, 30, 40, 50 or 100 pcs.
		Capsules 400 mg: 10, 30 or 100 pcs.; combination package: Capsules 400 mg 1 pc. and Capsules 200 mg 1, 5, 9 or 13 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin (containing white or almost white granules); the white opaque capsule body has a blue band with white marking “100”, the white opaque capsule cap has a blue band with white marking “7767”; each blue band does not completely encircle the capsule.

Excipients: lactose monohydrate – 149.7 mg, sodium lauryl sulfate – 8.1 mg, povidone K30 – 6.8 mg, croscarmellose sodium – 2.7 mg, magnesium stearate – 2.7 mg; shell: titanium dioxide – about 1.774 mg, gelatin – about 50.57 mg. Blue ink SB-6018 contains: shellac – 22-27%, ethanol – 33-38%, isopropanol – 0.5-4%, butanol – 4-8%, propylene glycol – 3-6%, aqueous ammonia – 1-2%, aluminum lake blue FD&C Blue #2 (E132) – 24-28%.

10 pcs. – blisters (1) – cardboard packs with first opening control.
10 pcs. – blisters (2) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (4) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Capsules hard gelatin (containing white or almost white granules); the white opaque capsule body has a yellow band with white marking “200”, the white opaque capsule cap has a yellow band with white marking “7767”; each yellow band does not completely encircle the capsule.

Excipients: lactose monohydrate – 49.8 mg, sodium lauryl sulfate – 8.1 mg, povidone K30 – 6.7 mg, croscarmellose sodium – 2.7 mg, magnesium stearate – 2.7 mg; shell: titanium dioxide – about 1.774 mg, gelatin – about 50.57 mg. Yellow ink SB-3002 contains: shellac – 22-27%, ethanol – 33-38%, isopropanol – 3-7%, butanol – 4-9%, propylene glycol – 3-6%, aqueous ammonia – 1-2%, iron oxide yellow dye (E172) – 18-22%.

10 pcs. – blisters (1) – cardboard packs with first opening control.
10 pcs. – blisters (2) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (4) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Capsules hard gelatin (containing white or almost white granules); the white opaque capsule body has a green band with white marking “400”, the white opaque capsule cap has a green band with white marking “7767”; each green band does not completely encircle the capsule.

Excipients: lactose monohydrate – 99.6 mg, sodium lauryl sulfate – 16.2 mg, povidone K30 – 13.4 mg, croscarmellose sodium – 5.4 mg, magnesium stearate – 5.4 mg; shell: titanium dioxide – 2.79 mg, gelatin – 93.21 mg. Yellow ink SB-4027 contains: shellac – 22-28%, anhydrous ethanol – 35-41%, isopropanol – 1-6%, butanol – 4-9%, propylene glycol – 0.5-4.5%, aqueous ammonia – 0.5-3%, iron oxide yellow dye (E172) – 13-17%, aluminum lake blue FD&C Blue #1 (E133) – 4-9%.

10 pcs. – blisters (1) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Combination package (400 mg + 200 mg)

2 pcs. (1 caps. 400 mg and 1 caps. 200 mg) – blisters (1) – cardboard packs with first opening control.
6 pcs. (1 caps. 400 mg and 5 caps. 200 mg) – blisters (1) – cardboard packs with first opening control.
10 pcs. (1 caps. 400 mg and 9 caps. 200 mg) – blisters (1) – cardboard packs with first opening control.
14 pcs. (1 caps. 400 mg and 13 caps. 200 mg) – blisters (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

NSAID. Highly selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

Celecoxib has anti-inflammatory, analgesic, and antipyretic effects by blocking the formation of inflammatory prostaglandins (Pg) mainly through inhibition of COX-2. Induction of COX-2 occurs in response to the inflammatory process and leads to the synthesis and accumulation of prostaglandins, especially prostaglandin E₂, which enhances the manifestations of inflammation (edema and pain). In therapeutic doses in humans, Celecoxib does not significantly inhibit COX-1 and does not affect prostaglandins synthesized as a result of COX-1 activation, nor does it affect normal physiological processes associated with COX-1 occurring in tissues, primarily in the stomach, intestines, and platelets.

Effect on renal function

Celecoxib reduces urinary excretion of PgE₂ and 6-keto-PgF₁ (a metabolite of prostacyclin), but does not affect serum thromboxane B₂ and urinary excretion of 11-dehydro-thromboxane B₂, a metabolite of thromboxane (both are COX-1 products). Celecoxib does not cause a decrease in GFR in elderly patients and patients with chronic renal failure, transiently reduces sodium excretion. In patients with arthritis, the observed frequency of peripheral edema, arterial hypertension, and heart failure is comparable to that with the use of non-selective COX inhibitors, which have inhibitory activity against COX-1 and COX-2. This effect was most pronounced in patients receiving diuretic therapy. However, there was no increase in the frequency of cases of increased blood pressure and development of heart failure, and peripheral edema were mild and resolved spontaneously.

Pharmacokinetics

Absorption

When taken on an empty stomach, Celecoxib is well absorbed, reaching C_max in plasma in approximately 2-3 hours. After taking the drug at a dose of 200 mg, C_max in plasma is 705 ng/ml. Absolute bioavailability has not been studied. C_max and AUC are approximately proportional to the dose taken in the dose range up to 200 mg twice/day; when using celecoxib in higher doses, the degree of increase in C_max and AUC is less proportional.

Effect of food intake: taking celecoxib with fatty food increases the time to reach C_max by approximately 4 hours and increases total absorption by approximately 20%.

Distribution

Plasma protein binding is concentration-independent and is about 97%, Celecoxib does not bind to red blood cells. Penetrates the BBB.

The mean V_d at steady state is approximately 500 L/70 kg in young healthy adult patients, indicating wide distribution of celecoxib in tissues.

Metabolism

Celecoxib is metabolized in the liver by hydroxylation, oxidation, and partially by glucuronidation. Metabolism occurs mainly with the participation of cytochrome P450 CYP2C9 (see section “Drug Interactions”). Metabolites detected in the blood are pharmacologically inactive against COX-1 and COX-2.

The activity of cytochrome P450 CYP2C9 is reduced in individuals with genetic polymorphism, such as homozygous CYP2C9*3 polymorphism, which leads to reduced enzyme efficiency.

Excretion

Celecoxib is metabolized in the liver, excreted in feces and urine as metabolites (57% and 27%, respectively), less than 1% of the administered dose is excreted unchanged. With repeated use, T_1/2 is 8-12 hours, and clearance is about 500 ml/min. With repeated use, C_ss in plasma is reached by day 5.

The variability of the main pharmacokinetic parameters (AUC, C_max, T_1/2) is about 30%.

Pharmacokinetics in special clinical cases

Elderly patients. In patients over 65 years of age, there is a 1.5-2 times increase in the mean values of C_max and AUC of celecoxib, which is more due to changes in body weight than age (elderly patients typically have a lower average body weight than younger individuals, so they achieve higher concentrations of celecoxib under otherwise equal conditions). For the same reason, elderly women usually have higher plasma concentrations of the drug than elderly men. These pharmacokinetic features generally do not require dose adjustment. However, in elderly patients with a body weight below 50 kg, treatment should be started at the lowest recommended dose.

Race. In representative Black individuals, the AUC of celecoxib is approximately 40% higher than in Caucasians. The reasons and clinical significance of this fact are unknown.

Impaired liver function. Plasma concentrations of celecoxib in patients with mild hepatic insufficiency (Child-Pugh class A) change insignificantly. In patients with moderate hepatic insufficiency (Child-Pugh class B), the plasma concentration of celecoxib may increase almost 2-fold.

Impaired renal function. In elderly patients with a decrease in GFR > 65 ml/min/1.73 m² associated with age-related changes, and in patients with GFR equal to 35-60 ml/min/1.73 m², the pharmacokinetics of celecoxib does not change. No significant correlation was found between serum creatinine content (or creatinine clearance) and celecoxib clearance. It is assumed that the presence of severe renal failure does not affect the clearance of celecoxib, since its main route of elimination is conversion in the liver to inactive metabolites.

Indications

• Symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis;
• Pain syndrome: back pain, musculoskeletal, postoperative and other types of pain;
• Treatment of primary dysmenorrhea.

ICD codes

Dosage Regimen

Take orally, regardless of meals.

Since the risk of possible cardiovascular complications may increase with increasing dose and duration of celecoxib use, it should be used for the shortest possible course at the minimum effective dose. The maximum recommended daily dose for long-term use is 400 mg.

For symptomatic treatment of osteoarthritis the recommended dose is 200 mg/day in 1 or 2 doses.

For symptomatic treatment of rheumatoid arthritis the recommended dose is 100 mg or 200 mg twice/day.

For symptomatic treatment of ankylosing spondylitis the recommended dose is 200 mg/day in 1 or 2 doses. In some patients, efficacy was noted at a dose of 400 mg twice/day.

For treatment of pain syndrome and primary dysmenorrhea the recommended initial dose is 400 mg followed by, if necessary, an additional dose of 200 mg on the 1st day. On subsequent days, the recommended dose is 200 mg twice/day, as needed.

Elderly patients usually do not require dose adjustment. However, in patients with a body weight below 50 kg it is better to start treatment with the lowest recommended dose.

In patients with mild hepatic insufficiency (Child-Pugh class A) dose adjustment is not required. In patients with moderate hepatic insufficiency (Child-Pugh class B), the initial recommended dose of the drug should be reduced by half. Experience of use in patients with severe hepatic insufficiency (Child-Pugh class C) is absent.

In patients with mild to moderate renal impairment dose adjustment is not required. Experience of use in patients with severe renal impairment is absent.

When fluconazole (CYP2C9 isoenzyme inhibitor) and celecoxib are used concomitantly, the initial recommended dose of celecoxib should be reduced by half. Caution should be exercised when used concomitantly with other CYP2C9 isoenzyme inhibitors.

Celecoxib should be used with caution in patients who are slow metabolizers or suspected of such a condition, as this may lead to accumulation of high plasma concentrations of celecoxib. In such patients, the initial recommended dose of celecoxib should be reduced by half.

Adverse Reactions

Frequency assessment criteria: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%).

Cardiovascular system common – peripheral edema, increased blood pressure, including worsening of arterial hypertension; uncommon – “hot flashes”, palpitations; rare – manifestation of chronic heart failure, arrhythmia, tachycardia, ischemic stroke and myocardial infarction.

Digestive system common – abdominal pain, diarrhea, dyspepsia, flatulence, vomiting; uncommon – dental diseases (post-extraction alveolar osteitis); rare – gastric and duodenal ulcer, esophageal ulceration; very rare – intestinal perforation, pancreatitis.

Hepatobiliary system uncommon – increased activity of liver enzymes (including ALT and AST).

Nervous system common – dizziness, insomnia; uncommon – anxiety, increased muscle tone, drowsiness; rare – confusion (psychosis).

Urinary system common – urinary tract infection.

Respiratory system common – bronchitis, cough, sinusitis, upper respiratory tract infections; uncommon – pharyngitis, rhinitis.

Skin common – skin itching (including generalized), skin rash; uncommon – urticaria, ecchymoses; rare – alopecia.

Hematopoietic system uncommon – anemia; rare – thrombocytopenia.

Immune system rare – angioedema; very rare – bullous eruptions (bullous dermatitis).

Sense organs uncommon – tinnitus, blurred vision.

Other uncommon – hypersensitivity, flu-like syndrome, accidental injuries, facial edema.

Adverse effects identified in post-marketing surveillance

Although these reactions were identified during post-marketing surveillance, they were distributed by frequency as follows: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%), frequency unknown (cannot be estimated from available data).

Immune system very rare – anaphylactic reactions.

Nervous system rare – hallucinations; very rare – cerebral hemorrhage, aseptic meningitis, loss of taste, loss of smell.

Organ of vision uncommon – conjunctivitis.

Cardiovascular system very rare – vasculitis.

Respiratory system rare – pulmonary embolism, pneumonitis.

Digestive system rare – gastrointestinal bleeding.

Hepatobiliary system rare – hepatitis; very rare – hepatic failure, fulminant hepatitis, liver necrosis, cholestasis, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue rare – photosensitivity reactions; very rare – Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome), acute generalized exanthematous pustulosis, exfoliative dermatitis.

Urinary system rare – acute renal failure, hyponatremia; very rare – tubulointerstitial nephritis, nephrotic syndrome, minimal change disease.

Reproductive system disorders rarely – menstrual cycle disorders; frequency unknown – decreased fertility in women.

General disorders infrequently – chest pain.

Contraindications

• Hypersensitivity to celecoxib or to any of the excipients of the used medicinal product;
• Known hypersensitivity to sulfonamides;
• Complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinusitis and intolerance to acetylsalicylic acid or other NSAIDs, including other COX-2 inhibitors (including in the anamnesis);
• Postoperative period after coronary artery bypass graft surgery;
• Active erosive and ulcerative lesions of the gastric or duodenal mucosa, or peptic ulcer of the stomach and duodenum in the acute stage or gastrointestinal bleeding;
• Inflammatory bowel disease (Crohn’s disease, ulcerative colitis) in the acute phase;
• Chronic heart failure (NYHA functional class II-IV);
• Clinically confirmed coronary artery disease, peripheral arterial disease and cerebrovascular disease in the severe stage;
• Hemorrhagic stroke;
• Subarachnoid hemorrhage;
• Severe hepatic impairment (no experience with use);
• Severe renal impairment (creatinine clearance less than 30 ml/min), progressive kidney disease, confirmed hyperkalemia (no experience with use);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (no experience with use).

With caution

Gastrointestinal diseases (peptic ulcer of the stomach and duodenum, ulcerative colitis, Crohn’s disease, history of bleeding), presence of Helicobacter pylori infection; concomitant use with anticoagulants (warfarin), antiplatelet agents (acetylsalicylic acid, clopidogrel), oral corticosteroids (prednisolone), diuretics, selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline), digoxin; fluid retention and edema; moderate hepatic impairment, history of liver disease, hepatic porphyria; chronic renal failure (creatinine clearance 30-60 ml/min); significant decrease in circulating blood volume (including after surgery); cardiovascular diseases, arterial hypertension; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; peripheral arterial diseases; concomitant use with inhibitors of the CYP2C9 isoenzyme; in patients who are poor metabolizers or suspected of such condition; long-term use of NSAIDs; severe somatic diseases; elderly patients (including those receiving diuretics, debilitated patients with low body weight); smoking; tuberculosis; alcoholism.

Use in Pregnancy and Lactation

Pregnancy

There are insufficient data on the use of celecoxib in pregnant women. The potential risk of using celecoxib during pregnancy has not been established but cannot be excluded.

In accordance with the mechanism of action, when using NSAIDs, including Celecoxib, some women may develop changes in the ovaries, which may cause complications during pregnancy or impaired fertility. In women planning pregnancy or undergoing infertility examination, the issue of discontinuing NSAIDs, including Celecoxib, should be considered.

Celecoxib, belonging to the group of prostaglandin synthesis inhibitors, when taken during pregnancy, especially in the third trimester, can cause weakness of uterine contractions and premature closure of the arterial duct. The use of prostaglandin synthesis inhibitors in the early stages of pregnancy may adversely affect the course of pregnancy.

The use of celecoxib is contraindicated during pregnancy and breastfeeding. When used in the second and third trimesters of pregnancy, NSAIDs can provoke impaired renal function in the fetus, which can lead to a decrease in amniotic fluid volume or, in severe cases, to oligohydramnios. These phenomena can occur shortly after the start of treatment and are usually reversible after discontinuation of celecoxib. Careful monitoring of amniotic fluid volume should be carried out in pregnant women taking Celecoxib.

Breastfeeding period

There are limited data that Celecoxib passes into breast milk. Studies have shown that Celecoxib passes into breast milk in very low concentrations. Nevertheless, taking into account the potential for the development of side effects of celecoxib in the breastfed infant, the advisability of discontinuing either breastfeeding or taking celecoxib should be assessed, taking into account the importance of taking celecoxib for the mother.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Should be used with caution in moderate hepatic impairment, history of liver disease, hepatic porphyria.

Use in Renal Impairment

Contraindicated in severe renal impairment (creatinine clearance less than 30 ml/min), progressive kidney diseases, confirmed hyperkalemia.

Should be used with caution in chronic renal failure (creatinine clearance 30-60 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Celecoxib, given its antipyretic effect, may reduce the diagnostic value of such a symptom as fever and affect the diagnosis of infection.

Effect on the cardiovascular system

Celecoxib (like all coxibs) can increase the risk of serious cardiovascular complications, such as thrombosis, myocardial infarction and stroke, which can be fatal. The risk of these reactions may increase with dose and duration of drug use. The relative increase in this risk in patients known to have cardiovascular disease or risk factors for cardiovascular disease appears to be the same as in patients without cardiovascular disease and risk factors. However, the absolute incidence of cardiovascular events in patients known to have cardiovascular disease or risk factors for cardiovascular disease may be higher because they had a higher baseline incidence. To reduce the risk of these reactions in patients taking Celecoxib, it should be used at the lowest effective doses and for the shortest possible course (at the discretion of the attending physician). The attending physician and the patient should be aware of the possibility of such complications even in the absence of previously known symptoms of impaired cardiovascular function. Patients should be informed about the signs and symptoms of negative effects on the cardiovascular system and the measures to be taken in case of their occurrence.

When using NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass graft surgery for pain relief in the first 10-14 days, an increase in the frequency of myocardial infarction and cerebrovascular accidents is possible.

Due to the weak effect of celecoxib on platelet function, it cannot be a substitute for acetylsalicylic acid for the prevention of thromboembolism. Also, for this reason, antiplatelet therapy (e.g., acetylsalicylic acid) should not be discontinued in patients at risk of thromboembolic complications.

Like all NSAIDs, Celecoxib can lead to an increase in blood pressure, which can also cause cardiovascular complications. All NSAIDs, including Celecoxib, should be used with caution in patients with arterial hypertension. Blood pressure should be monitored at the beginning of celecoxib therapy and during the course of treatment.

Effect on the gastrointestinal tract

Very rare cases of perforation, ulceration and gastrointestinal bleeding have been observed in patients taking Celecoxib. The risk of developing these complications during treatment with NSAIDs is highest in the elderly, patients with cardiovascular diseases, and patients with such gastrointestinal diseases as ulcer, bleeding, inflammatory processes in the acute stage and in the anamnesis. Other risk factors for gastrointestinal bleeding are concomitant use with oral corticosteroids, anticoagulants, and antiplatelet agents (acetylsalicylic acid), long-term NSAID therapy, smoking, alcohol consumption. Most spontaneous reports of serious gastrointestinal side effects were in elderly and debilitated patients.

Concomitant use with oral anticoagulants

When NSAIDs are used concomitantly with oral anticoagulants, the risk of bleeding increases. Caution should be exercised when using these drugs concomitantly. Oral anticoagulants include warfarin, coumarin anticoagulants and direct oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban). Serious (some of them fatal) bleeding has been reported in patients receiving concomitant treatment with warfarin or similar agents. Since an increase in prothrombin time (INR) has been reported, anticoagulant activity and/or INR should be monitored in patients simultaneously receiving oral anticoagulant therapy after starting celecoxib treatment or changing its dose.

Fluid retention and edema

As with the use of other drugs that inhibit prostaglandin synthesis, some patients taking Celecoxib may experience fluid retention and edema, so caution should be exercised when using this drug in patients with conditions predisposing to or worsened by fluid retention. Patients with a history of heart failure or arterial hypertension should be under close observation.

Effect on renal function

NSAIDs, including Celecoxib, can have a toxic effect on renal function. Celecoxib has been found to be no more toxic than other NSAIDs. Celecoxib should be used with caution in patients with impaired renal function, heart failure, impaired liver function and in elderly patients. Renal function in such patients should be carefully monitored.

Caution should be exercised when using celecoxib in patients with dehydration. In such cases, it is advisable to first carry out rehydration and then start therapy with celecoxib.

Effect on hepatic function

Celecoxib should not be used in patients with severe hepatic impairment (Child-Pugh class C). Celecoxib should be used with caution when treating patients with moderate hepatic insufficiency and the initial recommended dose of celecoxib should be reduced by half.

In some cases, severe hepatic reactions have been observed, including fulminant hepatitis (sometimes fatal), hepatic necrosis and hepatic failure (sometimes fatal or requiring liver transplantation). Most of these reactions developed within 1 month after starting celecoxib.

Patients with symptoms and/or signs of impaired liver function, or those patients in whom impaired liver function has been detected by laboratory methods, should be closely monitored for the development of more severe hepatic reactions during treatment with celecoxib.

Anaphylactic reactions

Cases of anaphylactic reactions have been reported with celecoxib.

Serious skin reactions

Very rarely, serious skin reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been observed with celecoxib, some of which were fatal. The risk of such reactions is higher in patients at the beginning of therapy, in most reported cases such reactions began in the first month of therapy. Celecoxib should be discontinued if skin rash, mucosal changes or other signs of hypersensitivity appear.

Corticosteroid therapy

Celecoxib cannot replace corticosteroids or be used as therapy for glucocorticoid insufficiency.

Inhibition of CYP2D6 isoenzyme function

Celecoxib has been found to be a moderate inhibitor of the CYP2D6 isoenzyme. During the initiation of celecoxib therapy, the dose of drugs metabolized by the CYP2D6 isoenzyme should be reduced, and after the end of celecoxib treatment, the dose of these drugs should be increased.

Effect on ability to drive and operate machinery

The effect of celecoxib on the ability to drive and operate machinery has not been studied. However, based on pharmacodynamic properties and the overall safety profile, it seems unlikely that Celecoxib has such an effect.

Caution should be exercised when driving and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.

Drug Interactions

Concomitant use of celecoxib with inhibitors of the CYP2C9 isoenzyme may lead to an increase in its plasma concentration. In such cases, a reduction in the dose of celecoxib may be required.

Concomitant use of celecoxib with inducers of the CYP2C9 isoenzyme, such as rifampicin, carbamazepine and barbiturates, may lead to a decrease in its plasma concentration. In such cases, an increase in the dose of celecoxib may be required.

Clinical pharmacokinetic studies and in vitro studies have shown that Celecoxib, although not a substrate of the CYP2D6 isoenzyme, inhibits its activity. Therefore, there is a possibility of in vivo drug interaction with drugs whose metabolism is associated with the CYP2D6 isoenzyme.

Warfarin and other anticoagulants with concomitant use, an increase in prothrombin time is possible.

Fluconazole, ketoconazole with concomitant use of fluconazole at a dose of 200 mg once/day, a 2-fold increase in the plasma concentration of celecoxib is observed. This effect is associated with inhibition of celecoxib metabolism by fluconazole via the CYP2C9 isoenzyme. Patients taking fluconazole (an inhibitor of the CYP2C9 isoenzyme) should reduce the recommended dose of celecoxib by half. Ketoconazole (an inhibitor of the CYP3A4 isoenzyme) does not have a clinically significant effect on the metabolism of celecoxib.

Dextromethorphan and metoprolol: it was found that concomitant use of celecoxib at a dose of 200 mg/day led to an increase in the concentrations of dextromethorphan and metoprolol (substrates of the CYP2D6 isoenzyme) by 2.6 and 1.5 times, respectively. This increase in concentrations is associated with inhibition of the metabolism of CYP2D6 isoenzyme substrates by celecoxib through inhibition of the activity of the CYP2D6 isoenzyme itself. In this regard, during the initiation of celecoxib therapy, the dose of drugs that are substrates of the CYP2D6 isoenzyme should be reduced, and after the end of celecoxib treatment, the dose of these drugs should be increased.

Methotrexate: no clinically significant pharmacokinetic interaction between celecoxib and methotrexate was observed.

Antihypertensive drugs, including ACE inhibitors/angiotensin II receptor antagonists (or angiotensin receptor blockers), diuretics and beta-blockers inhibition of prostaglandin synthesis may reduce the effect of antihypertensive drugs, including ACE inhibitors and/or angiotensin receptor blockers, diuretics and beta-blockers. This interaction should be taken into account when using celecoxib concomitantly with ACE inhibitors and/or angiotensin receptor blockers, diuretics and beta-blockers.

In elderly patients, dehydrated (including patients receiving diuretic therapy) or patients with impaired renal function, concomitant use of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II receptor antagonists and diuretics, may lead to deterioration of renal function, including possible acute renal failure. Usually these effects are reversible. In this regard, caution should be exercised when using these drugs concomitantly. In such cases, it is advisable to first carry out rehydration and then start therapy with celecoxib. In addition, consideration should be given to monitoring renal function at the start of therapy and periodically during concomitant use of the drugs.

Cyclosporine given that NSAIDs affect renal prostaglandin synthesis, they may increase the risk of nephrotoxicity when used concomitantly with cyclosporine.

Diuretics previously known NSAIDs in some patients may reduce the natriuretic effect of furosemide and thiazides by reducing renal prostaglandin synthesis, this should be kept in mind when using celecoxib.

Oral contraceptives no clinically significant effect on the pharmacokinetics of the contraceptive combination (1 mg norethisterone/35 mcg ethinyl estradiol) was observed.

Lithium an increase in plasma lithium concentration of approximately 17% was observed with concomitant administration of lithium and celecoxib. Patients receiving lithium therapy should be closely monitored when starting or discontinuing celecoxib.

Other NSAIDs concomitant use of celecoxib and other NSAIDs (not containing acetylsalicylic acid) should be avoided.

Lisinopril study results in a 28-day study of patients with grade 1 and 2 arterial hypertension receiving lisinopril for this condition, it was found that concomitant use of celecoxib at a dose of 200 mg twice daily did not lead to a clinically significant increase in mean systolic or diastolic pressure (determined by 24-hour blood pressure monitoring), compared with placebo. Among patients receiving Celecoxib at a dose of 200 mg twice daily, 48% of them did not show a response to lisinopril therapy (the response criteria were diastolic pressure levels greater than 90 mm Hg or an increase in diastolic pressure by 10% compared to baseline), compared with patients receiving placebo (in this group, no response was observed in 27% of patients).

Other drugs

No clinically significant interaction was observed between celecoxib and antacids (aluminum- and magnesium-containing preparations), omeprazole, glibenclamide, phenytoin or tolbutamide.

Celecoxib does not affect the antiplatelet effect of low-dose acetylsalicylic acid. Celecoxib has a weak effect on platelet function, so it cannot be considered as a substitute for acetylsalicylic acid used for the prevention of cardiovascular diseases.

In healthy volunteers, NSAIDs do not affect the pharmacokinetics of digoxin. However, with concomitant use of digoxin and indomethacin and ibuprofen, an increase in plasma digoxin concentration was observed in patients. This must be taken into account when used concomitantly with other drugs that increase plasma digoxin concentration. There is no information on the interaction of celecoxib and digoxin. Given other effects of celecoxib on the cardiovascular system, it should be taken with caution concomitantly with digoxin. In this case, careful monitoring of adverse reactions is recommended.

Celecoxib is primarily metabolized in the liver by the isoenzyme CYP2C9. Since barbiturates are inducers of the CYP2C9 isoenzyme, their simultaneous use with celecoxib may lead to a decrease in the plasma concentration of the latter.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.