Date of approval.
Date of revision.
Celecoxib Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Celecoxib Capsules
English name: Celecoxib Capsules
Hanyu Pinyin: Sailaixibu Jiaonang
Ingredients
The main ingredient of this product is Celecoxib, the chemical name of which is: 4-[5-(4-tolyl)-3-(trifluoromethyl)-1-hydro-1-pyrazol-1-yl]benzenesulfonamide.
Chemical structure formula.
Molecular formula: C17H14F3N3O2S
Molecular weight: 381.38
【Properties】.
This product is a hard capsule with white granules and powder as its content.
Indications
Celecoxib is indicated for.
1) For relieving the signs and symptoms of osteoarthritis (OA).
2) For the relief of signs and symptoms of rheumatoid arthritis (RA) in adults.
3) For the treatment of acute pain (AP) in adults.
4) Used to relieve the signs and symptoms of ankylosing spondylitis.
Specification
(1) 0.1g (2) 0.2g
Dosage]
The potential benefits and risks of celecoxib and other treatment options should be carefully considered before deciding to use celecoxib. Use the lowest effective dose for the shortest treatment period according to the treatment goal for each patient (see [Precautions]-Warnings).
For osteoarthritis and rheumatoid arthritis, the lowest dose of celecoxib therapy is determined on an individual basis. The timing of food intake has no effect on the dose used.
Osteoarthritis: The dose of celecoxib for osteoarthritis is 200 mg orally once daily or 100 mg orally twice daily.
Rheumatoid arthritis: Celecoxib for the treatment of rheumatoid arthritis at a dose of 100 mg to 200 mg orally twice daily.
Acute pain: The dose for the treatment of acute pain is 400mg as the first dose on day 1 and, if necessary, an additional 200mg; subsequently, 200mg twice daily as needed.
Ankylosing spondylitis: The dose of this product for the treatment of ankylosing spondylitis is 200 mg daily in a single dose (once daily) or in divided doses (twice daily). If no effect is seen after 6 weeks, try 400 mg daily. if no effect is seen after 6 weeks of 400 mg daily, other treatment options should be considered.
Special Populations
Patients with hepatic insufficiency: The dose should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh Class B). Celecoxib is not recommended for patients with severe hepatic impairment (see [Pharmacokinetics]-Special Populations).
[Adverse Reactions].
As reported in foreign literature.
The following adverse reactions are discussed in more detail elsewhere in the instruction.
– Cardiovascular thrombotic events (see [Precautions])
– Gastrointestinal bleeding, ulceration and perforation (see [Precautions])
– Hepatotoxicity (see [Precautions])
– Hypertension (see [Precautions])
– Heart failure and edema (see [Precautions])
– Nephrotoxicity and hyperkalemia (see [Precautions])
– Allergic reactions (see [Precautions])
– Severe skin reactions (see [Precautions])
– Hematologic toxicity (see [Precautions])
Clinical trial experience
It is not appropriate to directly compare the incidence of adverse reactions between two drugs in different clinical studies because clinical studies are not identical. Also, the incidence of adverse reactions in clinical studies may differ from that in clinical practice. However, information on adverse reactions in clinical trials does provide a reference for identifying the relevance of adverse events to drug use and estimating their incidence.
Approximately 4250 patients with osteoarthritis, 2100 patients with rheumatoid arthritis and 1050 patients with postoperative pain have been treated with celecoxib in pre-marketing controlled clinical studies. More than 8,500 patients received a total daily dose of 200 mg (100 mg twice daily or 200 mg once daily) or higher, including more than 400 patients who received a total daily dose of 800 mg (400 mg twice daily). Approximately 3900 patients received these doses for 6 months or more, including approximately 2300 patients for one year or more and 124 patients for 2 years or more.
Adverse Events in Premarketing Controlled Clinical Studies in Arthritis.
In clinical studies involving placebo or positive drug controls, the rate of discontinuation due to adverse events was 7.1% in the celecoxib capsule group and 6.1% in the placebo group. The most common reasons for discontinuation due to adverse events in the celecoxib group were dyspepsia and abdominal pain (0.8% and 0.7%, respectively, among patients treated with celecoxib). 0.6% of patients in the placebo group withdrew from the study due to dyspepsia, as did 0.6% of patients who withdrew due to abdominal pain.
Adverse events with an incidence of 2% in the celecoxib capsule treatment group in the controlled study of arthritis
Table 1 shows the 2% incidence of adverse events (whether causally related to treatment or not) in all celecoxib capsule treatment groups in 12 clinical studies with placebo and/or positive drug controls in patients with osteoarthritis or rheumatoid arthritis. Cumulative incidence rates cannot be obtained from these percentages because the study periods of these 12 trials differed and patients in these trials took the drug for different periods of time.
Table 1: Adverse events with an incidence of 2% in the celecoxib capsule treatment group in pre-marketing controlled studies in rheumatoid arthritis
Celecoxib Placebo Naproxen Diclofenac Ibuprofen (100-200 mg twice daily or 200 mg once daily) 500 mg
75mg twice daily
800mg twice daily
Three times daily (N=4146)(N=1864)(N=1366)(N=387)(N=345) Gastrointestinal Abdominal pain 4.1%2.8%7.7%9.0%9.0% Diarrhea 5.6%3.8%5.3%9.3%5.8% Dyspepsia 8.8%6.2%12.2%10.9%12.8% Gastrointestinal distention 2.2%1.0% 3.6%4.1%3.5%Nausea3.5%4.2%6.0%3.4%6.7%General back pain2.8%3.6%2.2%2.6%0.9%Peripheral edema2.1%1.1%2.1%1.0%3.5%Accidental injury2.9%2.3%3.0%2.6%3.2%Central and peripheral nervous systemDizziness2.0%1.7%2.6% 1.3%2.3% Headache15.8%20.2%14.5%15.5%15.4% Mental insomnia2.3%2.3%2.9%1.3%1.4% Respiratory pharyngitis2.3%1.1%1.7%1.6%2.6% Rhinitis2.0%1.3%2.4%2.3%0.6% Sinusitis5.0%4.3%4.0%5.4%5.8% Upper respiratory tract infection8.1%6.7%9.9%9.8%9.9% Skin rash2.2%2.1%2.1%2.1%1.3%1.2% The following are adverse events (patients taking celecoxib capsules 100-200 mg twice daily or 200 mg once daily) with an incidence of less than 2% (0.1-1.9%) regardless of whether they were causally related to treatment.
Gastrointestinal system: constipation, diverticulitis, dysphagia, belching, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, black stools, dry mouth, stomatitis, lining, dental disease, vomiting.
Cardiovascular system: exacerbation of hypertension, angina pectoris, coronary artery lesions, myocardial infarction.
Systemic: hypersensitivity reactions, allergic reactions, malaise, chest pain, cysts, generalized edema, facial edema, fatigue, fever, hot flashes, flu-like symptoms, pain, peripheral pain.
Immune system disorders: herpes simplex, herpes zoster, bacterial infections, fungal infections, soft tissue infections, viral infections, candidiasis, genital candidiasis, otitis media.
Central peripheral nervous system: leg spasms, hypertonia, hyperalgesia, migraine, neuralgia, neuropathy, sensory abnormalities, vertigo.
Female reproductive system: breast fibroadenoma, breast tumor, breast pain, dysmenorrhea, menstrual disorders, vaginal bleeding, vaginitis.
Male reproductive system: prostate disorders.
Hearing and vestibular: deafness, hearing disorders, ear pain, tinnitus.
Heart rate and rhythm: palpitations, tachycardia.
Hepatobiliary system: elevated liver enzymes (including elevated alanine aminotransferase (ALT), elevated aspartate aminotransferase (AST)).
Metabolic and nutritional: elevated urea nitrogen (BUN), elevated creatine phosphokinase (CPK), diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, increased non-protein nitrogen, increased creatinine, increased alkaline phosphatase, weight gain.
Musculoskeletal: arthralgia, arthropathy, bone disease, accidental fracture, myalgia, cervical ankylosis, synovitis, tendonitis.
Platelets (clotting): bruising, rhinorrhea, thrombocytosis.
Psychiatric: anorexia, anxiety, increased appetite, depression, neuroticism, lethargy.
Hematologic system: anemia.
Respiratory system: bronchitis, bronchospasm, worsening of bronchospasm, cough, dyspnea, laryngitis, pneumonia.
Skin and its appendages: alopecia, dermatitis, nail lesions, photosensitivity reactions, pruritus, erythematous rash, maculopapular rash, skin lesions, dry skin, hyperhidrosis, urticaria.
Administration site lesions: cellulitis, contact dermatitis, injection site reactions, skin nodules.
Special sensations: taste disorders.
Urinary system: proteinuria, cystitis, dyspareunia, hematuria, dysuria, renal calculi, urinary incontinence, urinary tract infection.
Vision: blurred vision, cataracts, conjunctivitis, eye pain, glaucoma.
The following are other rare serious adverse reactions with an incidence <0.1% regardless of whether they are causally related to treatment: The following serious adverse events have occurred rarely in patients taking celecoxib
Cardiovascular system: syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis.
Gastrointestinal system: intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis bleeding, esophageal perforation, pancreatitis, intestinal occlusion.
Systemic: sepsis, sudden death.
Hepatobiliary system: cholelithiasis.
Hematologic and lymphatic system: thrombocytopenia.
Nervous system: ataxia, suicide (see [Drug Interactions] – Warfarin).
Renal: acute renal failure.
Adverse reactions in long-term, placebo-controlled adenomatous polyp prophylaxis studies.
In two clinical studies, the APC (Celecoxib Adenoma Prevention Trial) and PreSAP (Spontaneous Polypoid Adenoma Prevention Trial), celecoxib was administered at dosages of 400 mg/day to 800 mg/day for up to 3 years.
The incidence of some adverse reactions was higher than in the premarketing arthritis clinical study (treatment lasted 12 weeks; see adverse events in the premarketing controlled clinical study of celecoxib for arthritis). The adverse reactions with a higher incidence of celecoxib treatment compared to the premarketing arthritis clinical studies were as follows.
Celecoxib
(400-800 mg/day)
(n=2285) Placebo
(n=1303) Diarrhea 10.5% 7.0% Gastroesophageal reflux 4.7% 3.1% Nausea 6.8% 5.3% Vomiting 3.2% 2.1% Dyspnea 2.8% 1.6% Hypertension 12.5% 9.8% Kidney stones 2.1% 0.8% In the long-term adenomatous polyp prophylaxis study, the incidence of the following adverse reactions in the celecoxib treatment group was between 0.1% and <1%, higher than in the placebo group. Also, these adverse reactions were not reported in pre-marketing controlled studies of arthritis or occurred more frequently in long-term placebo-controlled adenomatous polyp prophylaxis studies.
Neurological abnormality: cerebral infarction.
Ocular abnormalities: vitreous moth disease, conjunctival hemorrhage.
Ear and vagus abnormalities: vaginitis, hypoacusis.
Cardiac abnormalities: unstable angina, aortic valve insufficiency, sinus bradycardia, ventricular hypertrophy.
Vascular anomalies: deep vein thrombosis.
Reproductive system and breast abnormalities: ovarian cysts.
Laboratory test abnormalities: elevated blood potassium, elevated blood sodium, decreased blood testosterone.
Injury, toxicity and surgical complications: epicondylitis, tendon rupture.
Gastrointestinal abnormalities: increased frequency of bowel movements.
Post-marketing experience
The following are the adverse reactions reported during the use of celecoxib after its marketing approval. Because these reactions were spontaneously reported from a variable number of people, it was not always possible to reliably estimate their frequency or to determine a causal relationship with drug exposure.
Cardiovascular: vasculitis, deep vein thrombosis.
Systemic: allergic-like reactions, angioedema.
Hepatobiliary system: hepatic necrosis, hepatitis, jaundice, liver failure, cholestasis, cholestatic hepatitis.
Hematologic and lymphatic system: granulocyte deficiency, aplastic anemia, holocytopenia, leukopenia.
Metabolic: hypoglycemia, hyponatremia.
Neurological: aseptic meningitis, loss of taste, loss of smell, lethal intracranial hemorrhage.
Renal: interstitial nephritis, nephrotic syndrome, microscopic lesions, hyponatremia.
Psychiatric: hallucinations.
Safety data from the Celecoxib Long-Term Arthritis Safety Study (CLASS).
Hematologic events.
In that study, the incidence of clinically significant hemoglobin reductions (>2 g/dL) determined by review was lower in patients taking celecoxib 400 mg twice daily (four and two times the recommended dose for osteoarthritis and rheumatoid arthritis, respectively) than in patients taking diclofenac 75 mg twice daily or ibuprofen 800 mg three times daily, 0.5%, 1.3%, and 1.9%. The incidence of celecoxib adverse events was lower with or without concomitant aspirin (see [Pharmacology and Toxicology] – Platelets).
Withdrawal from study/serious adverse events (SAEs).
The cumulative Kaplan-Meier rates of study withdrawal due to adverse events (AEs) in patients taking celecoxib, diclofenac, and ibuprofen at month 9 were 24%, 29%, and 26%, respectively. The incidence of serious adverse events (e.g., resulting in hospitalization, life-threatening, or other medically significant conditions), whether or not causally related to the drug, did not differ between the three treatment groups, at 8%, 7%, and 8%, respectively.
Adverse events observed in the Ankylosing Spondylitis Study.
A total of 378 patients were treated with celecoxib in the placebo and positive-controlled ankylosing spondylitis studies. The drug dose in the study was up to 400 mg once daily. The types of adverse events reported in the ankylosing spondylitis study were similar to those reported in the osteoarthritis/rheumatoid arthritis study.
Adverse events in analgesia and dysmenorrhea studies.
Approximately 1700 patients were treated with celecoxib in the Analgesia and Dysmenorrhea Study. All patients in the post-oral surgery pain study received a single dose of study drug. Doses of up to 600 mg/day of celecoxib were used in the primary dysmenorrhea and post-operative orthopedic pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in the arthritis study. The only additional adverse event in the post-oral surgery pain study was post-extraction alveolar osteitis (dry socket).
Contraindications]
This product is contraindicated in persons with hypersensitivity (e.g., anaphylaxis and severe skin reactions) to celecoxib or any of the other components of the drug.
Celecoxib should not be used in persons with known hypersensitivity to sulfonamide.
Celecoxib should not be used in patients with asthma, urticaria, or other allergic-type reactions induced by the administration of aspirin or other NSAIDs including other cyclooxygenase-2 (COX-2)-specific inhibitors. Severe (sometimes fatal) allergic-like reactions induced by NSAIDs have been reported in these patients (see [Precautions]).
Celecoxib is contraindicated in coronary artery bypass grafting (CABG) surgery (see [PRECAUTIONS] – WARNINGS).
Celecoxib is contraindicated in patients with active peptic ulceration/bleeding.
Celecoxib is contraindicated in patients with severe heart failure.
[Precautions].
Warnings
Cardiovascular Thrombotic Events
Clinical trials (up to three years) of various COX-2 selective and non-selective NSAIDs have shown that administration of these drugs can increase the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, and that the risk may be fatal. Based on the available data, it is unclear whether the risk of cardiovascular thrombotic events is similar for all NSAIDs. The increase in serious cardiovascular thrombotic events relative to baseline appears to be similar for patients on NSAIDs regardless of whether they have known cardiovascular disease or have risk factors for cardiovascular disease. However, the absolute incidence of extremely severe cardiovascular thrombotic events was higher in patients with known cardiovascular disease or with risk factors for cardiovascular disease because of their relatively increased baseline incidence. Several observational studies have found that this increased risk of severe cardiovascular thrombotic events begins as early as the first week of treatment. A corresponding increase in the risk of cardiovascular thrombotic events was observed when the drug was administered at higher doses.
In the APC (celecoxib for adenoma prevention) trial, the risk of the composite endpoint of cardiovascular death, myocardial infarction, or stroke was increased approximately threefold in the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment groups compared to placebo. The increased risk of the composite endpoint in both celecoxib dose groups compared with the placebo-treated group was primarily due to an increased incidence of myocardial infarction.
A randomized controlled trial entitled “Prospective Randomized Evaluation of the Combined Safety of Celecoxib versus Ibuprofen or Naproxen (PRECISION)” was conducted to assess the relative cardiovascular thrombosis risk of the COX-2 inhibitor celecoxib versus the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was not inferior to naproxen 375 – 500 mg twice daily and ibuprofen 600 – 800 mg three times daily for the composite endpoint (consisting of cardiovascular death (including bleeding death), nonfatal myocardial infarction, and nonfatal stroke) in the Antiplatelet Study Collaborative (APTC) group.
To minimize the potential risk of cardiovascular adverse events in patients receiving NSAID therapy, the lowest effective dose should be used for the shortest treatment period possible. Even in the absence of prior cardiovascular symptoms, physicians and patients should remain alert for the occurrence of such events throughout the course of therapy. Patients should be informed of the symptoms of serious cardiovascular events and their response.
There is no consistent evidence that concomitant aspirin use can reduce the increased risk of serious cardiovascular thrombotic events associated with the use of NSAIDs. Concomitant use of aspirin and an NSAID, such as celecoxib, will increase the risk of serious gastrointestinal events (see Gastrointestinal Effects – Risk of Gastrointestinal Ulcers, Bleeding, and Perforation).
Status After Coronary Artery Bypass Graft (CABG) Surgery
The use of another COX-2 selective NSAID for the treatment of pain in the first 10-14 days after CABG surgery in two large, controlled clinical trials revealed an increased incidence of myocardial infarction and stroke. NSAID is contraindicated in coronary artery bypass grafting (CABG) surgery (see [Contraindications]).
Celecoxib should not be used as an alternative to aspirin for the prevention of cardiovascular thromboembolic disease because of its lack of effect on platelets. Because celecoxib does not inhibit platelet clumping, antiplatelet therapy drugs (e.g., acetylsalicylic acid) should not be discontinued.
Post-myocardial infarction patients
Observational studies performed in the Danish National Registry Study demonstrated an increased risk of myocardial reinfarction and cardiovascular-related death in patients treated with NSAIDs after myocardial infarction, as well as all-cause mortality beginning in the first week of treatment. In the same cohort, the incidence of death in the first year after myocardial infarction was 20/100 patient-years in patients treated with NSAID, compared with 12/100 patient-years in patients not treated with NSAID. Despite a decrease in the absolute incidence of death after the first year of myocardial infarction, the relative risk of death among NSAID users remained increased during at least the next four years of follow-up.
Avoid using celecoxib in patients with recent myocardial infarction unless the expected benefit outweighs the risk of recurrent cardiovascular thrombotic events. If celecoxib is administered to a patient with a recent myocardial infarction, monitor the patient for signs of myocardial ischemia.
Gastrointestinal bleeding, ulceration, and perforation
NSAIDs, including celecoxib, can cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation in the esophagus, stomach, small intestine, or large intestine, all of which can be fatal. In patients treated with celecoxib, these serious adverse events can occur at any time and may or may not be accompanied by warning signs. Only 1 in 5 patients treated with NSAIDs who experience a serious upper gastrointestinal adverse event will develop symptoms. Upper gastrointestinal ulcers, overt bleeding, or perforation due to NSAID occur in about 1% of patients treated for 3-6 months; these events occur in about 2%-4% of patients treated for one year. However, even short-term NSAID treatment is not without risk.
Risk factors for gastrointestinal bleeding, ulceration and perforation
Patients with a prior history of peptic ulcers and/or gastrointestinal bleeding have a more than 10-fold higher risk of gastrointestinal bleeding with NSAIDs than patients without these risk factors. Other factors that increase the risk of gastrointestinal bleeding in patients treated with NSAIDs include: long-term NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; alcohol consumption; old age; and poor general health. Most post-marketing reports of fatal gastrointestinal events have come from older or frail patients. In addition to this, patients with advanced liver disease and/or coagulation disorders are at increased risk of gastrointestinal bleeding.
In CLASS, the incidence of complicated and symptomatic ulcers at month 9 was 0.78% in all patients and 2.19% in the low-dose aspirin group. At month 9, the incidence was 1.40% in patients aged greater than and equal to 65 years and 3.06% in those taking concomitant aspirin.
Strategies to minimize gastrointestinal risk in NSAID-treated patients.
Use the lowest effective dose for the shortest treatment time possible.
Avoid giving more than one NSAID at a time.
Avoid dosing patients at higher risk unless the expected therapeutic benefit outweighs the risk of increased bleeding. Consider alternative therapies to NSAIDs for these patients and for patients with active gastrointestinal bleeding.
Remain alert for signs and symptoms of gastrointestinal ulceration and bleeding during NSAID therapy.
If a serious gastrointestinal adverse event is suspected, promptly initiate evaluation and treatment and discontinue celecoxib until the serious gastrointestinal adverse event subsides.
Patients should be monitored more closely for signs of gastrointestinal bleeding when low-dose aspirin is also used to prevent heart disease (see [Drug Interactions]).
Hepatotoxicity
In clinical trials, elevated ALT or AST (at least 3 times the upper limit of normal [ULN]) was reported in approximately 1% of patients treated with NSAIDs. In addition, severe liver injury (sometimes fatal), including fulminant hepatitis, hepatic necrosis, and liver failure, has been reported in rare cases.
Up to 15% of patients treated with NSAIDs, including celecoxib, may have elevated ALT or AST (less than 3 times the upper limit of normal [ULN]).
In controlled clinical studies with celecoxib, the incidence of critical elevations (greater than or equal to 1.2 times the upper limit of normal and less than 3 times) of liver-related enzymes was 6% in the celecoxib-treated group and 5% in the placebo group; the incidence of significant ALT or AST elevations was approximately 0.2% in the celecoxib-treated group compared with 0.3% in the placebo group.
Patients were informed of signs and symptoms indicative of hepatotoxic reactions (e.g., nausea, fatigue, drowsiness, diarrhea, pruritus, jaundice, right upper abdominal tenderness, and “flu-like” symptoms). If clinical signs and symptoms are suggestive of progressive liver disease or systemic manifestations (e.g., eosinophilia, rash, etc.), discontinue celecoxib immediately and evaluate the patient clinically.
Celecoxib should be used with caution in patients with moderate hepatic impairment (Child-Pugh class B) and the lowest recommended dose is recommended for initiation of therapy (see [DOSAGE]).
Hypertension
NSAIDs, including celecoxib, can cause new-onset hypertension or exacerbate existing hypertension, either of which can lead to an increased incidence of cardiovascular events. The efficacy of these treatments may be compromised in patients taking angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, or medullary collaterals diuretics when taking NSAIDs.
Blood pressure (BP) should be monitored closely at the start of NSAID therapy and throughout the course of therapy.
Heart Failure and Edema
A meta-analysis of multiple randomized, controlled trials conducted by a collaboration of cribriform and conventional NSAID trialists showed that patients receiving selective COX-2 therapy and those receiving non-selective NSAID therapy had approximately two times more hospitalizations for heart failure than those receiving placebo. In the Danish National Registry Study of patients with heart failure, treatment with NSAIDs increased the risk of myocardial infarction, hospitalization for heart failure, and death.
As with other drugs known to inhibit prostaglandin synthesis, some patients taking NSAIDs developed fluid retention and edema. The use of celecoxib may inhibit the cardiovascular efficacy of multiple therapeutic agents used to treat these conditions (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor antagonists [ARBs]) (see [Drug Interactions]).
In the CLASS study, Kaplan-Meier cumulative rates of peripheral edema at month 9 were 4.5%, 6.9%, and 4.7% in patients taking celecoxib 400 mg twice daily (four and two times the recommended doses for OA and RA, respectively), ibuprofen 800 mg three times daily, and diclofenac 75 mg twice daily, respectively.
Avoid using celecoxib in patients with severe heart failure unless the expected benefit outweighs the risk of worsening heart failure. If celecoxib is administered to a patient with severe heart failure, the patient should be monitored for signs of worsening heart failure.
Therefore, patients with prior congestive heart failure or hypertension should be monitored closely. Celecoxib should be used with caution in patients with fluid retention, heart failure, or other conditions that may cause or exacerbate fluid retention (including those on diuretic therapy or at risk for volume reduction).
Nephrotoxicity and Hyperkalemia
Nephrotoxicity
Long-term use of NSAIDs can lead to renal papillary necrosis and other kidney damage. Nephrotoxicity is also seen in patients in whom prostaglandins play a compensatory role in renal perfusion maintenance. In these patients, the use of NSAIDs leads to a dose-dependent decrease in prostaglandin production and a subsequent decrease in renal blood flow, which leads to significant renal failure. Patients at highest risk in this category are those with impaired renal function, dehydration, hypovolemia, heart failure, abnormal liver function, patients on diuretics and angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), and elderly patients. Such patients treated with celecoxib should be closely monitored. Discontinuation of NSAIDs usually results in a return to pretreatment status.
In the available controlled clinical studies, there is no information on the use of celecoxib in patients with progressive renal disease. Celecoxib may accelerate the progression of renal impairment in patients with existing renal disease.
The volume status of dehydrated patients or patients with hypovolemia should be corrected before starting celecoxib therapy. Monitor renal function in patients with hepatic or renal impairment, heart failure, dehydration, or hypovolemia during the use of celecoxib (see [Drug Interactions]). Avoid using celecoxib in patients with end-stage renal disease unless the expected benefit outweighs the risk of worsening renal function. If celecoxib is used in patients with advanced renal disease, monitor the patient for signs of worsening renal function.
Hyperkalemia
Increased serum potassium concentrations (including hyperkalemia) have been reported in patients treated with NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects are the result of a hyporenin-hypoaldosteronism state.
Allergic reactions
Celecoxib can cause anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin-allergic asthma. Celecoxib is a sulfonamide, and both NSAIDs and sulfonamides may cause allergic reactions in certain susceptible individuals, including allergic symptoms and life-threatening or less severe asthma attacks (see [Contraindications] and [Precautions]).
If any anaphylactic reaction occurs, seek emergency medical attention.
Asthma worsening associated with aspirin allergy
Some patients with asthma may suffer from aspirin-allergic asthma, which may include chronic sinusitis complicated by nasal polyps; severe fatal bronchospasm; and/or aspirin and other NSAID intolerance. Because cross-reactivity between aspirin and other NSAIDs has been reported in these aspirin-allergic patients, celecoxib is contraindicated in this type of aspirin-allergic patient (see [Contraindications]). When celecoxib is used in patients with preexisting asthma (without a known history of aspirin allergy), patients should be monitored for changes in asthma signs and symptoms.
Serious skin reactions
Celecoxib treatment has caused serious skin reactions, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic necrolytic epidermolysis bullosa (TEN), drug reactions with eosinophilia and systemic symptoms (DRESS), and acute generalized eruptive pustulosis (AGEP). These serious events can occur without warning and can be fatal.
Inform patients of the signs and symptoms of a serious skin reaction and discontinue celecoxib at the first sign of rash or any other sign of hypersensitivity reaction. Celecoxib is contraindicated in patients with prior severe skin reactions to NSAIDs (see [Contraindications]).
Premature Closure of Fetal Arterial Ducts
Celecoxib may induce premature closure of the ductus arteriosus. Avoid the use of NSAIDs (including celecoxib) in pregnant women in late pregnancy (beginning in the 30th week of pregnancy) (see [Use in Pregnant and Lactating Women]).
Hematologic Toxicity
Anemia occurs in patients receiving NSAID therapy. This may be due to occult or overt blood loss, fluid retention, or an effect of the drug on erythropoiesis (this effect is not fully understood). Monitor hemoglobin or hematocrit if patients treated with celecoxib develop any signs or symptoms of anemia.
In controlled clinical studies, the incidence of anemia was 0.6% in the celecoxib-treated group and 0.4% in the placebo group. Patients on long-term celecoxib should have their hemoglobin and hematocrit checked at the onset of any signs and symptoms of anemia or blood loss.
NSAIDs (including celecoxib) may increase the risk of bleeding events. Coexisting disorders (e.g., coagulation disorders) or the combination of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin/norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor such patients for signs of bleeding (see [Drug Interactions]).
Masking inflammation and fever
The pharmacologic properties of celecoxib to reduce inflammation and possibly relieve fever diminish the value of positive signs in the diagnosis of infection.
Other Precautions
Laboratory monitoring
Because severe gastrointestinal bleeding, hepatotoxicity, and renal damage can occur without warning, monitoring of patients on long-term NSAIDs with periodic complete blood counts (CBC) and blood biochemistry should be considered (see [Precautions]).
Controlled clinical studies have shown that the incidence of elevated blood urea nitrogen (BUN) is higher in patients treated with celecoxib than in those on placebo. Other laboratory test abnormalities seen more frequently in patients taking celecoxib than placebo include hypophosphatemia and elevated BUN. These laboratory test abnormalities were also seen in patients receiving controlled treatment with NSAIDs in these clinical studies. The clinical significance of these abnormalities has not been determined.
Note to patients.
Inform patients, their families, or their caregivers of the following information prior to initiation of celecoxib therapy and periodically during the course of therapy
Cardiovascular Thrombotic Events
Advise patients to be alert for symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurred speech, and to report any such symptoms to their healthcare provider immediately (see [PRECAUTIONS]).
Gastrointestinal bleeding, ulcers, and perforations
Patients should be told to report symptoms of ulcers and bleeding to their healthcare provider, including epigastric pain, dyspepsia, black stools, and vomiting of blood. Inform patients of the increased risk of gastrointestinal bleeding and the signs and symptoms of gastrointestinal bleeding when low-dose aspirin is used concomitantly to prevent heart disease (see [Precautions]).
Hepatotoxicity
Inform patients of signs and symptoms that predict hepatotoxicity (e.g., nausea, fatigue, drowsiness, pruritus, diarrhea, jaundice, right upper abdominal tenderness, and “flu-like” symptoms). Patients should be instructed to discontinue celecoxib and seek prompt drug therapy if such signs and symptoms occur (see [PRECAUTIONS]).
Heart Failure and Edema
Alert patients to symptoms of congestive heart failure, including shortness of breath, unexplained weight gain, or edema, and contact their physician if such symptoms occur (see [Precautions]).
Allergic reactions
Patients should be informed of signs of anaphylactic reactions (e.g., dyspnea, facial or laryngeal edema). Instruct the patient to seek immediate emergency care if such symptoms occur (see [Contraindications] and [Precautions]).
Severe skin reactions
Advise patients to discontinue celecoxib immediately if any type of rash develops and to contact their physician as soon as possible (see [Precautions]).
Female Fertility
Women of childbearing potential who are planning to become pregnant should be advised that NSAIDs, including celecoxib, may cause a reversible delay in ovulation (see [Use in Pregnant and Lactating Women]).
Fetal toxicity
Advise pregnant women to avoid celecoxib and other NSAIDs beginning in the 30th week of pregnancy because of the potential for premature closure of the fetal ductus arteriosus (see [PRECAUTIONS] and [PRECAUTIONS FOR PREGNANCY AND BREASTFEEDING WOMEN]).
Avoid concurrent use of multiple NSAIDs
Advise patients that concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, bisalicylate) is not recommended because it increases the risk of gastrointestinal toxicity with little to no increase in efficacy (see [Precautions] and [Drug Interactions]). Warn patients that NSAIDs may be present in “over-the-counter” medications used to treat colds, fever, or insomnia.
Application of NSAIDs and low-dose aspirin
Advise patients not to use celecoxib with low-dose aspirin unless their physician agrees (see [Drug Interactions]).
Effects on driving and ability to operate machinery
The effect of celecoxib on the ability to drive or operate machinery has not been studied, but based on the pharmacodynamic properties and overall safety of this product, it is unlikely that celecoxib will have an effect.
Pregnant women and nursing mothers
Pregnancy
Risk Summary
The use of NSAIDs (including celecoxib) in late pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid the use of NSAIDs, including celecoxib, in pregnant women in the 30th week of pregnancy and beyond.
There are insufficient controlled studies of celecoxib in pregnant women. Data from observational studies on the potential embryo-fetal risk of using NSAIDs in women with early or midterm pregnancies are inconclusive. The estimated background risk of significant birth defects and miscarriage in the specified population is not known. All pregnancies are at background risk for birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the background risk for major malformations in all cases of clinically confirmed pregnancies (with or without drug exposure) is 2-4%, and the background risk for miscarriage is 15-20%.
Clinical Considerations
Labor or Delivery
The effects of celecoxib during labor or delivery have not been studied. In animal studies, NSAIDs (including celecoxib) inhibited prostaglandin synthesis, caused delays in labor and increased the incidence of stillbirth.
Data
Human data
The available data do not confirm the presence of developmental toxicity associated with celecoxib use.
Lactation
Risk Summary
Limited data from 3 published medical reports (including a total of 12 breastfeeding women) suggest low levels of celecoxib in breast milk. The mean daily dose for infants was calculated to be 10-40 mcg/kg/day, which is less than 1% of the therapeutic dose for two-year-olds based on body weight. Reports of two breastfed infants (17 and 22 months of age) indicate that these infants did not experience any adverse events. Celecoxib therapy should be given with caution to breastfeeding females. The developmental and health benefits of breastfeeding, the maternal clinical need for celecoxib, and any potential adverse effects of celecoxib or the underlying maternal condition on the breastfed infant should be considered in combination.
Women of childbearing potential and men with
Infertility
Females
Depending on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib, may delay or inhibit ovulation, resulting in reversible infertility in some women. Published animal studies suggest that the application of prostaglandin synthesis inhibitors may disrupt prostaglandin-mediated follicle rupture required for ovulation. Reversible ovulation delay has also been shown in small studies in women treated with NSAIDs. Consider discontinuing NSAIDs, including celecoxib, in women who have difficulty conceiving or finding a cause for infertility.
Pediatric Dosage]
No information is available on the efficacy and safety of celecoxib in children under 18 years of age.
Geriatric use]
Older patients are at greater risk of serious cardiovascular, gastrointestinal and/or renal adverse reactions associated with NSAIDs than younger patients. If the expected benefit to elderly patients outweighs the potential risk, start with the lowest dose in the dose range and monitor patients for adverse reactions (see [Precautions]).
Of the total number of patients treated with celecoxib in each clinical study, more than 3,300 were 65 to 74 years of age, while approximately 1,300 were 75 years of age or older. No significant differences were seen in the efficacy of the drug between older and younger patients. In clinical studies in which renal function was measured by glomerular filtration rate (GFR), BUN and creatinine, and platelet function was measured by bleeding time and platelet aggregation tests, no differences were found in older and younger volunteers. However, with other NSAIDs, including selective COX-2 inhibitors, there were more spontaneous post-marketing reports of fatal gastrointestinal events and acute renal failure in older patients than in younger patients (see [Precautions]-Warnings-Gastrointestinal Bleeding, Ulceration, and Perforation).
[Drug Interactions].
See Table 2 for information related to clinically significant celecoxib drug interactions.
Table 2: Clinically Significant Celecoxib Drug Interaction Information
Clinical effects of drugs that interfere with hemostasis: Celecoxib has a synergistic effect with anticoagulants (e.g., warfarin) on bleeding. Concomitant use of both increases the risk of severe bleeding compared with the use of celecoxib or anticoagulant drugs alone.
Platelet serotonin release plays an important role in the coagulation process. Case-control and cohort epidemiologic studies suggest that combining an NSAID with a drug that can interfere with serotonin reuptake may produce a higher risk of bleeding compared to NSAID alone. Intervention: Monitor for signs of bleeding in patients on concomitant celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin/norepinephrine reuptake inhibitors (SNRIs) (see [Precautions]). Clinical Impact of Aspirin: Controlled clinical studies have shown that combined NSAID and analgesic doses of aspirin do not produce more significant efficacy than NSAID alone. In clinical studies, concomitant use of NSAID and aspirin resulted in a significantly increased incidence of gastrointestinal adverse reactions compared with NSAID alone (see [Precautions]).
In two studies in healthy volunteers and in patients with osteoarthritis and heart disease, respectively, celecoxib (200-400 mg daily) did not show interference with the cardioprotective antiplatelet effects of aspirin (100-325 mg). INTERVENTION: Concomitant use of celecoxib with analgesic doses of aspirin is generally not recommended because it increases the risk of bleeding (see [Precautions]).
Clinical effects of ACE inhibitors, angiotensin receptor blockers, and beta-blockers: NSAIDs may reduce the effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers. (ARB) or beta-blockers (including propranolol).
Combining an NSAID with an ACE inhibitor or ARB in the elderly, in persons with volume deficits (including those on diuretic therapy), or in persons with impaired renal function may result in deterioration of renal function, including the possibility of acute renal failure. These effects are usually reversible. Intervention: Monitor the patient’s blood pressure during the combination of celecoxib with an ACE inhibitor, ARB, or beta-blocker to ensure that the blood pressure is at the desired value.
Monitor patients for signs of worsening renal function during concomitant use of celecoxib with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in elderly, hypovolemic, or renally impaired patients (see [PRECAUTIONS]).
When these drugs are used concomitantly, patients should be adequately hydrated. Renal function should be assessed at the initiation of combination therapy and periodically thereafter. Clinical Effects of Diuretics: Clinical studies and post-marketing surveillance have shown that NSAIDs reduce the pro-urinary sodium excretion of medullary collaterals diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect is associated with inhibition of prostaglandin synthesis in the kidney by the NSAID. Intervention: When using celecoxib concomitantly with diuretics, in addition to ensuring diuretic efficacy (including hypotensive effects), patients should be observed for signs of worsening renal function (see [Precautions]). Digoxin clinical effects: Concomitant use of celecoxib with digoxin has been reported to increase serum concentrations and prolong the half-life of digoxin. Intervention: Monitor patients’ serum digoxin levels during the combined use of celecoxib and digoxin. Lithium clinical effects: NSAID can result in increased blood lithium concentrations and decreased renal lithium clearance. The average minimum lithium concentration increases by 15%, while renal clearance decreases by approximately 20%. This effect is related to the inhibition of prostaglandin synthesis in the kidney by the NSAID. Intervention: Monitor patients for signs of lithium toxicity during the combination of celecoxib and lithium. Methotrexate Clinical Effects: Combining NSAID and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal insufficiency).
Celecoxib does not affect the pharmacokinetics of methotrexate. Intervention: Monitor patients for the development of methotrexate toxicity during the combination of celecoxib and methotrexate. Cyclosporine clinical impact: Combining celecoxib and cyclosporine may increase the risk of cyclosporine nephrotoxicity. Intervention: Monitor patients for signs of worsening renal function during concomitant use of celecoxib and cyclosporine. nSAID and salicylate clinical impact: Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, bisalicylate) has little to no increase in efficacy but does increase the risk of gastrointestinal toxicity (see [Precautions]). Intervention: Concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Implications: Combining celecoxib and pemetrexed may increase the risk of myelosuppression, renal and gastrointestinal toxicity associated with pemetrexed (see Pemetrexed Prescribing Information). INTERVENTION: Monitor for signs of myelosuppression, renal and gastrointestinal toxicity in patients with impaired renal function with creatinine clearance between 45 and 79 mL/min during the combination of celecoxib and pemetrexed.
NSAIDs with short clearance half-lives (e.g., diclofenac, indomethacin) should be avoided during the first two days, the day of, and the second two days of pemetrexed administration.
Due to the lack of data on potential interactions between pemetrexed and longer half-life NSAIDs (e.g., meloxicam, nabumetone), patients using these NSAIDs should discontinue the drug at least five days prior to, the day of, and two days after pemetrexed administration. clinical implications of CYP2C9 inhibitors or inducers: Celecoxib is primarily metabolized via hepatic cytochrome P450 (CYP) 2C9 metabolism. Combining celecoxib with known inhibitors of CYP2C9 (e.g., fluconazole) can increase celecoxib exposure and toxicity, and combining celecoxib with inducers of CYP2C9 (e.g., rifampin) can result in decreased efficacy of celecoxib. INTERVENTION: Assess each patient’s medical history when considering prescribing celecoxib. Dose adjustment may be required when combining celecoxib with CYP2C9 inhibitors or inducers.
(See [Pharmacokinetics].) CYP2D6 Substrate Clinical Implications: In vitro studies have shown that celecoxib is not a substrate but an inhibitor of CYP2D6, so it has the potential to interact in vivo with drugs that require metabolism by CYP2D6 (e.g., tomoxetine), and celecoxib may increase exposure and toxicity of these drugs. Intervention: Assess each patient’s medical history when considering prescribing celecoxib. Dose adjustment may be required when combining celecoxib with CYP2D6 substrates.
(See [Pharmacokinetics]). Corticosteroid Clinical Implications: Concomitant use of celecoxib with corticosteroids may increase the risk of gastrointestinal ulceration or bleeding. Intervention: Monitor for signs of bleeding in patients using concomitant celecoxib with corticosteroids (see [PRECAUTIONS]). [Drug overdose].
Symptoms of acute NSAIDs overdose are usually limited to sleepiness, drowsiness, nausea, vomiting, and epigastric pain, and usually resolve with supportive therapy. Gastrointestinal bleeding may also occur. Rarely, hypertension, acute renal failure, respiratory depression, and coma have been observed (see [Precautions]).
There were no reports of celecoxib overdose in clinical studies. 12 patients received doses up to 2400 mg/day for 10 days, which did not cause serious toxicity. There is no information on studies of celecoxib removal by hemodialysis, but because of its high plasma protein binding (>97%), dialysis therapy may be ineffective in overdose.
Overdose should be followed by symptomatic management and supportive therapy. No specific antidote is available. Patients who are asymptomatic within 4 hours of overdose or in case of very large overdose (5-10 times the recommended dose) can also be rescued by pharmacological emetic, and/or activated charcoal (60-100g for adults, 1-2g/kg for children), and/or osmotic catheterization. Because of the high protein binding rate, diuresis, alkalinization of urine, hemodialysis or hemoperfusion may not be effective.
Pharmacology and Toxicology
Pharmacological effects
Celecoxib is a non-steroidal anti-inflammatory drug that inhibits prostaglandin production by inhibiting cyclooxygenase-2 (COX-2).
Toxicological studies
Animal toxicity studies: An increased incidence of seminal cysts with secondary changes such as epididymal sperm reduction, and very mild to mild varicocele dilation was observed in juvenile rats. Although these reproductive findings were clearly associated with drug treatment, the incidence did not increase with increasing dose, nor did the severity of these toxic reactions increase with increasing dose; this suggests a possible worsening of the natural condition. Similar reproductive findings have not been observed in young/adult dogs, or adult rats treated with celecoxib. The clinical significance of these findings is not clear.
Genotoxicity
Celecoxib has not been shown to be mutagenic in the Ames test in Chinese hamster ovary (CHO) cells, in the chromosomal aberration test in CHO cells, or in the bone marrow micronucleus test in rats in vivo.
Reproductive toxicity
Celecoxib did not impair reproduction in male and female rats at oral doses up to 600 mg/kg/day (approximately 11 times the clinical dose of 200 mg twice daily exposure on an AUC0-24 basis).
Oral administration of celecoxib 150 mg/kg/day in rabbits during the organogenesis phase (at AUC0-24, approximately twice the clinical dose of 200 mg twice daily exposure) increased the incidence of septal defects (a rare event), and fetal changes such as rib fusion, sternal joint fusion, and sternal joint deformity. There was a dose-dependent increase in the occurrence of diaphragmatic hernia in rats given oral celecoxib ≥30 mg/kg/day (approximately 6 times the clinical dose of 200 mg twice daily exposure dose on an AUC0-24 basis). There are no studies of the use of this product in pregnant women. Celecoxib should be used in pregnancy only if the potential benefit to the fetus outweighs the harm to the fetus.
Oral administration of celecoxib to rats at doses ≥50 mg/kg/day (approximately 6 times the clinical dose of 200 mg twice daily exposure on an AUC0-24 basis) resulted in reduced pre-laying and post-laying abortions and embryo survival. This effect is due to inhibition of prostaglandin synthesis and has no permanent effect on reproductive function, which does not occur under normal clinical application. No human studies evaluating the effect of this product on ductus arteriosus closure are available. Therefore, avoid the use of this product during the second trimester of pregnancy.
There is no evidence of delayed labor and delivery in rats given oral doses of celecoxib up to 100 mg/kg (approximately 7 times the clinical dose of 200 mg twice daily exposure on an AUC0-24 basis). The effects of this product on labor and delivery in women during pregnancy are unknown.
Studies in lactating rats have shown that celecoxib is secreted via the milk at concentrations similar to plasma concentrations. Lactating women taking celecoxib showed very low lactation. Celecoxib may cause potentially serious adverse reactions in nursing infants and children, so the decision to discontinue nursing or discontinue the drug should be based on considerations of the importance of the drug to the mother.
Carcinogenicity
Celecoxib has been shown to cause carcinogenicity in rats at oral doses up to 200 mg/kg (males) and 10 mg/kg (females) (exposure doses comparable to clinical doses of approximately 200 mg twice daily at AUC0-24), or in mice at oral doses up to 25 mg/kg (males) and 50 mg/kg (females) (exposure doses comparable to clinical doses of approximately 200 mg twice daily at AUC0-24). The doses were comparable to clinical doses of about 200 mg twice daily) for two years and no carcinogenic effects were found.
Pharmacokinetics]
According to foreign literature.
When the oral dose was not higher than 200 mg twice daily, celecoxib showed an increase in exposure proportional to the dose; this positive relationship diminished when the dose was further increased. It is widely distributed in tissues and has a high protein binding rate. It is metabolized primarily via CYP2C9 and has a half-life of approximately 11 hours.
Absorption
Maximum blood levels are reached approximately 3 hours after oral administration of a single dose of celecoxib. In the fasted state, the maximum blood concentration (Cmax) and area under the curve (AUC) of celecoxib at doses as high as 200 mg twice daily are approximately proportional to the dose; at further dose increases, this proportional relationship diminishes (see Food Effects). Absolute bioavailability studies have not been performed. Steady-state blood levels are achieved within 5 days after multi-dose administration.
Table 3 shows the pharmacokinetic parameters of celecoxib in a group of healthy subjects.
Table 3: Pharmacokinetics of celecoxib in a single dose (200 mg) in healthy subjects1
Mean (%CV) PK parameter value 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 Subjects in fasted state (n=36, 19-52 years)
Effect of food
Celecoxib taken with high-fat foods delays reaching maximum blood levels by 1 to 2 hours, while overall absorption (AUC) is increased by 10% to 20%. In the fasted state, the relationship between Cmax and AUC increasing proportionally to dose is diminished at doses above 200 mg, probably due to its low solubility in aqueous solutions. When celecoxib is administered with antacids (aluminum and magnesium), its blood concentration decreases, with a 37% decrease in Cmax and a 10% decrease in AUC. At doses as high as 200 mg twice daily, the timing of dosing is not affected by the timing of meals. Higher doses of 400 mg twice daily should be taken with food to increase absorption.
Overall systemic exposure (AUC) was the same for healthy subjects taking celecoxib capsules as for those taking celecoxib capsule contents mixed with apple puree. Cmax, Tmax and T1/2 were not significantly altered when the contents of celecoxib capsules were taken mixed with apple puree.
Distribution
Plasma protein binding of celecoxib was high in healthy subjects at therapeutic doses up to 97%. In vitro studies have shown that celecoxib binds primarily to albumin and, to a lesser extent, to alpha1 acid glycoprotein. The apparent volume of distribution (Vss/F) at steady-state blood levels was 400 L, suggesting that celecoxib is widely distributed in tissues. Celecoxib does not preferentially bind to erythrocytes.
Clearance
Metabolism
Celecoxib is primarily metabolized by cytochrome P450 2C9. Three metabolites have been demonstrated in human plasma, the alcohol, the corresponding carboxylic acid and its glucosinolate conjugate. These metabolites did not inhibit the activity of COX-1 or COX-2. Celecoxib should be used with caution in patients with known or suspected P450 2C9 metabolizing enzyme deficiencies based on medical history, as the reduced metabolic clearance can lead to abnormally high blood levels of celecoxib.
Excretion
Celecoxib is primarily metabolized by the liver, with less than 3% of the dose being excreted in the urine and feces as a prototype. Following administration of a single dose of isotopically labeled drug, 57% is excreted in the feces and 27% is excreted in the urine. The vast majority of metabolites excreted in the urine and feces were carboxylic acids (73% of the dose), with a small amount of glucosinolates excreted in the urine. The drug half-life (t1/2) varies widely due to the prolonged absorption process caused by the low solubility of the drug. The effective half-life is approximately 11 hours in fasting conditions. Apparent plasma clearance (CL/F) is about 500 ml/min.
Special Populations
Elderly.
In the elderly population (>65 years), the Cmax and AUC of celecoxib were increased by 40% and 50%, respectively, compared to the younger population. The Cmax and AUC of celecoxib are higher in older women than in older men, but this increase is most often associated with lower body weight in older women. Dose adjustment of celecoxib is generally not required in the elderly population. However, for patients weighing less than 50 kg, the lowest recommended dose is recommended at initiation of therapy.
Children.
Celecoxib has not been clinically studied in people under 18 years of age.
Ethnicity.
A meta-analysis of several pharmacokinetic studies suggests that the AUC of celecoxib is increased by approximately 40% in Blacks compared to Caucasians. The reason for this and the resulting clinical significance is unclear.
Impaired liver function.
Pharmacokinetic studies in patients with mild hepatic impairment (Child-Pugh Class A) and moderate hepatic impairment (Child-Pugh Class B) showed that the steady-state AUC of celecoxib was increased by 40% and 180%, respectively, compared to healthy subjects. Therefore, the recommended daily dose of celecoxib should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment. Celecoxib is not recommended for use in patients with severe hepatic impairment (see [DOSAGE]).
Impaired renal function.
A crossover design study showed that in patients with chronic renal insufficiency (glomerular filtration rate (GFR) 35-60 ml/min), the AUC of celecoxib was reduced by approximately 40% compared to those with normal renal function. No significant correlation was found between GFR and celecoxib clearance. No relevant studies have been conducted in patients with severe renal insufficiency. Similar to other NSAIDs, celecoxib is not recommended in patients with severe renal insufficiency (see [Precautions]-Warnings).
Drug Interaction Studies
In vitro studies have shown that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
In vivo studies have shown the following results.
Aspirin
When combined with aspirin, protein binding of NSAID is reduced but clearance of free NSAID is unchanged. The clinical significance of this interaction has not been clarified. See Table 2 for clinically meaningful drug interactions of NSAID with aspirin (see [Drug Interactions]).
Lithium
Studies in healthy subjects have shown that mean lithium steady-state plasma concentrations were increased by approximately 17% in subjects receiving both lithium 450 mg twice daily and celecoxib 200 mg twice daily compared to lithium alone (see [Drug Interactions]).
Fluconazole
Concurrent administration of fluconazole 200 mg once daily resulted in a twofold increase in celecoxib blood concentrations. This was due to inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see [Drug Interactions]).
Other Drugs
In vivo trials have studied the pharmacokinetic and/or pharmacodynamic effects of celecoxib with glibenclamide, ketoconazole (see [Drug Interactions]), phenytoin, and toluenosulfonylurea. No clinically significant drug interactions have been identified.
Storage】Store at room temperature and keep tightly closed.
Package】 Pharmaceutical aluminum foil/polyvinyl chloride solid pharmaceutical blister package, 10 capsules/plate x 1 plate/box.
Expiration date】 24 months
Execution Standard
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[Drug Marketing Licensee
Name: Sichuan Guowei Pharmaceutical Co.
Registered Address: New District, Meishan Economic Development Zone, Sichuan Province
Manufacturer
Company name: Sichuan Guowei Pharmaceutical Co.
Production address: Meishan Economic Development Zone New District
Postal code: 620000
Telephone number: 028-85319552 (sales) 028-38662609 (quality)
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