Celebrex

Celecoxib.

Each 200 mg capsule contains 200 mg celecoxib.
Each 400 mg capsule contains 400 mg celecoxib.
Excipients/Inactive Ingredients: 200 mg and 400 mg capsules contain lactose monohydrate, sodium lauryl sulphate, polyvidone K30, croscarmellose sodium and magnesium stearate. Capsule shells contain gelatin, titanium dioxide, and ink gold SB-3002 (200 mg capsule) or ink green SB-4027 (400 mg capsule).

Pharmacotherapeutic Group: M01AH Coxibs.
Pharmacology: Pharmacodynamics: The mechanism of action of celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of cyclooxygenase 2 (COX-2). At therapeutic concentrations in humans, celecoxib does not inhibit cyclooxygenase 1 (COX-1). COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent in animal models by blocking the production of inflammatory prostanoids via COX-2 inhibition. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed COX-1 enzyme. Consequently at therapeutic doses celecoxib has no effect on prostanoids synthesised by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in tissues, particularly the stomach, intestine and platelets.
Clinical Studies: Osteoarthritis (OA): Celecoxib has demonstrated significant reduction in joint pain compared to placebo. Celecoxib was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in approximately 4200 patients in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with celecoxib 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, celecoxib doses of 100 mg twice daily or 200 mg twice daily provided significant reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the efficacy of celecoxib was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily.
Rheumatoid Arthritis (RA): Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib was evaluated for treatment of the signs and symptoms of RA in approximately 2100 patients in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Celecoxib was shown to be superior to placebo in these studies, using the American College of Rheumatology 20 (ACR20) Responder Index, a composite of clinical, laboratory, and functional measures in RA. Celecoxib doses of 100 mg twice daily and 200 mg twice daily were similar in efficacy and both were comparable to naproxen 500 mg twice daily.
Although celecoxib 100 mg twice daily and 200 mg twice daily provided similar overall efficacy, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100 mg - 200 mg twice daily.
Analgesia, including Primary Dysmenorrhea: In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, celecoxib relieved pain that was rated by patients as moderate to severe. Single doses of celecoxib provided pain relief within 60 minutes (see Dosage & Administration).
Ankylosing Spondylitis (AS): Celecoxib was evaluated in AS patients in two placebo- and active-controlled (naproxen or ketoprofen) clinical trials of 6 and 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale), and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg celecoxib doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to celecoxib 400 mg, 53%, than to celecoxib 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines response as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global, pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks.
Further information from clinical studies: Endoscopic Studies: Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in 5 controlled randomized 12-24 week trials using active comparators, 2 of which also included placebo controls. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of celecoxib over the range studied.
Table 1 summarizes the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers. (See Table 1.)

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Table 2 summarizes data from two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers. Patients underwent interval endoscopies every 4 weeks to give information on ulcer risk over time. (See Table 2.)

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One randomized and double-blind 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months.
The incidence of endoscopic ulcers in patients taking celecoxib 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily (p <0.001).
In 4 of the 5 endoscopic studies, approximately 11% of patients (440/4,000) were taking aspirin (≤325 mg/day). In the celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.
The correlation between findings of endoscopic studies and the relative incidence of clinically significant serious upper GI events has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving celecoxib in controlled and open-labeled trials, albeit infrequently (see GI Effects under Precautions).
Gastrointestinal Safety Meta-Analysis from Osteoarthritis and Rheumatoid Arthritis Studies: An analysis of 31 randomized controlled clinical studies in OA and RA, involving 39,605 patients with OA (N=25,903), RA (N=3,232), or patients with either condition (N=10,470) compared the incidence of GI adverse events in celecoxib-treated patients to the incidence in patients administered placebo or NSAIDs (including naproxen, diclofenac and ibuprofen). The incidence of clinical ulcers and ulcer bleeds with 200 mg - 400 mg total daily dose was 0.2% compared to an incidence of 0.6% with NSAIDs (RR=0.35; 95% CI 0.22-0.56).
The Celecoxib Long-term Arthritis Safety Study (CLASS) Including Use with Aspirin: In a prospective long-term safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients, patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily, or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for celecoxib (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The Kaplan-Meier cumulative rates at 9 months are provided for all analyses. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation, or obstruction). Patients were allowed to take concomitant low-dose (≤325 mg/day) aspirin (ASA) for CV prophylaxis (ASA subgroups: celecoxib, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between celecoxib and the combined group of ibuprofen and diclofenac were not statistically significant. Those patients on celecoxib and concomitant low-dose ASA experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (see GI Effects under Precautions). The results for celecoxib are displayed in Table 3. (See Table 3.)

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Platelet function: In healthy volunteers, celecoxib at therapeutic doses and at multiple doses of 600 mg twice daily (three times the highest recommended dose) had no effect on platelet aggregation and bleeding time compared to placebo. Active controls (non-specific COX inhibitors) all significantly reduced platelet aggregation and prolonged bleeding time (see figure).

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Celecoxib versus Omeprazole and Diclofenac for at-risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) Trial: In this prospective, 24-week study in patients with age ≥60 years or history of gastroduodenal ulcers (users of low-dose aspirin excluded), the percentage of patients with clinically significant GI events (composite primary endpoint) was lower in patients treated with celecoxib 200 mg twice daily compared to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily. This difference was driven by clinically significant decreases in hemoglobin (≥2 g/dL) and/or hematocrit (≥10%) of defined or presumed GI origin. Results for the individual components of this composite endpoint were as follows: (See Table 4.)

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Cardiovascular Safety: Long-term Studies Involving Patients With Sporadic Adenomatous Polyps: Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib, i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of CV death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the hazard ratios compared to placebo for a composite endpoint of CV death, myocardial infarction, or stroke (adjudicated) were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400 mg twice daily, and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671) and 2.5% (17/685) for 400 mg twice daily and 200 mg twice daily celecoxib treatment groups respectively, compared to 0.9% (6/679) for placebo group. The increases for both celecoxib dose groups versus placebo were mainly driven by myocardial infarction.
In the PreSAP trial, the hazard ratios compared to placebo for this same composite endpoint was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once daily. Cumulative rate for this composite endpoint over 3 years was (21/933), compared to 1.9% (12/628) for placebo group.
Cardiovascular Safety - Long Term Study of Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): Data from the ADAPT study did not show a significantly increased CV risk with celecoxib 200 mg twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61 - 2.15) with celecoxib 200 mg twice daily.
Cardiovascular Safety - Meta-analysis from Chronic Usage Studies: A meta-analysis of safety data (adjudicated, investigator - reported serious adverse events) from 39 completed celecoxib clinical studies of up to 65 weeks duration has been conducted, representing 41,077 patients: [23,030 (56.1%) patients exposed to celecoxib 200 mg - 800 mg total daily dose (TDD); 13,990 (34.1%) patients exposed to non-selective NSAIDs; and 4,057 (9.9%) patients exposed to placebo].
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke was similar between celecoxib (N = 19,773; 0.96 events/100 patient-years) and non-selective NSAIDs (N = 13,990; 1.12 events/100 patient-years) treatment (RR = 0.90, 95% CI 0.60 - 1.33). This pattern of effect was maintained with or without ASA use (≤325 mg). The adjudicated event rate of non-fatal myocardial infarction trended higher (RR = 1.76, 95% CI 0.93 - 3.35); however that of non-fatal stroke trended lower (RR = 0.51, 95% CI 0.23 - 1.10), and that of CV death was comparable (RR = 0.57, 95% CI 0.28 - 1.14) for celecoxib compared to combined non-selective NSAIDs.
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke was 1.42/100 patient-years for celecoxib (N = 7,462) and 1.20/100 patient-years for placebo (N = 4,057) treatment (RR = 1.11, 95% CI 0.47 - 2.67). This pattern of effect was maintained with or without ASA use (≤325 mg). The incidence of non-fatal myocardial infarction trended higher (RR = 1.56, 95% CI 0.21 – 11.90), as did that of CV death (RR = 1.26, 95% CI 0.33 - 4.77), and that of non-fatal stroke was similar (RR = 0.80, 95% CI 0.19 - 3.31) for celecoxib compared to placebo.
Cardiovascular Safety: CV safety outcomes were evaluated in the CLASS trial (see as previously mentioned for description of trial). Kaplan-Meier cumulative rates for investigator-reported serious CV thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the celecoxib, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for celecoxib, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree.
Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION): Design: The PRECISION study was a double-blind study of cardiovascular safety in OA or RA patients with or at high risk for cardiovascular disease comparing Celecoxib (200-400 mg daily) with Naproxen (750-1000 mg daily) and Ibuprofen (1800-2400 mg daily). The primary endpoint, Antiplatelet Trialists Collaboration (APTC), was an independently adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction or non-fatal stroke. The study was planned with 80% power to evaluate non-inferiority. All patients were prescribed open-label esomeprazole (20-40 mg) for gastro protection. Patients who were taking low-dose Aspirin were permitted to continue therapy.
Other independently adjudicated secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. Additionally, there was a 4-month substudy focusing on the effects of the three drugs on blood pressure as measured by ambulatory monitoring (ABPM).
Results: (See Table 5.)

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Primary Endpoint: Celecoxib, as compared with either naproxen or ibuprofen, met all four prespecified non-inferiority requirements (p<0.001 for non-inferiority in both comparisons). Non-inferiority is established when the hazard ratio (HR) ≤1.12 in both ITT and mITT analyses, and upper 95% CI ≤1.33 for ITT analysis and ≤1.40 for mITT analysis.
The primary analysis for ITT and mITT are described as follows in Table 6. (See Table 6.)

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Key Secondary and Tertiary Endpoints: The analysis of Major Adverse Cardiovascular Events (MACE)* for mITT are described as follows in Table 7. (See Table 7.)

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The analysis of Gastrointestinal Events for mITT are described as follows in Table 8. (See Table 8.)

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In the ITT population for the CSGIE endpoint there were no significant differences, in the pairwise comparisons between treatment regimens (data not shown). For the endpoint of iron deficiency anemia of GI origin, significant differences (celecoxib vs. naproxen; celecoxib vs. ibuprofen) and non-significant differences (ibuprofen vs. naproxen) were observed in a manner consistent with the data presented as previously mentioned.
The analysis of clinically significant renal events*, hospitalization for CHF and hypertension for mITT are described as follows in Table 9. (See Table 9.)

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In the ITT population for the endpoint of clinically significant renal events, only the pairwise comparison between celecoxib and ibuprofen was significant, HR 0.61 (0.44, 0.85), no significant differences were observed between treatment regimens in the incidence of hospitalization for congestive heart failure, and a significantly lower incidence of hospitalization for hypertension was observed between celecoxib and ibuprofen, HR 0.59 (0.36, 0.99).
All-cause mortality: In the mITT populations celecoxib, naproxen and ibuprofen were associated with 53 (0.7%), 79 (1.0%), and 73 (0.9%) deaths, respectively. Significant differences were observed in the pairwise comparisons between celecoxib and either naproxen HR 0.65 (0.46, 0.92) or celecoxib and ibuprofen HR 0.68 (0.48, 0.97). In the ITT population the celecoxib, naproxen and ibuprofen were associated with 132 (1.6%), 163 (2.0%) and 142 (1.8%) deaths, respectively. No significant differences were observed in pairwise comparisons between treatments.
ABPM Substudy: In the PRECISION-ABPM substudy, among the total of 444 analyzable patients, at Month 4, celecoxib-treated patients had the smallest change in 24-hour ambulatory systolic blood pressure (SBP) compared to ibuprofen and naproxen: celecoxib produced a slight reduction of 0.3 mmHg while ibuprofen and naproxen increased mean 24-hour SBP by 3.7 and 1.6 mmHg, respectively. These changes resulted in a statistically significant and clinically meaningful difference of -3.9 mmHg (p=0.0009) between celecoxib and ibuprofen; a non-significant difference of -1.8 (p=0.119) mmHg between celecoxib and naproxen, and a non-significant difference of -2.1 mmHg (p=0.0787) between naproxen and ibuprofen.
Pharmacokinetics: Absorption: The pharmacokinetics of celecoxib has been evaluated in approximately 1500 individuals. When given under fasting conditions celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Oral bioavailability from capsules is about 99% relative to administration in suspension (optimally available oral dosage form). Under fasting conditions, both peak plasma levels (C_max) and area under the curve (AUC) are roughly dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in C_max and AUC.
Distribution: Plasma protein binding, which is concentration independent, is about 97% at therapeutic plasma concentrations and the drug is not preferentially bound to erythrocytes in the blood.
Metabolism: Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma: a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median C_max and AUC_0-24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC_0-24 increased by approximately 3-fold compared to normal metabolizers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% - 1.0% among different ethnic groups.
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose (see Dosage & Administration and Interactions).
Excretion: Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. After multiple dosing, elimination half-life is 8-12 hours and the rate of clearance is about 500 ml/min. With multiple dosing steady-state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, C_max, elimination half-life) is about 30%. The mean steady-state volume of distribution is about 500 L/70 kg in young healthy adults indicating wide distribution of celecoxib into tissues. Pre-clinical studies indicate that the drug crosses the blood/brain barrier.
Food Effects: Dosing with food (high fat meal) delays absorption of celecoxib resulting in a T_max of about 4 hours and increases bioavailability by about 20% (see Dosage & Administration).
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in C_max, T_max or T_1/2 after administration of capsule contents on applesauce.
Special Populations: Elderly: In the population >65 years there is a one and a half to two-fold increase in mean C_max and AUC for celecoxib. This is a predominantly weight-related rather than age-related change, celecoxib levels being higher in lower weight individuals and consequently higher in the elderly population who are generally of lower mean weight than the younger population. Therefore, elderly females tend to have higher drug plasma concentrations than elderly males. No dosage adjustment is generally necessary. However, for elderly patients with a lower than average body weight (<50 kg), initiate therapy at the lowest recommended dose.
Race: A meta analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in the Black population compared to Caucasians. The cause and clinical significance of this finding is unknown.
Hepatic impairment: Plasma concentrations of celecoxib in patients with mild hepatic impairment (Child-Pugh Class A) are not significantly different from those of age and sex matched controls. In patients with moderate hepatic impairment (Child-Pugh Class B) celecoxib plasma concentrations are about twice those of matched controls (see Dosage & Administration).
Renal impairment: In elderly volunteers with age-related reductions in glomerular filtration rate (GFR) (mean GFR >65 ml/min/1.73 m²) and in patients with chronic stable renal insufficiency (GFR 35-60 ml/min/1.73 m²) celecoxib pharmacokinetics was comparable to those seen in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance. Severe renal insufficiency would not be expected to alter clearance of celecoxib since the main route of elimination is via hepatic metabolism to inactive metabolites.
Renal Effects: The relative roles of COX-1 and COX-2 in renal physiology are not completely understood. Celecoxib reduces the urinary excretion of PGE₂ and 6-keto-PGF_1∞ (a prostacyclin metabolite) but leaves serum thromboxane B₂ (TXB₂) and urinary excretion of 11-dehydro-TXB₂, a thromboxane metabolite (both COX-1 products) unaffected. Specific studies have shown Celecoxib produces no decreases in GFR in the elderly or those with chronic renal insufficiency. These studies have also shown transient reductions in fractional excretion of sodium. In studies in patients with arthritis a comparable incidence of peripheral edema has been observed to that seen with non-specific COX-inhibitors (which also possess COX-2 inhibitory activity). This was most evident in patients receiving concomitant diuretic therapy. However, increased incidences of hypertension and cardiac failure have not been observed and the peripheral edema has been mild and self-limiting.
Toxicology: Preclinical safety data: Nonclinical safety data revealed no special hazard for humans based on conventional studies of repeated dose toxicity, mutagenicity or carcinogenicity.
Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC_0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC_0-24 at 200 mg twice daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/fetal survival.
Animal Toxicology: An increase in the incidence of background findings of spermatocele with or without secondary changes, such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown.

For the management of acute pain in adults and for the treatment of primary dysmenorrhoea.
Relief of the acute and chronic pain and inflammation of rheumatoid arthritis and osteoarthritis.
Relief of signs and symptoms of ankylosing spondylitis.
For the management of low back pain (200 mg only).

Celecoxib capsules can be taken with or without food.
Given the association between cardiovascular (CV) risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment.
Adults: Symptomatic Treatment of Osteoarthritis (OA): The recommended dose of celecoxib is 200 mg administered as a single dose or as 100 mg twice per day.
Symptomatic Treatment of Rheumatoid Arthritis (RA): The recommended dose of celecoxib is100 mg or 200 mg twice per day.
Ankylosing Spondylitis (AS): The recommended dose of celecoxib is 200 mg administered as a single dose or 100 mg twice per day. Some patients may benefit from a total daily dose of 400 mg.
Management of Acute Pain: The recommended dose of celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
Treatment of Primary Dysmenorrhea: The recommended dose of celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
Low Back Pain (LBP): Usual dosage for adults is 100 mg of celecoxib orally twice daily, morning and evening after meal, or 200 mg once daily (100 mg and 200 mg only).
Elderly: No dosage adjustment is generally necessary. However, for elderly patients with a lower than average body weight (<50 kg), it is advisable to initiate therapy at the lowest recommended dose.
Hepatic impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). Introduce celecoxib at half the recommended dose in arthritis or pain patients with moderate hepatic impairment (Child-Pugh Class B).
Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied (see Hepatic Effects under Precautions).
Renal impairment: No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment (see Renal Effects under Precautions).
Children: Celecoxib is not indicated for use in children.
CYP2C9 Poor Metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose (see Pharmacology: Pharmacokinetics: Metabolism under Actions).

Clinical experience of overdose is limited. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have been administered to healthy subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of drug removal because of high protein binding of the drug.

Celecoxib is contraindicated in: Patients with known hypersensitivity to celecoxib or any other ingredient of the product.
Patients with known sulfonamide hypersensitivity.
Patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid (ASA [aspirin]) or other non-steroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase-2 (COX-2) specific inhibitors.
Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see Precautions).
Patients who have established CV disease (ischaemic heart disease and stroke).

RISK OF GI ULCERATION, BLEEDING AND PERFORATION WITH NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious GI events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking, and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events.

Patients with risk factors of heart disease, hypertension, hyperlipidaemia, diabetes mellitus, smoking patients and patients with peripheral arterial disease should only be treated with celecoxib after careful consideration.
Cardiovascular Effects: Cardiovascular Thrombotic Events: Celecoxib may cause an increased risk of serious CV thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with dose and duration of use. The relative increase of this risk appears to be similar in those with or without known CV disease or CV risk factors. However, patients with CV disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline. To minimize the potential risk for an adverse CV event in patients treated with celecoxib, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and symptoms of serious CV toxicity and the steps to take if they occur (see Pharmacology: Pharmacodynamics under Actions).
Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see Contraindications).
Celecoxib is not a substitute for acetylsalicylic acid for prophylaxis of CV thrombo-embolic diseases because of the lack of effect on platelet function. Because celecoxib does not inhibit platelet aggregation, anti-platelet therapies (e.g., acetylsalicylic acid) should not be discontinued.
Hypertension: As with all NSAIDS, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy (see Pharmacology: Pharmacodynamics: Clinical Studies: ABPM Substudy under Actions).
Fluid Retention and Edema: As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking celecoxib. Therefore, patients with pre-existing congestive heart failure (CHF) or hypertension should be closely monitored. Celecoxib should be used with caution in patients with compromised cardiac function, pre-existing edema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia.
Gastrointestinal (GI) Effects: Upper and lower GI perforations, ulcers or bleeds have occurred in patients treated with celecoxib. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with Celecoxib. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with CV disease, patients using concomitant aspirin, glucocorticoids, or other NSAIDs, patients using alcohol or patients with a prior history of, or active, GI disease, such as ulceration, GI bleeding or inflammatory conditions. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most spontaneous reports of fatal GI events have been in elderly or debilitated patients.
Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Celecoxib until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.
Renal Effects: NSAIDs including celecoxib may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, and the elderly. Such patients should be carefully monitored while receiving treatment with celecoxib.
Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with celecoxib.
Advanced Renal Disease: Renal function should be closely monitored in patients with advanced renal disease who are administered celecoxib (see Dosage & Administration).
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients exposed to celecoxib (see Contraindications).
Serious Skin Reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Hepatic Effects: Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of celecoxib in patients with severe hepatic impairment is not recommended. Celecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh Class B), and initiated at half the recommended dose (see Dosage & Administration).
Rare cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis, and hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib.
A patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with celecoxib.
Use with Oral Anticoagulants: The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and should be given with caution. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban). In patients on concurrent therapy with warfarin or similar agents, serious bleeding events, some of them fatal, have been reported. Because increases in prothrombin time (INR) have been reported, anticoagulation/INR should be monitored in patients taking a warfarin/coumarin-type anticoagulant after initiating treatment with celecoxib or changing the dose (see Interactions).
General: By reducing inflammation, celecoxib may diminish the utility of diagnostic signs, such as fever, in detecting infections.
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
CYP 2D6 inhibition: Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated drugs that are metabolised by CYP2D6 (see Interactions).
Effects on ability to drive and use machines: The effect of celecoxib on ability to drive or use machinery has not been studied, but based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect.

Fertility: Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including celecoxib, should be considered.
Pregnancy: There are no studies in pregnant women. Studies in animals have shown reproductive toxicity, (see Pharmacology: Toxicology: Preclinical safety data under Actions). The relevance of these data for humans is unknown.
Celecoxib, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during the third trimester of pregnancy.
Celecoxib should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss.
If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on celecoxib should be closely monitored for amniotic fluid volume.
Lactation: Studies in rats show that celecoxib is excreted in milk at concentrations similar to those in plasma. Administration of celecoxib to lactating women has shown very low transfer of celecoxib into breast milk. Because of the potential for adverse reactions in nursing infants from celecoxib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.

Clinical Trials Experience: The following adverse drug reactions (ADRs) in Table 10 were identified with incidence rates greater than 0.01% in celecoxib group and greater than those reported in placebo group, during 12 placeboand/or active-controlled clinical trials of treatment duration up to 12 weeks at daily doses from 100 mg up to 800 mg in adults.
The frequencies on the ADRs in Table 10 are updated based on a more recent pooling of 89 randomized, controlled clinical trials data representing clinical exposure in 38,102 patients taking celecoxib. ADR frequencies are defined as: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%) very rare (<0.01%). The ADRs in Table 10 are listed by system organ class and ranked by frequency in descending order. (See Table 10.)

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The following additional adverse drug reactions* in Table 11 were identified with incidence rates greater than placebo in long-term polyp prevention studies of duration up to 3 years at daily doses from 400 mg up to 800 mg (see Pharmacology: Pharmacodynamics: Cardiovascular Safety: Long-term Studies Involving Patients With Sporadic Adenomatous Polyps under Actions).
Frequencies of ADRs in Table 11 were determined based on these long-term polyp prevention studies and defined as: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%). The ADRs in Table 11 are listed by system organ class and ranked by frequency in descending order. (See Table 11.)

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Post-marketing Experience: Adverse reactions identified from post-marketing experience are provided as follows. Even though these were identified as reactions from post-marketing reports, trial data was consulted to estimate frequency. As previously mentioned, frequencies are based on a pooling of trials representing exposure in 38,102 patients. Frequencies are defined as: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%)), not known (cannot be estimated from the available data): Immune system disorders: Very rare: anaphylactic reaction.
Psychiatric disorders: Rare: hallucination.
Nervous system disorders: Very rare: cerebral haemorrhage, meningitis aseptic, ageusia, anosmia.
Eye disorders: Uncommon: conjunctivitis.
Vascular disorders: Very rare: vasculitis.
Respiratory, thoracic and mediastinal disorders: Rare: pulmonary embolism, pneumonitis.
Gastrointestinal disorders: Rare: gastrointestinal haemorrhage.
Hepatobiliary disorders: Rare: hepatitis; Very rare: hepatic failure, hepatitis fulminant, hepatic necrosis (see Hepatic Effects under Precautions), cholestasis, hepatitis cholestatic, jaundice.
Skin and subcutaneous tissue disorders: Rare: photosensitivity reaction; Very rare: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis exfoliative.
Renal and urinary disorders: Rare: renal failure acute (see Renal Effects under Precautions), hyponatremia; Very rare: tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.
Reproductive system and breast disorders: Rare: menstrual disorder; Not known: infertility female (female fertility decreased) (see Fertility, pregnancy and lactation under Use in Pregnancy & Lactation)^†.
General disorders and administration site conditions: Uncommon: chest pain.
^†Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable.

General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in theliver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose (see Pharmacology: Pharmacokinetics: Metabolism under Actions and Dosage & Administration).
Concomitant administration of celecoxib with inhibitors of CYP2C9 can lead to increases in plasma concentrations of celecoxib. Therefore, a dose reduction of celecoxib may be necessary when celecoxib is co-administered with CYP2C9 inhibitors.
Concomitant administration of celecoxib with inducers of CYP2C9, such as rifampicin, carbamazepine and barbiturates can lead to decreases in plasma concentrations of celecoxib.
Clinical pharmacokinetics study and in vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.
Drug-specific: Interaction of celecoxib with warfarin or similar agents: (see Use with Oral Anticoagulants under Precautions).
Lithium: In healthy subjects, lithium plasma levels increased approximately 17% in subjects receiving lithium together with celecoxib. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Aspirin: Celecoxib does not interfere with the anti-platelet effect of low-dose aspirin (see GI Effects under Precautions). Because of its lack of platelet effects, celecoxib is not a substitute for aspirin in the prophylactic treatment of CV disease.
Anti-hypertensives including Angiotensin-converting enzyme inhibitors (ACEIs), Angiotensin II antagonists (also known as angiotensin receptor blockers, ARBs), diuretics and beta-blockers: Inhibition of prostaglandins may diminish the effect of anti-hypertensives including ACEIs), and/or ARBs, diuretics and beta-blockers. This interaction should be given consideration in patients taking celecoxib concomitantly with ACEIs and/or ARBs, diuretics and beta-blockers.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Results from lisinopril study: In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients co-administered with celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients co-administered with placebo; this difference was statistically significant.
Cyclosporine: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with cyclosporine.
Fluconazole and ketoconazole: Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib C_max of 60% and in AUC of 130%. Ketoconazole, a CYP3A4 inhibitor, showed no clinically relevant inhibition in the metabolism of celecoxib.
Dextromethorphan and metoprolol: Concomitant administration of celecoxib 200 mg twice daily resulted in a 2.6-fold and a 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs as CYP2D6 substrate may need to be reduced when treatment with celecoxib is initiated or increased when treatment with celecoxib is terminated (see Use with Oral Anticoagulants under Precautions).
Diuretics: Clinical studies have shown that NSAIDs, in some patients, can reduce the natriuretic effect of furosemide and thiazides by inhibition of renal prostaglandin synthesis.
Methotrexate: No pharmacokinetic and clinically important interactions have been observed in a clinical study between celecoxib and methotrexate.
Oral contraceptives: In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/0.035 mg ethinyl estradiol).
Other drugs: No clinically important interactions have been observed with celecoxib and antacids (aluminum and magnesium), omeprazole, glibenclamide (glyburide), phenytoin, or tolbutamide.

Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product: None.
Incompatibilities: None known.

Store at or below 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AH01 - celecoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.

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