Celebrex®

Celecoxib

Anti-inflammatory Agent--Analgesic

Pfizer

http://www.pfizer.com/pfizer/main.jsp

Celebrex Monograph PDF download here.

 

CPS:PIS_m113500

 

 

 

Pharmacology

Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animals. The mechanism of action of celecoxib is believed to be related to inhibition of cyclooxygenase-2 (COX-2). COX-2 is expressed at high levels in inflamed tissues where it is induced by mediators of inflammation. COX-2 also plays physiological roles in a limited number of tissues, including those of the female reproductive tract, the kidney and possibly the vascular endothelium. COX-2 has the same catalytic activity as COX-1. COX-1 is expressed constitutively in most tissues including the gastrointestinal tract, kidney, lungs, brain, and platelets. The prostaglandins produced by COX-1 play key roles in the maintenance of physiological functions such as platelet aggregation and are among the factors that maintain the GI mucosal barrier. At therapeutic concentrations (see Dosage) celecoxib inhibits COX-2 and does not inhibit COX-1.

 

Pharmacokinetics

The pharmacokinetics of celecoxib have been evaluated in approximately 1500 individuals. In addition to healthy, young and elderly volunteers (male and female), pharmacokinetic measurements have been done in patients and also in special populations including individuals with hepatic or renal impairment.

Absorption: Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Both peak plasma levels (C_max) and area under the curve (AUC) are roughly dose proportional across the clinical dose range of 100 to 200 mg studied. Under fasting conditions, at higher doses, there is a less than proportional increase in C_max and AUC which is thought to be due to the low solubility of the drug in aqueous media. Because of the low solubility, absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before day 5.

     The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in  Table 1.

CPS:Celebrex_t1Click here for Table 1

Table 1: Celebrex

Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects^a

 

Mean (% CV) Pharmacokinetic (PK) Parameter Values (95% Confidence Interval)
Cmax (ng/mL)	Tmax (h)	Effective t1/2 (h)	Vss/F (L)	CL/F (L/h)
705 (38) (484.2–925.0)	2.8 (37) (1.95–3.71)	11.2 (31) (8.3–14.0)	429 (34) (307.2–551.5)	27.7 (28) (21.3–34.1)

 

 ^a Subjects under fasting conditions (n=36, 19 to 52 years).

 

 

Food Effects: When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10 to 20%. Coadministration of celecoxib with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C_max and 10% in AUC. Celecoxib capsules can be administered without regard to the timing of meals.

Distribution: In healthy subjects, celecoxib is highly protein bound (approximately 97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α₁-acid glycoprotein. The apparent volume of distribution at steady state (V_ss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.

Metabolism: Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t_1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.

Special Populations: Geriatrics: At steady state, elderly subjects (over 65 years old) had a 40% higher C_max and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib C_max and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for elderly patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose, and as with all other NSAIDs, exercise caution in the use of higher doses.

Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in black patients compared to caucasians. The cause and clinical significance of this finding is unknown.

Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, celecoxib capsules should be introduced at a reduced dose in patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. The use of celecoxib in patients with severe hepatic impairment is not recommended (see Contraindications).

Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35 to 60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied (see Contraindications).

Clinical Studies

Osteoarthritis (OA): The clinical effectiveness of celecoxib in the treatment of the signs and the symptoms of OA of the knee and hip was demonstrated in placebo- and active-controlled clinical trials of up to 12 weeks duration, involving approximately 4200 patients. Celecoxib demonstrated significant reductions in joint pain and disease activity, and also improvement in patient functional activity and health-related quality of life compared to placebo. Clinically significant effects on joint pain were seen as early as 24 hours after the first dose of celecoxib. Doses of 200 mg b.i.d. provided no additional efficacy above that seen with 100 mg b.i.d. In the repeated dose OA studies with 100 mg b.i.d. of celecoxib, pain was significantly decreased by the end of the first day of dosing, continued to be significantly less than placebo and was comparable to naproxen 500 mg b.i.d., diclofenac 75 mg b.i.d., and ibuprofen 800 mg t.i.d.

     A total daily dose of 200 mg has been shown to be equally effective when administered as 100 mg b.i.d. or 200 mg once daily. Response to celecoxib was independent of age, gender, severity, or duration of OA. Celecoxib has shown continued efficacy at doses of up to 400 mg a day in a long-term (up to 12 months) open label study of 2500 patients.

     In patients with OA, treatment with celecoxib 100 mg b.i.d. or 200 mg once daily resulted in improvement in functional activity as demonstrated by an improvement in pain, stiffness, function and total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores. Improvement in quality of life, as measured by the MOS-SF-36 (Short Form 36 Item Health Survey) has been shown by improvements in Physical Function, Role Physical, Bodily Pain, Vitality and Social Functioning domains.

Rheumatoid Arthritis (RA): The clinical effectiveness of celecoxib in the treatment of the signs and the symptoms of RA was demonstrated in placebo- and active-controlled clinical trials of up to 24 weeks in duration, involving approximately 2100 patients. Celecoxib demonstrated significant reductions in joint tenderness and pain, joint swelling, disease activity, and morning stiffness compared to placebo. Improvements were demonstrated in the ACR20 Index for RA (American College of Rheumatology 20% Responder Index), patient functional activity, and health-related quality of life compared to placebo. Celecoxib doses of 100 mg b.i.d. and  200 mg b.i.d. were similar in efficacy and  both were comparable to naproxen 500 mg b.i.d. Although celecoxib 100 mg b.i.d. and 200 mg b.i.d. provided similar efficacy overall, some patients derive additional benefit from the 200 mg b.i.d. dose. Doses of 400 mg b.i.d. provided no additional efficacy above that seen with 100 to 200 mg b.i.d.

     Additional studies demonstrated that celecoxib 200 mg b.i.d. was comparable to diclofenac 75 mg b.i.d. and ibuprofen 800 mg t.i.d. Response to celecoxib was independent of age, gender, severity, or duration of RA. In an open label study of up to 12 months in approximately 1900 RA patients, celecoxib has shown continued efficacy.

     In patients with RA, treatment with celecoxib 200 mg b.i.d. resulted in improvement in functioning as shown by an improvement in the Health Assessment Questionnaire (HAQ) functional disability index. Improvement in quality of life as measured by the MOS-SF-36 has been shown by improvements in Physical Function, Role Physical Bodily Pain, Vitality and Social Functioning domains. Compared to celecoxib 100 mg b.i.d., celecoxib 200 mg b.i.d. resulted in greater improvement in the HAQ disability index and the MOS-SF-36 domains of Physical Function and Bodily Pain.

Special Studies: Clinical Experience with Higher-than-therapeutic Dose for OA and RA (800 mg/day) in the presence of concomitant ASA: Celecoxib Long-term Arthritis Safety Study (CLASS): Study Design: A prospective long-term outcome study was conducted in approximately 5800 OA and 2200 RA patients. Patients received celecoxib 400 mg b.i.d. (4-fold and 2-fold greater than the daily recommended 200 mg OA and 400 mg RA doses, respectively), ibuprofen 800 mg t.i.d. or diclofenac 75 mg b.i.d. (common therapeutic doses for OA and RA) for a median exposure of 9 months for celecoxib and diclofenac, and 6 months for ibuprofen. The primary endpoint of this outcome study was the incidence of complicated ulcers (GI bleeding, perforation or obstruction). Additional protocol specified endpoints included the incidence of symptomatic ulcers (gastroduodenal ulcers identified based on UGI symptoms such as abdominal pain, dyspepsia, nausea, diarrhea or vomiting) and clinically relevant decreases in hemoglobin (>2 g/dl) and/or hematocrit (≥ 10 points). Patients were allowed to take concomitant low-dose ASA (≤ 325 mg), mostly for cardiovascular prophylaxis.

Study Results: No statistically significant differences were demonstrated for the incidence of complicated ulcers at the doses studied among the three treatment groups in all patients. Study results for the complete study duration are presented in  Table 2.

     Secondary analysis showed that the incidence of complicated and symptomatic ulcers was lower for celecoxib than for ibuprofen in all patients and in those patients not taking ASA. Approximately 22% of patients were taking low-dose ASA.

     Concomitant low-dose ASA use increased the rates of complicated and symptomatic ulcers to 4 times that of patients not taking ASA (see Precautions, Drug Interactions—Use With ASA or other NSAIDs).

     Celecoxib at the doses studied had a significantly lower incidence of GI intolerability compared to diclofenac, but not ibuprofen (see Adverse Effects).

CPS:Celebrex_t2Click here for Table 2

Table 2: Celebrex

Complicated and Symptomatic Ulcers in OA and RA Patients (Incidence rates at 12 months [%], events/patients)

 

	Higher-than-therapeutic Dose (4X OA; 2X RA) Celebrex 400 mg b.i.d.	Common Therapeutic Dose
		Ibuprofen 800 mg t.i.d.	Diclofenac 75 mg b.i.d.
All Patients (Exposure)	2320 Pt-years	1112 Pt-years	1081 Pt-years
Complicated ulcers	0.43 (17/3987)	0.55 (11/1985)	0.50 (10/1996)
Complicated and symptomatic ulcers	1.05a (42/3987)	1.76 (35/1985)	1.30 (26/1996)
Patients without ASA (Exposure)	1803 Pt-years	874 Pt-years	841 Pt-years
Complicated ulcers	0.26b (8/3105)	0.64 (10/1573)	0.26 (4/1551)
Complicated and symptomatic ulcers	0.68c (21/3105)	1.72 (27/1573)	0.64 (10/1551)
Patients with ASA (Exposure)	517 Pt-years	248 Pt-years	240 Pt-years
Complicated ulcers	1.02 (9/882)	0.24 (1/412)	1.35 (6/445)
Complicated and symptomatic ulcers	2.38 (21/882)	1.94 (8/412)	3.60 (16/445)

 

 ^a p=0.017 vs ibuprofen.

 ^b p=0.037 vs ibuprofen.

 ^c p=<0.001 vs ibuprofen.

 

 

     In a prospective long-term outcome study, celecoxib (4-fold and 2-fold greater than the recommended OA and RA doses, respectively) also demonstrated a significantly lower incidence of clinically relevant decreases in hemoglobin (>2 g/dL) or hematocrit (≥ 10­points) than ibuprofen and diclofenac ( Figure 1) regardless of ASA use. The corresponding incidence rates from the controlled arthritis trials (1 to 6 months duration, most of 3 months duration) were 0.4% in placebo, 0.9% in celecoxib, and 1.7%, 3.3%, 5.2% for naproxen, diclofenac, and ibuprofen respectively. In the controlled arthritis trials celecoxib was studied at doses up to 400 mg b.i.d. Similar significant differences were seen in the absence of bleeding ulcers, in patients not on ASA, and in OA and RA patients.

 

Figure 1:

Celebrex

Incidence of Clinically Relevant Decreases in Hemoglobin and/or Hematocrit (Incidence rates at 12 months [%] events/patients)

 

 

p<0.05 vs ibuprofen and diclofenac.

 

 

 

Endoscopic Studies: Scheduled upper GI endoscopic evaluations were performed in over 4500 arthritis patients who were enrolled in 5 controlled randomized 12-to 24-week trials using active comparators, 2 of which also included placebo controls. Twelve-week endoscopic ulcer data are available on approximately 1400 patients and 24-week endoscopic ulcer data are available on 184 patients on celecoxib at doses ranging from 50 to 400 mg b.i.d. NSAID comparators included naproxen 500 mg b.i.d., diclofenac 75 mg b.i.d., and ibuprofen 800 mg t.i.d.

     In active-controlled studies, the endoscopic gastroduodenal ulceration rate observed with all doses of celecoxib was less than what was seen with the NSAID comparator (see  Table 3 to  Table 5) and, in placebo-controlled studies, was similar to that seen with placebo (see  Table 3). Studies were designed to detect differences between celecoxib and the NSAID comparator, therefore were not powered to detect small differences relative to placebo. Moreover, celecoxib doses above the highest recommended therapeutic dose of 200 mg b.i.d. were evaluated, and demonstrated that with supratherapeutic doses (2 to 4 times the recommended dose), the incidence of endoscopic ulcers was similar to placebo. Duration of observation had no impact on the celecoxib gastroduodenal ulcer rate, as shown in a 24-week trial in which the celecoxib endoscopic ulcer rate was significantly lower than diclofenac SR and comparable to ulcer rates observed with placebo in other studies.

     In all 3 studies that included naproxen 500 mg b.i.d., and in the study that included ibuprofen 800 mg t.i.d., celecoxib was associated with a statistically significantly lower incidence of endoscopic ulcers over the study period. Two studies compared celecoxib with diclofenac 75 mg b.i.d.; one study revealed a statistically significantly higher prevalence of endoscopic ulcers in the diclofenac group at the study endpoint (6 months on treatment), and 1 study revealed no statistically significant difference between cumulative endoscopic ulcer incidence rates in the diclofenac and celecoxib groups after 1, 2, and 3 months of treatment. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of celecoxib over the range studied.

      Table 3 summarizes the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers.

CPS:Celebrex_t3Click here for Table 3

Table 3: Celebrex

Incidence of Gastroduodenal Ulcers from Endoscopic Studies in OA and RA Patients

 

	3-month Studies
	Study 1 (n=1108)	Study 2 (n=1049)
Placebo	2.3% (5/217)	2.0% (4/200)
Celebrex 50 mg b.i.d.	3.4% (8/233)	—
Celebrex 100 mg b.i.d.	3.1% (7/227)	4.0% (9/223)
Celebrex 200 mg b.i.d.	5.9% (13/221)	2.7% (6/219)
Celebrex 400 mg b.i.d.	—	4.1% (8/197)
Naproxen 500 mg b.i.d.	16.2% (34/210)a	17.6% (37/210)a

 

 ^a p≤ 0.05 vs all other treatments.

 

 

Note: Studies were designed to detect differences between celecoxib and NSAID comparator, therefore were not powered to detect small differences relative to placebo.

 

      Table 4 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.

CPS:Celebrex_t4Click here for Table 4

Table 4: Celebrex

Incidence of Gastroduodenal Ulcers from 3-month Serial Endoscopy Studies in OA and RA Patients

 

	Week 4	Week 8	Week 12	Final
Study 3 (n=523)
Celebrex 200 mg b.i.d.	4.0% (10/252)a	2.2% (5/227)a	1.5% (3/196)a	7.5% (20/266)a
Naproxen 500 mg b.i.d.	19.0% (47/247)	14.2% (26/182)	9.9% (14/141)	34.6% (89/257)
Study 4 (n=1062)
Celebrex 200 mg b.i.d.	3.9% (13/337)b	2.4% (7/296)b	1.8% (5/274)b	7.0% (25/356)b
Diclofenac 75 mg b.i.d.	5.1% (18/350)	3.3% (10/306)	2.9% (8/278)	9.7% (36/372)
Ibuprofen 800 mg t.i.d.	13.0% (42/323)	6.2% (15/241)	9.6% (21/219)	23.3% (78/334)

 

 ^a p≤ 0.05 Celebrex vs naproxen based on interval and cumulative analyses.

 ^b p≤ 0.05 Celebrex vs ibuprofen based on interval and cumulative analyses.

 

 

     One randomized and double-blinded 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The results are shown in  Table 5.

CPS:Celebrex_t5Click here for Table 5

Table 5: Celebrex

Incidence of Gastroduodenal Ulcers from a 6-month Endoscopy Study in RA Patients

 

Study 5 (n=430)	6 months
Celecoxib 200 mg b.i.d.	4% (8/212)
Diclofenac 75 mg b.i.d.	15% (33/218)a

 

 ^a Significantly different from Celebrex; p<0.001.

 

 

     The correlation between findings of endoscopic studies, and the relative incidence of clinically serious upper GI events that may be observed with different products, has not been fully established. (see Warnings, Gastrointestinal).

Use with ASA: Patients with cardiovascular risk factors, including those with a recent history of myocardial infarction or stroke and patients deemed to require low-dose ASA for cardiovascular prophylaxis were included in the long-term outcome study (see Adverse Effects). As a result, approximately 22% of patients enrolled in the long-term outcome study were taking ASA (≤ 325 mg/day). As with the NSAID comparators, the incidence rate of ulcers and ulcer complications (perforations, obstructions and bleeds) in celecoxib patients was higher in ASA users as opposed to non-ASA users (see Special Studies—Long-term Outcome Study).

     Approximately 11% of patients (440/4000) enrolled in 4 of the 5 endoscopic studies were taking ASA (≤  325 mg/day). In the celecoxib groups, the endoscopic ulcer rate appeared to be higher in subjects taking both celecoxib and ASA than in subjects taking only celecoxib. However, the increased rate of ulcers in these ASA users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without ASA.

Platelets: In 4 clinical trials involving 118 subjects, celecoxib did not affect platelet function. Celecoxib at single doses up to 800 mg and multiple doses of 600 mg b.i.d. for up to 7 days duration (i.e., 3 times the highest recommended therapeutic dose), had no effect on platelet aggregation and bleeding time compared to placebo. In contrast, the NSAIDs naproxen 500 mg b.i.d., ibuprofen 800 mg t.i.d., and diclofenac 75 mg b.i.d. significantly reduced platelet aggregation and prolonged bleeding time.

 

Indications

For acute and chronic use in the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults.

 

Contraindications

In patients with known hypersensitivity to celecoxib.

     In patients who have demonstrated allergic-type reactions to sulfonamides.

     In patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see Warnings, Anaphylactoid Reactions, and Precautions, Hypersensitivity Reactions).

     In patients with active peptic ulcer, active GI bleeding, or active inflammatory disease of the bowel.

     In patients with significant liver impairment or active liver disease.

     In patients with severe renal impairment (creatinine clearance <0.5 mL/s: 30 mL/min) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored).

     Celecoxib is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

 

Warnings

GI: Celecoxib exhibited a low incidence of gastroduodenal ulceration and serious clinically significant GI events within clinical trials. Among 5285 patients who received celecoxib in controlled clinical trials of 1 to 6 months duration (most were 3 month studies) at a daily dose of 200 mg or more, 2 (0.04%) experienced significant upper GI bleeding, at 14 and 22 days after initiation of dosing. Approximately 40% of these 5285 patients were in studies that required them to be free of ulcers by endoscopy at study entry. Thus it is unclear if this study population is representative of the general population.

     In a prospective randomized controlled long-term outcome trial in 8000 OA and RA patients in which low-dose ASA (≤ 325 mg/day) use was allowed, approximately 0.43% of patients on higher-than-recommended dose of celecoxib (400 mg b.i.d.) demonstrated ulcer complications (perforation, obstruction, or bleeding) over 12 months. In the absence of low-dose ASA use the rate was 0.26% (see Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study).

     The following general warnings for NSAIDs should be borne in mind.

     Serious GI toxicity, such as peptic ulceration, perforation and bleeding, sometimes severe and occasionally fatal, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Minor upper GI problems, such as dyspepsia, are common, and may also occur at any time during NSAID therapy. Therefore, physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for 1 year. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

     NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or GI bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered (see Contraindications).

     For elderly patients of less than 50 kg body weight, initiate therapy at the lowest recommended dose for arthritis and, as with all other NSAIDs, exercise caution in the use of higher doses.

     Studies have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other cotherapies or comorbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age and poor general health status.

Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions may occur in patients without known prior exposure to celecoxib. In postmarketing experience, very rare cases of anaphylactic reactions and angioedema have been reported in patients receiving celecoxib.

     Celecoxib should not be given to patients with the ASA triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see Contraindications and Precautions, Hypersensitivity Reactions). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Advanced Renal Disease: No information is available regarding the use of celecoxib in patients with advanced kidney disease. In postmarketing experience, serious renal failure, including the need for dialysis, and fatalities have been reported in patients with impaired renal function. Therefore, treatment with celecoxib, as with NSAIDs, is not recommended in these patients with advanced renal disease. Kidney function should be monitored, especially in high-risk populations, such as the elderly, patients with cardiovascular disease and diabetes mellitus, as well as in the setting of concomitant use of diuretics and ACE inhibitors (see Contraindications).

Cross-sensitivity: Patients sensitive to any one of the NSAIDs may be sensitive to any of the other NSAIDs also.

Allergies to Sulfonamides: See Contraindications.

Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must  be vigilant to the development of this complication.

Pregnancy

There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. No studies to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans have been carried out, therefore use of celecoxib during the third trimester of pregnancy should be avoided.

Lactation

Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Studies of celecoxib excretion in human milk have not been conducted, therefore, the benefit of celecoxib treatment in nursing mothers should be weighed against the potential risk to the newborn.

Children

Safety and effectiveness in pediatric patients below the age of 18 years have not been evaluated.

 

Precautions

 

General

Celecoxib cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

Gastrointestinal: There is no definitive evidence that the concomitant administration of histamine H₂-receptor antagonists and/or antacids will either prevent the occurrence of GI side effects or allow the continuation of celecoxib when and if these adverse reactions appear.

Renal Function: Long-term administration of  NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs (see Contraindications and Warnings, Advanced Renal Disease).

     Caution should be used when initiating treatment with celecoxib in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with celecoxib.

Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with celecoxib must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hepatic Function: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of celecoxib, the incidence of borderline elevations of liver tests was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.

     A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with celecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), celecoxib should be discontinued (see Contraindications).

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in some patients taking celecoxib (see Adverse Effects). In the CLASS study, the rates of hypertension in patients on celecoxib 400 mg b.i.d. (4-fold and 2-fold the recommended doses for OA and RA respectively), and common therapeutic doses of ibuprofen (800 mg t.i.d.) and diclofenac (75 mg b.i.d.) were 2.0%, 3.1% and 2.0%, respectively. The corresponding rates for edema were: 3.7%, 5.2% and 3.5%, respectively. Therefore, as with other NSAIDs known to inhibit prostaglandin synthesis, the possibility of precipitating CHF in elderly patients or those with compromised cardiac function should be borne in mind. Celecoxib should be used with caution in patients with heart failure, left ventricular dysfunction, hypertension, edema from any cause or other conditions predisposing to fluid retention.

     With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure, elderly patients, or in patients receiving concomitant therapy with β -adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

Hematology: Anemia is sometimes seen in patients receiving celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages (see Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study and Platelets).

     Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

Infection: In common with other anti-inflammatory drugs, celecoxib may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms develop, celecoxib should be discontinued and an ophthalmologic examination performed; ophthalmologic examination should be carried out at periodic intervals in any patient receiving celecoxib for an extended period of time.

 

Occupational Hazards

CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of NSAIDs. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Hypersensitivity Reactions

Patients with asthma may have ASA-sensitive asthma. The use of ASA in patients with ASA-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between ASA and other NSAIDs has been reported in such ASA-sensitive patients, celecoxib should not be administered to patients with this form of ASA sensitivity and should be used with caution in patients with pre-existing asthma.

 

Drug Interactions

General: Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver (commonly used drugs which are also substrates and/or inhibitors for cytochrome P450 2C9 include coumadin, fluoxetine, fluconazole, phenytoin, and tolbutamide). Coadministration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution.

     In vitro studies indicate that celecoxib, although not a substrate, is a relatively weak inhibitor of cytochrome P450 2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6.

     In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.

ASA or other NSAIDs: Because of its lack of platelet effects, celecoxib is not a substitute for ASA for cardiovascular prophylaxis. Therefore, in celecoxib patients with an indication for cardiovascular prophylaxis, antiplatelet therapies should be used as medically indicated.

     ASA is a known risk factor for GI ulceration. As with all other NSAIDs the concomitant administration of ASA with celecoxib results in an increased rate of GI ulceration or other complications, compared to use of celecoxib alone (see Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study). In the long-term outcomes study (at 4- and 2-fold the recommended doses for OA and RA respectively), there was no statistically significant difference for the incidence of complicated ulcers between celecoxib and comparator groups in patients taking ASA. Concomitant low dose ASA use increased the rate of complicated ulcers to 4 times that of patients not taking ASA. Resulting incidence rate for complicated ulcers in patients taking celecoxib and ASA was 1.02%.

Anticoagulants: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing celecoxib therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2 to 5 mg of warfarin (dose sufficient to prolong prothrombin times to 1.2 to 1.7 times their baseline values). In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in postmarketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving celecoxib concurrently with warfarin.

Oral Hypoglycemics: The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide and tolbutamide has been studied and clinically important interactions have not been found.

Diuretics: Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Although prospective studies of celecoxib with diuretics have not been conducted, no adverse reactions indicative of elevations in blood pressure were seen in clinical trials in which arthritis patients were taking celecoxib concurrently with diuretics (n=485). No adverse reactions indicative of sodium retention or renal impairment were seen in clinical trials in patients taking celecoxib concurrently with diuretics.

Antihypertensives: Reports suggest that NSAIDs may diminish the antihypertensive effects of Angiotensin Converting Enzyme (ACE) inhibitors. This interaction should be given consideration. Although prospective studies of celecoxib with ACE inhibitors have not been conducted, no adverse reactions indicative of elevations in blood pressure were seen in clinical trials in which arthritis patients were taking celecoxib concurrently with ACE inhibitors (n=305).

Glucocorticoids: Oral glucocorticoids should be used with caution since they increase the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Antacids: Coadministration of celecoxib with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C_max and 10% in AUC.

Methotrexate: Celecoxib did not have a significant effect on the pharmacokinetics of methotrexate.

Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg b.i.d. with celecoxib 200 mg b.i.d. as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.

Fluconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a 2-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see Pharmacology, Pharmacokinetics—Metabolism). Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole.

Ketoconazole: Celecoxib did not have a significant effect on the pharmacokinetics of ketoconazole.

Phenytoin: Celecoxib did not have a significant effect on the pharmacokinetics of phenytoin.

Other Drug Interactions: No drug interaction data are available for celecoxib and the coadministration of the following products: acetaminophen, alcohol, aminoglycosides, bone marrow depressants, butemide, cholestyramine, colchicine, corticosteroids, cyclosporine, digoxin, gold compounds, indapamide, insulin, nephrotoxic agents, NSAIDs, oral contraceptives, potassium supplements, probenecid, valproic acid, zidovudine.

Laboratory Tests: During the controlled clinical trials, there was an increased incidence of hyperchloremia in patients receiving celecoxib compared with patients on placebo. Other laboratory abnormalities that occurred more frequently in the patients receiving celecoxib included hypophosphatemia, and elevated urea. These laboratory abnormalities were also seen in patients who received comparator NSAIDs in these studies. The clinical significance of these abnormalities has not been established.

 

Adverse Effects

Of the celecoxib-treated patients in controlled trials, approximately 4250 were patients with OA, approximately 2100 were patients with RA, and approximately 1050 were patients with postsurgical pain. More than 8500 patients have received a total daily dose of celecoxib of 200 mg (100 mg b.i.d. or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg b.i.d.). Approximately 3900 patients have received celecoxib at these doses for 6 months or more; approximately 2300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Geriatrics: Celecoxib has been extensively studied in elderly patients. Of the total number of patients who received celecoxib in clinical trials, more than 3300 patients were 65 to 74 years of age, while approximately 1300 additional patients were 75 years and over. While the incidence of adverse experiences tended to be higher in elderly patients, no substantial differences in safety and effectiveness were observed between these subjects and younger patients. In GI endoscopy studies involving over 800 elderly patients, the rate of gastroduodenal ulceration was not different in elderly patients compared to the young. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

     In clinical studies comparing renal function as measured by the GFR, urea and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.

Adverse Events From Original New Drug Submission (NDS) Arthritis Trials:  Table 6 lists all adverse events, regardless of causality, occurring in ≥ 2% of patients receiving celecoxib from 12 controlled studies conducted in patients with osteoarthritis and rheumatoid arthritis that included a placebo and/or a positive control group.

CPS:Celebrex_t6Click here for Table 6

Table 6: Celebrex

Adverse Events Occurring in ≥% of Celebrex Patients from Original NDS Arthritis Trials

 

	Celebrex  100–200 mg  b.i.d. and 200 mg once daily (n=4146) (%)	Placebo (n=1864) (%)	Naproxen 500 mg b.i.d. (n=1366) (%)	Ibuprofen 800 mg t.i.d. (n=387) (%)	Diclofenac 75 mg b.i.d. (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
Flatulence	2.2	1.0	3.6	4.1	3.5
Nausea	3.5	4.2	6.0	3.4	6.7
Body as a Whole
Back Pain	2.8	3.6	2.2	2.6	0.9
Peripheral Edema	2.1	1.1	2.1	1.0	3.5
Injury-Accidental	2.9	2.3	3.0	2.6	3.2
Central and Peripheral Nervous Systems
Dizziness	2.0	1.7	2.6	1.3	2.3
Headache	15.8	20.2	14.5	15.5	15.4
Psychiatric
Insomnia	2.3	2.3	2.9	1.3	1.4
Respiratory
Pharyngitis	2.3	1.1	1.7	1.6	2.6
Rhinitis	2.0	1.3	2.4	2.3	0.6
Sinusitis	5.0	4.3	4.0	5.4	5.8
Upper Respiratory Tract Infection	8.1	6.7	9.9	9.8	9.9
Skin
Rash	2.2	2.1	2.1	1.3	1.2

 

 

     In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8 and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.

     The adverse event profile from the long-term outcomes trial (at 4- and 2-fold the recommended doses for OA and RA respectively) is similar to those reported in the arthritis-controlled trials. In the arthritis-controlled trials, the celecoxib endoscopic gastroduodenal ulceration rate was consistently less than what was seen with the NSAID comparators. In the long-term outcome study however, there was no statistically significant difference for the incidence of complicated ulcers (perforation, obstruction, or bleeding) among the celecoxib 400 mg b.i.d. and NSAID comparators (see Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study). The major differences in study design and patient populations preclude direct comparison between the GI endpoint results in the arthritis controlled and the long-term outcome trials.

     The incidences of withdrawals due to adverse events and the incidences of selected serious adverse events (i.e., those causing hospitalization or felt to be life-threatening or otherwise medically significant) observed in this trial are shown in  Table 7. No significant differences were seen across treatment groups in the incidences of serious adverse events (see  Table 7).

CPS:Celebrex_t7Click here for Table 7

Table 7: Celebrex

Summary of Withdrawal and Serious Cardiovascular Adverse Event Data from the CLASS Trial

 

	Incidence Rates (%) in all OA and RA Patients and in Patients without ASA
	Celecoxib 400 mg b.i.d.	Diclofenac 75 mg b.i.d.	Ibuprofen 800 mg t.i.d.
All Patients	(n=3987)	(n=1996)	(n=1985)
All Withdrawals	22.4	26.5a	23.0
Withdrawals for GI symptoms	12.2	16.6a	13.4
Serious Adverse Events	6.8	5.6	6.0
Myocardial Infarction     (fatal and nonfatal)	0.5	0.2	0.5
Deep Vein Thrombosis	0.2	0.3	0.0
Cardiac Failure	0.2	0.1	0.5
Unstable Angina	0.2	0.2	0.0
Cerebrovascular Disorder	0.1	0.3	0.3
Patients without ASA	(n=3105)	(n=1551)	(n=1573)
All Withdrawals	21.2	25.4a	22.5
Withdrawals for GI symptoms	11.5	15.4a	13.2
Serious Adverse Events	5.0	4.2	4.3
Myocardial Infarction     (fatal and nonfatal)	0.2	0.1	0.1
Deep Vein Thrombosis	0.2	0.2	0.0
Cardiac Failure	0.1	<0.1	0.3
Unstable Angina	<0.1	0.0	0.0
Cerebrovascular Disorder	<0.1	0.3	0.1

 

 ^a p<0.05 vs celecoxib.

 

 

     The following adverse events occurred in 0.1 to 1.9% of patients regardless of causality: Celecoxib (100 to 200 mg b.i.d. or 200 mg once daily).

 

Gastrointestinal

constipation, diverticulitis, dry mouth, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, stomatitis, tenesmus, tooth disorder, vomiting.

 

Cardiovascular

aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction.

General

allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain.

Resistance Mechanism Disorders

herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media.

 

Central, Peripheral Nervous Systems

leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo.

Female Reproductive

breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis.

Male Reproductive

prostatic disorder.

Hearing and Vestibular

deafness, ear abnormality, earache, tinnitus.

 

Heart Rate and Rhythm

palpitation, tachycardia.

Liver and Biliary Systems

ALT increased, AST increased, hepatic function abnormal.

 

Metabolic and Nutritional

urea increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase.

 

Musculoskeletal

arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, synovitis, tendinitis.

Platelets (bleeding or clotting)

ecchymosis, epistaxis, thrombocythemia.

Psychiatric

anorexia, anxiety, appetite increased, depression, nervousness, somnolence.

Hemic

anemia.

 

Respiratory

bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia.

 

Skin and Appendages

alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria.

Application Site Disorders

cellulitis, dermatitis contact, injection site reaction, skin nodule.

Special Senses

taste perversion.

 

Urinary System

albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection.

 

Vision

blurred vision, cataract, conjunctivitis, eye pain, glaucoma.

     Other serious adverse reactions which occur rarely (estimated <0.1%) regardless of causality: the following adverse events have occurred rarely in patients taking celecoxib. Cases reported only in the postmarketing experience are indicated in italics.

 

Cardiovascular

syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, vasculitis.

 

Gastrointestinal

intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, cholelithiasis, ileus.

 

Hemic and Lymphatic

thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia.

Liver and Biliary System

cholelithiasis, hepatitis, jaundice, liver failure.

 

Metabolic

hypoglycemia.

 

Nervous System

ataxia.

Renal

acute renal failure, interstitial nephritis.

 

Skin

erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

General

sepsis, sudden death, anaphylactoid reaction, angioedema.

 

Overdose

 

 

Symptoms

No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity.

     Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. GI bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

 

 

Treatment

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

 

Dosage

Osteoarthritis: The recommended daily dose is 200 mg administered as a single dose or as 2 divided doses, with or without food.

Rheumatoid Arthritis: The recommended starting dose is 100 mg twice per day, with or without food, which may be increased to 200 mg twice per day as needed.

 

Supplied

100 mg

Each white capsule, with printed blue markings of “7767” on the cap and “100” on the body, contains: celecoxib 100 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate; shell: edible ink (indigotine [E132]), gelatin and titanium dioxide (E171). Bottles of 100 and 500.

200 mg

Each white capsule, with printed gold markings of “7767” on the cap and “200” on the body, contains: celecoxib 200 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate; shell: edible ink (ferric oxide [E172]), gelatin and titanium dioxide (E171). Bottles of 100 and 500.

     Store at room temperature (15 to 30°C).