CATEGORIES: Arthritis, osteoarthritis; Pain, moderate to severe; Arthritis, rheumatoid; Dysmenorrhea; Familial adenomatous polyposis; Pregnancy Category C; FDA Approved December 1998
Drug Classes: Analgesics, non-narcotic; COX-2 inhibitors; Nonsteroidal anti-inflammatory drugs
BRAND NAMES: Celebrex
FOREIGN BRAND AVAILABILITY:
Artroxil (Colombia);
Celcox (Israel);
Celebra (Israel);
Celebrex (Israel, Canada, Colombia, England, France, Germany, Hong Kong, Indonesia, Korea, Mexico, Philippines, Singapore, Taiwan, Thailand);
Celib (India);
Coxid (Philippines);
Dilox (Colombia);
Lexfin (Colombia)
COST OF THERAPY:
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Celecoxib is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole.
The empirical formula for celecoxib is C17H14F3N3O2S, and the molecular weight is 381.38.
Celebrex oral capsules contain 100 and 200 mg of celecoxib.
The inactive ingredients in Celebrex capsules include: Croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, sodium lauryl sulfate and titanium dioxide.
Mechanism of Action
Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
Pharmacokinetics
Absorption
Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg bid; at higher doses there are less than proportional increases in Cmax and AUC (see Food Effects). 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.
Food Effects
When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1-2 hours with an increase in total absorption (AUC) of 10-20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Coadministration of celecoxib with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Celecoxib, at doses up to 200 mg bid can be administered without regard to timing of meals. Higher doses (400 mg bid) should be administered with food to improve absorption.
Distribution
In healthy subjects, celecoxib is highly protein bound (∼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 (Vss/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 (T½) 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
Geriatric
At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax 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 patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose.
Pediatric
Celecoxib capsules have not been investigated in pediatric patients below 18 years of age.
Race
Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks 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, the daily recommended dose of celecoxib capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class II) hepatic impairment. Patients with severe hepatic impairment have not been studied. The use of celecoxib in patients with severe hepatic impairment is not recommended.
Renal Insufficiency
In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 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. Similar to other NSAIDs, celecoxib is not recommended in patients with severe renal insufficiency (see WARNINGS, Advanced Renal Disease.
Drug Interactions
Also see DRUG INTERACTIONS.
General
Significant interactions may occur when celecoxib is administered together with drugs that inhibit P450 2C9. In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
Clinical studies with celecoxib have identified potentially significant interactions with fluconazole and lithium. Experience with nonsteroidal anti-inflammatory drugs (NSAIDs) suggests the potential for interactions with furosemide and ACE inhibitors. The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found.
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 bid or 200 mg qd 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 and 200 mg bid provided significant reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 or 200 mg bid the effectiveness of celecoxib was shown to be similar to that of naproxen 500 mg bid. Doses of 200 mg bid provided no additional benefit above that seen with 100 mg bid. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg bid or 200 mg qd.
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 ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. Celecoxib doses of 100 and 200 mg bid were similar in effectiveness and both were comparable to naproxen 500 mg bid.
Although celecoxib 100 and 200 mg bid provided similar overall effectiveness, some patients derived additional benefit from the 200 mg bid dose. Doses of 400 mg bid provided no additional benefit above that seen with 100-200 mg bid.
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 (see DOSAGE AND ADMINISTRATION) of celecoxib provided pain relief within 60 minutes.
Familial Adenomatous Polyposis (FAP)
Celecoxib was evaluated to reduce the number of adenomatous colorectal polyps. A randomized double-blind placebo-controlled study was conducted in 83 patients with FAP. The study population included 58 patients with a prior subtotal or total colectomy and 25 patients with an intact colon. Thirteen (13) patients had the attenuated FAP phenotype.
One area in the rectum and up to four areas in the colon were identified at baseline for specific follow-up, and polyps were counted at baseline and following 6 months of treatment. The mean reduction in the number of colorectal polyps was 28% for celecoxib 400 mg bid, 12% for celecoxib 100 mg bid and 5% for placebo. The reduction in polyps observed with celecoxib 400 mg bid was statistically superior to placebo at the 6 month timepoint (p=0.003).
Special Studies
Endoscopic Studies
Scheduled upper GI endoscopic evaluations were performed in over 4500 arthritis patients who were enrolled in five controlled randomized 12-24 week trials using active comparators, two 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 2 summarizes the incidence of endoscopic ulcers in two 12 week studies that enrolled patients in whom baseline endoscopies revealed no ulcers.
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| * p ≤0.05 versus all other treatments. | ||||||||||||||||||||||||||||||
TABLE 3 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.
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| * p ≤0.05 celecoxib versus naproxen based on interval and cumulative analyses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| † p ≤0.05 celecoxib versus ibuprofen based on interval and cumulative analyses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 bid was 4% vs 15% for patients taking diclofenac SR 75 mg bid (p <0.001).
In 4 of the 5 endoscopic studies, approximately 11% of patients (440/4000) 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 Use With Aspirin and WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation).
Use With Aspirin
The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective long-term safety outcome study conducted postmarketing in approximately 5800 OA patients and 2200 RA patients. Patients received celecoxib 400 mg bid (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP), ibuprofen 800 mg tid or diclofenac 75 mg bid (common therapeutic doses). Median exposures for celecoxib (n=3987) and diclofenac (n=1996) were 9 months while ibuprofen (n=1985) 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 cardiovascular 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 WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation). The results for celecoxib are displayed in TABLE 4. For complicated and symptomatic ulcer rates, see WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation.
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Platelets
In clinical trials, celecoxib at single doses up to 800 mg and multiple doses of 600 mg bid for up to 7 days duration (higher than recommended therapeutic doses) had no effect on platelet aggregation and bleeding time. Comparators (naproxen 500 mg bid, ibuprofen 800 mg tid, diclofenac 75 mg bid) significantly reduced platelet aggregation and prolonged bleeding time.
Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis.
Celecoxib is Indicated:
Celecoxib is contraindicated in patients with known hypersensitivity to celecoxib.
Celecoxib should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
Celecoxib should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma).
Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms (see PRECAUTIONS, Hematological Effects). 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 3-6 months, and in about 2-4% 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 gastrointestinal 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.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal 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 co-therapies or co-morbid 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.
CLASS Study
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers (an adverse event similar but not identical to the "upper GI ulcers, gross bleeding or perforation" described in the preceding paragraphs) for patients treated with celecoxib 400 mg bid (see CLINICAL STUDIES, Special Studies, Use With Aspirin) are described in TABLE 5. TABLE 5 also displays results for patients less than or greater than or equal to the age of 65 years. The differences in rates between the celecoxib alone and celecoxib with ASA groups may be due to the higher risk for GI events in ASA users.
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In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking celecoxib alone or celecoxib with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease (see WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation).
Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to celecoxib. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving celecoxib. Celecoxib should not be given to patients with the aspirin 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 aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced kidney disease. Therefore, treatment with celecoxib is not recommended in these patients with advanced kidney disease. If celecoxib therapy must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS, Renal Effects).
Pregnancy
In late pregnancy celecoxib should be avoided because it may cause premature closure of the ductus arteriosus.
Familial Adenomatous Polyposis (FAP)
Treatment with celecoxib in FAP has not been shown to reduce the risk of gastrointestinal cancer or the need for prophylactic colectomy or other FAP-related surgeries. Therefore, the usual care of FAP patients should not be altered because of the concurrent administration of celecoxib. In particular, the frequency of routine endoscopic surveillance should not be decreased and prophylactic colectomy or other FAP-related surgeries should not be delayed.
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.
The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of 1 or more liver associated enzymes 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, including celecoxib (see ADVERSE REACTIONS). In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes 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.
Renal Effects
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 nonsteroidal anti-inflammatory drug 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.
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. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS, Advanced Renal Disease).
Hematological Effects
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 CLINICAL STUDIES, Special Studies, Platelets).
Fluid Retention, Edema, and Hypertension
Fluid retention and edema have been observed in some patients taking celecoxib (see ADVERSE REACTIONS). In the CLASS study (see CLINICAL STUDIES, Special Studies, Use With Aspirin), the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg bid (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP), ibuprofen 800 mg tid and diclofenac 75 mg bid were 4.5%, 6.9% and 4.7%, respectively. The rates of hypertension in the celecoxib, ibuprofen and diclofenac treated patients were 2.4%, 4.2% and 2.5%, respectively. As with other NSAIDs, celecoxib should be used with caution in patients with fluid retention, hypertension, or heart failure.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for the Patient
Celecoxib can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation).
Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, unexplained weight gain, or edema to their physicians.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS).
In late pregnancy celecoxib should be avoided because it may cause premature closure of the ductus arteriosus.
Patients with familial adenomatous polyposis (FAP) should be informed that celecoxib has not been shown to reduce colorectal, duodenal or other FAP-related cancers, or the need for endoscopic surveillance, prophylactic or other FAP-related surgery. Therefore, all patients with FAP should be instructed to continue their usual care while receiving celecoxib.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females [approximately 2- to 4-fold the human exposure as measured by the AUC(0-24) at 200 mg bid] or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females [approximately equal to human exposure as measured by the AUC(0-24) at 200 mg bid] for 2 years.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.
Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day [approximately 11-fold human exposure at 200 mg bid based on the AUC(0-24)].
Pregnancy Category C
Teratogenic Effects
Celecoxib at oral doses ≥150 mg/kg/day [approximately 2-fold human exposure at 200 mg bid 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 bid] throughout organogenesis. There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Celecoxib produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day [approximately 6-fold human exposure based on the AUC(0-24) at 200 mg bid]. These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of celecoxib during the third trimester of pregnancy should be avoided.
Labor and Delivery
Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats [approximately 7-fold human exposure as measured by the AUC(0-24) at 200 mg bid]. The effects of celecoxib on labor and delivery in pregnant women are unknown.
Nursing Mothers
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious 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 importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 years have not been evaluated.
Geriatric Use
Of the total number of patients who received celecoxib in clinical trials, more than 3300 were 65-74 years of age, while approximately 1300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous postmarketing reports of fatal GI events and acute renal failure in the elderly than in younger patients (see WARNINGS, Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation).
General
Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Co-administration 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 an inhibitor of cytochrome P450 2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6.
Of the celecoxib treated patients in the premarketing controlled clinical trials, approximately 4250 were patients with OA, approximately 2100 were patients with RA, and approximately 1050 were patients with post-surgical pain. More than 8500 patients have received a total daily dose of celecoxib of 200 mg (100 mg bid or 200 mg qd) or more, including more than 400 treated at 800 mg (400 mg bid). 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.
Adverse Events From Celecoxib Premarketing Controlled 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 OA or RA that included a placebo and/or a positive control group.
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| * 100-200 mg bid or 200 mg qd. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| † 500 mg bid. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ‡ 75 mg bid. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| § 800 mg tid. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 following adverse events occurred in 0.1-1.9% of patients regardless of causality with celecoxib doses of 100-200 mg bid or 200 mg qd:
Other serious adverse reactions which occur rarely (estimated <0.1%), regardless of causality: The following serious adverse events have occurred rarely in patients taking celecoxib. Cases reported only in the post-marketing experience are indicated in italics.
Safety Data From CLASS Study
Hematological Events
During this study (see CLINICAL STUDIES, Special Studies, Use With Aspirin), the incidence of clinically significant decreases in hemoglobin (>2 g/dl) confirmed by repeat testing was lower in patients on celecoxib 400 mg bid (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP) compared to patients on either diclofenac 75 mg bid or ibuprofen 800 mg tid: 0.5%, 1.3% and 1.9%, respectively. The lower incidence of events with celecoxib was maintained with or without ASA use (see CLINICAL STUDIES, Special Studies, Platelets).
Withdrawals/Serious Adverse Events
Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac, and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., those causing hospitalization or felt to be life threatening or otherwise medically significant) regardless of causality were not different across treatment groups, respectively, 8%, 7%, and 8%.
Based on Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events*, there were no differences between the celecoxib, diclofenac, or ibuprofen treatment groups. The rates in all patients at 9 months for celecoxib, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The rates for non-ASA users in each of the three treatment groups were less than 1%. The rates for myocardial infarction in each of the three non-ASA treatment groups were less than 0.2%.
*Includes myocardial infarction, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks or ischemic cerebrovascular accidents.
Adverse Events From Analgesia and Dysmenorrhea Studies
Approximately 1700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies recieved a single dose of study medication. Doses up to 600 mg/day of celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.
Adverse Events From the Controlled Trial in Familial Adenomatous Polyposis
The adverse event profile reported for the 83 patients with familial adenomatous polyposis enrolled in the randomized, controlled clinical trial was similar to that reported for patients in the arthritis controlled trials. Intestinal anastomotic ulceration was the only new adverse event reported in the FAP trial, regardless of causality, and was observed in 3 of 58 patients (one at 100 mg bid, and two at 400 mg bid) who had prior intestinal surgery.
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. Gastrointestinal 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.
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 (60-100 g in adults, 1-2 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.
For osteoarthritis and rheumatoid arthritis, the lowest dose of celecoxib should be sought for each patient. These doses can be given without regard to timing of meals.
Special Populations
Hepatic Insufficiency
The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class II) should be reduced by approximately 50% (see CLINICAL PHARMACOLOGY, Special Populations).
Celebrex Capsules
Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
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