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CELEBREX®
celecoxib capsules
Cardiovascular Risk
- CELEBREX may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS and CLINICAL STUDIES).
- CELEBREX is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
Gastrointestinal Risk
- NSAIDs, including CELEBREX, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS ).
DESCRIPTION
CELEBREX (celecoxib) is chemically designated as 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. It has the following chemical structure:
CH 3
N N CF 3
S
NH 2 O
O
The empirical formula for celecoxib is C17H14F3N3O 2 S, and the molecular weight is 381.38.
CELEBREX oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg of celecoxib.
The inactive ingredients in CELEBREX capsules include: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.
CLINICAL PHARMACOLOGY
Mechanism of Action: CELEBREX is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
Platelets In clinical trials using normal volunteers, C ELEBREX at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of CELEBREX on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of CELEBREX.
Fluid Retention Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Pharmacokinetics: Absorption Peak plasma levels of celecoxib occur approximately 3 hrs 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.
absorption process making terminal half-life (t1/2 ) 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 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 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 patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose.
Pediatric:. The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 juvenile rheumatoid arthritis (JRA) patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient.
Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non- inferiority of celecoxib to naproxen 7.5 mg/kg twice daily (see DOSAGE AND ADMINISTRATION ). Celecoxib has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks.
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 A) and moderate (Child-Pugh Class B) 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 CELEBREX capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBREX in patients with severe hepatic impairment is not recommended (see DOSAGE AND ADMINISTRATION ).
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, CELEBREX is not recommended in patients with severe renal insufficiency (see WARNINGS – Advanced Renal Disease ).
Drug Interactions Also see PRECAUTIONS – 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.
CLINICAL STUDIES
Osteoarthritis (OA): CELEBREX has demonstrated significant reduction in joint pain compared to placebo. CELEBREX was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with CELEBREX 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, C ELEBREX doses of 100 mg BID and 200 mg BID provided significant reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 mg BID or 200 mg BID the effectiveness of CELEBREX 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): CELEBREX has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. CELEBREX was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. C ELEBREX 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. CELEBREX doses of 100 mg BID and 200 mg BID were similar in effectiveness and both were comparable to naproxen 500 mg BID.
Although CELEBREX 100 mg BID 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.
Juvenile Rheumatoid Arthritis (JRA): In a 12-week, randomized, double-blind active- controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17
treatment. The mean reduction in the number of colorectal polyps was 28% for CELEBREX 400 mg BID, 12% for CELEBREX 100 mg BID and 5% for placebo. The reduction in polyps observed with C ELEBREX 400 mg BID was statistically superior to placebo at the six-month timepoint (p=0.003). (See Figure 1.)
Figure 1Figure 1
Percent Change from Baseline inPercent Change from Baseline in
Number of Colorectal PolypsNumber of Colorectal Polyps
(FAP Patients)(FAP Patients)
-50-
-45-
-40-
-35-
-30-
-25-
-20-
-15-
-10-
-5-
00
-50-
-45-
-40-
-35-
-30-
-25-
-20-
-15-
-10-
-5-
Placebo -4.5% 100 mg BID -11.9%
400 mg BID -28.0%*
N=15 N=32 N=
Percent Change from BaselinePercent Change from Baseline
*** p=0.003 versus placebo**
Special Studies Celecoxib Long-Term Arthritis Safety Study (CLASS) The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective long-term safety outcome study conducted postmarketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received CELEBREX 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 CELEBREX (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. 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: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant.
n (^) n n
Those patients on CELEBREX and concomitant low-dose ASA (N=882) experienced 4- fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low dose ASA and those not on ASA, respectively (see WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding and Perforation ).
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with CELEBREX 400 mg BID are described in Table 2. Table 2 also displays results for patients less than or greater than 65 years of age. The difference in rates between CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users.
Table 2 Complicated and Symptomatic Ulcer Rates in Patients Taking C ELEBREX 400 mg BID (Kaplan-Meier Rates at 9 months [%]) Based on Risk Factors
Complicated and Symptomatic Ulcer Rates All Patients Celebrex alone (n=3105) 0. Celebrex with ASA (n=882) 2.
Patients <65 Years Celebrex alone (n=2025) 0. Celebrex with ASA (n=403) 1.
Patients ≥65 Years Celebrex alone (n=1080) 1. Celebrex with ASA (n=479) 3.
In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX 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 and ADVERSE REACTIONS – Safety Data from CLASS Study – Hematological Events ).
Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative
studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of CELEBREX (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of CELEBREX the incidence ranged between 2.7%-5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with C ELEBREX and naproxen.
In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the CELEBREX 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.
Serious clinically significant upper GI bleeding has been observed in patients receiving CELEBREX in controlled and open-labeled trials (see Special Studies - CLASS and WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding and Perforation ).
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of CELEBREX and other treatment options before deciding to use CELEBREX. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
CELEBREX is indicated:
For relief of the signs and symptoms of osteoarthritis.
For relief of the signs and symptoms of rheumatoid arthritis in adults.
For relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 2 years and older ( see CLINICAL STUDIES and ADVERSE REACTIONS - Adverse Events from JRA Study ).
For the relief of signs and symptoms of ankylosing spondylitis.
For the management of acute pain in adults (see CLINICAL STUDIES ).
For the treatment of primary dysmenorrhea.
To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery). It is not known whether there is a clinical benefit from a reduction in the number of colorectal
polyps in FAP patients. It is also not known whether the effects of C ELEBREX treatment will persist after CELEBREX is discontinued. The efficacy and safety of CELEBREX treatment in patients with FAP beyond six months have not been studied (see CLINICAL STUDIES , WARNINGS and PRECAUTIONS sections).
CONTRAINDICATIONS
CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib.
CELEBREX should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
CELEBREX 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 ).
CELEBREX is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS )
WARNINGS
Cardiovascular Effects Cardiovascular Thrombotic Events Chronic use of CELEBREX may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC trial, the relative risk for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for CELEBREX 400 mg twice daily and 2.5 (95% CI 1.0 – 6.4) for the CELEBREX 200 mg twice daily compared to placebo (see Special Studies – Adenomatous Polyp Studies ).
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with CELEBREX, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and CELEBREX does increase the risk of serious GI events (see GI WARNINGS - Risk of GI Ulceration, Bleeding, and Perforation ).
status. 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. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during CELEBREX therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
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 an 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, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with CELEBREX have shown renal effects similar to those observed with comparator NSAIDs.
Advanced Renal Disease No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced renal disease. Therefore, treatment with CELEBREX is not recommended in these patients with advanced renal disease. If CELEBREX therapy must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX. CELEBREX 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.
Skin Reactions CELEBREX is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TENS), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy In late pregnancy CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS – Pregnancy ).
Familial Adenomatous Polyposis (FAP): Treatment with CELEBREX 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 CELEBREX. In particular, the frequency of routine endoscopic surveillance should not be decreased and prophylactic colectomy or other FAP-related surgeries should not be delayed.
PRECAUTIONS
General: CELEBREX 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 concomitant use of CELEBREX with any dose of a non-aspirin NSAID should be avoided.
The pharmacological activity of CELEBREX 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 one 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 CELEBREX (see ADVERSE REACTIONS – post-marketing experience ). In controlled clinical trials of C ELEBREX, 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 CELEBREX and 5% for placebo, and approximately 0.2% of patients taking CELEBREX 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 C ELEBREX. If
— Gastrointestinal (GI) Effects – Risk of Gastrointestinal Ulceration, Bleeding, and Perforation ).
- Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. C ELEBREX is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TENS, which may result in hospitalizations and even death. These reactions can occur with all NSAIDs, even non-sulfonamides. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients with prior history of sulfa allergy should not take CELEBREX.
- Patients should promptly report signs or symptoms of 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). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur.
- Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms (see WARNINGS – Anaphylactoid Reactions ).
- Patients should be informed that in late pregnancy C ELEBREX should be avoided because it may cause premature closure of the ductus arteriosus.
- Patients with familial adenomatous polyposis (FAP) should be informed that CELEBREX 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 CELEBREX.
Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, CELEBREX should be discontinued.
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX 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.
Drug Interactions 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.
ACE-inhibitors and Angiotensin II Antagonists: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors and angiotensin II antagonists.
Aspirin: CELEBREX can be used with low-dose aspirin. However, concomitant administration of aspirin with C ELEBREX increases the rate of GI ulceration or other complications, compared to use of CELEBREX alone (see CLINICAL STUDIES — Special Studies — CLASS , WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation , and WARNINGS – Cardiovascular Effects ).
Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis.
Fluconazole: Concomitant administration of fluconazole at 200 mg QD resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see Pharmacokinetics — Metabolism ). CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole.
Furosemide: Clinical studies, as well as post marketing 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.
Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when C ELEBREX is introduced or withdrawn.
Methotrexate: In an interaction study of rheumatoid arthritis patients taking methotrexate, CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate.
Warfarin: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX therapy in patients receiving warfarin or similar
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 CELEBREX 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 AUC0-24 at 200 mg BID). The effects of CELEBREX 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. Limited data from one subject indicate that celecoxib is also 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 CELEBREX, 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 CELEBREX is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to C ELEBREX or other COX-2 selective and non-selective NSAIDS. (see Boxed Warning, WARNINGS, and CLINICAL STUDIES )
The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12- week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests. (see CLINICAL PHARMACOLOGY – Pediatric , CLINICAL STUDIES – JRA , PRECAUTIONS – Systemic Onset JRA, PRECAUTIONS - Animal Toxicology , ADVERSE REACTIONS - Adverse events from JRA studies , and DOSAGE and ADMINISTRATION - JRA ).
Geriatric Use Of the total number of patients who received CELEBREX in clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 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 post-marketing 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 ).
ADVERSE REACTIONS
Of the CELEBREX treated patients in the premarketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients have received a total daily dose of CELEBREX of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3, patients have received CELEBREX at these doses for 6 months or more; approximately 2,300 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 CELEBREX premarketing controlled arthritis trials: Table 3 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving CELEBREX from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.
Table 3 Adverse Events Occurring in ≥ 2% of CELEBREX Patients From CELEBREX Premarketing Controlled Arthritis Trials
Celebrex Placebo Naproxen Diclofenac Ibuprofen (100-200 mg BID 500 mg BID 75 mg BID 800 mg TID or 200 mg QD) (n=4146) (n=1864) (n=1366) (n=387) (n=345)
Gastrointestinal Abdominal pain 4.1% 2.8% 7.7% 9.0% 9.0% Diarrhea 5.6% 3.8% 5.3% 9.3% 5.8% Dyspepsia 8.8% 6.2% 12.2% 10.9% 12.8% 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 system Dizziness 2.0% 1.7% 2.6% 1.3% 2.3% Headache 15.8% 20.2% 14.5% 15.5% 15.4%
