CELEBREX

Celebrex is a non-steroidal anti-inflammatory drug (NSAID) that represents a huge breakthrough in the treatment of pain, inflammation, and stiffness of arthritis.

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What is CELEBREX used for?
CELEBREX is used for relief of:

Acute pain in adults
Menstrual pain (primary dysmenorrhea) in women
Pain, inflammation, and stiffness of osteoarthritis and rheumatoid arthritis in adults
How does CELEBREX work?
CELEBREX is a type of nonsteroidal anti-inflammatory drug (NSAID). Other NSAIDs, such as ibuprofen, block the actions of both COX-1 and COX-2 enzymes. COX-2 plays a role in pain and inflammation. COX-1 is involved in blood clotting, kidney function, and protection of the stomach lining. CELEBREX is different from some other NSAIDs because it blocks only the inflammation- and pain-producing COX-2 enzyme without inhibiting the COX-1 enzyme at therapeutic doses. Watch our animation to find out more about how CELEBREX works.

How should I take CELEBREX?
Always take CELEBREX exactly as prescribed. If you have any questions, ask your doctor or pharmacist. The following dosages of CELEBREX are recommended based on the cause of pain. These are recommended dosages only, and should not take the place of your doctor's instructions.

Acute pain: 400 mg initially, followed by an additional 200-mg dose on the first day if needed. On subsequent days, the recommended dose is 200 mg twice daily as needed.
Painful menstrual cramping (primary dysmenorrhea): 400 mg initially, followed by an additional 200-mg dose on the first day if needed. On subsequent days, the recommended dose is 200 mg twice daily as needed.
Osteoarthritis (OA): One 200-mg dose once a day or one 100-mg dose twice a day.
Adult rheumatoid arthritis (RA): 100 to 200 mg twice a day.
When should I take CELEBREX?
If you're prescribed a daily dose of CELEBREX, take it every day, not just when you're feeling pain or stiffness. Maintaining a consistent level of CELEBREX in your body helps manage arthritis pain, inflammation, and stiffness, or acute pain. CELEBREX can be taken at any time of the day, but if you take it at the same time, you'll be less likely to forget or accidentally skip it.

Do I need to take CELEBREX with food?
No. You can take CELEBREX with meals or between meals.

Who should not take CELEBREX?
You should not take CELEBREX if you:

Are allergic to celecoxib, the active ingredient in CELEBREX
Have had allergic reactions to certain drugs called sulfonamides
Have experienced asthma, hives, or allergic reactions after taking aspirin or other NSAIDs
Are in late pregnancy
What types of things should I tell my doctor?
Tell the doctor your complete medical history. Be sure to mention any kidney or liver problems, asthma, or pregnancy. Also, to make sure that you're well informed about your condition and about CELEBREX, print our:

Pre-visit checklist, with questions for you to consider prior to your doctor's visit
Questions for the doctor, so you'll be sure to get all the information you need during your appointment
Progress checklist, to help you keep track of how you're doing after you've seen your doctor
What if I'm pregnant or nursing?
There are no studies of CELEBREX in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women in the third trimester of pregnancy should not take CELEBREX. The effects of CELEBREX on labor and delivery in pregnant women are unknown. It is also unknown whether CELEBREX is excreted in breast milk.

Has the safety of CELEBREX been established?
Over 20 million people have taken CELEBREX. In fact, CELEBREX has been widely studied, and is one of the most prescribed treatments of arthritis. After reviewing the results of extensive clinical trials with many patients suffering from a variety of painful conditions, the FDA has approved CELEBREX for relief from the signs and symptoms of osteoarthritis and adult rheumatoid arthritis, acute pain, and primary dysmenorrhea.

What are the most common side effects of CELEBREX?
In clinical studies, the most common side effects were indigestion, diarrhea, and abdominal pain. In rare cases, serious stomach problems, such as bleeding, can occur without warning. The percentage of patients who stopped taking CELEBREX due to all side effects was similar to that seen with placebo (sugar pill).

Can I take other medications if I take CELEBREX?
When taken together, some medications can interact to increase or decrease their effects. Be sure to tell your doctor or pharmacist about all the medications you take, including over-the-counter drugs, vitamins, supplements, and herbal products.

If you take low-dose aspirin to help reduce the risk of heart attack or stroke, you can still take CELEBREX. However, taking CELEBREX and aspirin together may increase your risk for developing stomach ulcers compared with taking CELEBREX alone. CELEBREX is not a substitute for aspirin in preventing heart attack or stroke.

What should I expect from CELEBREX?
People respond differently to different pain medicines. While CELEBREX can provide pain relief, it may not eliminate all of your pain. Let your doctor know how and when you take CELEBREX, and be sure to ask about options to find the most effective way for you to take CELEBREX.

What if I forget to take a dose?
If you forget to take your medication, don't double up. You can resume taking it at your regularly scheduled time. If you have questions, be sure to call your doctor.

How is arthritis diagnosed?
Your doctor determines that you have osteoarthritis from a medical history, including symptoms you report, a physical exam, and x-rays, which can confirm the diagnosis. Your doctor detects adult rheumatoid arthritis by listening to your medical history, including the symptoms you describe, doing a physical exam, and ordering x-rays and lab tests.

Will I need surgery for my arthritis?
You may never need surgery for arthritis but, for some people, an operation can help relieve pain and disability. The decision to have surgery should be made only after careful consideration with your doctor. Surgery may be recommended to replace damaged joints, reposition and smooth out bones, remove loose pieces of bone or cartilage, or remove inflamed tissue lining a joint.

Does arthritis run in families?
Rheumatoid arthritis and osteoarthritis can run in families, as research is continuing to show. Tell your doctor if there is a history of arthritis in your family.

What is pain?
Pain is one way your body has of alerting you that something may need medical attention. Sometimes, if the message is ignored, other problems or complications might develop. It's important to see your doctor to find out the cause of the pain and get relief. Ask your doctor if CELEBREX is right for you.

Will my acute pain return?
Acute pain can be managed with proper diagnosis and treatments. If the acute pain is due to an injury, the pain should get better as that injury heals.

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Brand Name(s): Celebrex
Generic Name Celecoxib
Phonetic: (sell a kox' ib)

Who is this for?
Celecoxib is used to relieve the pain, tenderness, inflammation (swelling), and stiffness caused by arthritis. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

How does it work?
Celecoxib is a COX-2 inhibitor that works specifically on an enzyme called COX-2. Scientists discovered two COX enzymes, called COX-1 and COX-2. The COX-1 enzyme plays a role in stomach and kidney damage. The COX-2 enzyme mainly plays a role in inflammation and pain. While traditional non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen inhibit the COX-2 enzyme and help to relieve pain and inflammation, they also inhibit the COX-1 enzyme and thus can cause gastrointestinal side effects like ulcers. COX-2 inhibitors like celecoxib, have specific action on the COX-2 enzyme to decrease pain and inflammation, but have less action on the COX-1 enzyme and thus are associated with a lower occurrence of gastrointestinal side effects.

When should I be careful taking it?
Before taking celecoxib,

tell your doctor and pharmacist if you are allergic to celecoxib, aspirin or other nonsteroidal anti-inflammatory drugs, sulfas, or any other drugs.

tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially acetaminophen (Tylenol), amiodarone (Cordarone), anticoagulants ("blood thinners") such as warfarin (Coumadin), aspirin, chloramphenicol, cimetidine (Tagamet, Tagamet HB), diuretics ("water pills"), fluconazole (Diflucan), fluvoxamine (Luvox), lithium (Eskalith, Lithobid), medications for high blood pressure, omeprazole (Prilosec), zafirlukast (Accolate), other medications for arthritis, and vitamins. Do not take aspirin or acetaminophen when using celecoxib unless directed to do so by your doctor.

tell your doctor if you have or have ever had liver, heart, or kidney disease; high blood pressure; asthma; any stomach problems including ulcers or bleeding; or any other gastrointestinal disease.

tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking celecoxib, call your doctor.

if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking celecoxib.
What side effects should I watch for?
Stomach upset or tiredness may occur. If these effects persist or worsen, notify your doctor promptly. Unlikely but report promptly black or bloody stools, stomach pain, severe headache or a change in the amount of urine. Very unlikely but report promptly dark urine or yellowing eyes or skin. In the unlikely event you have an allergic reaction to this drug, seek immediate medical attention. Symptoms of an allergic reaction include rash, itching, swelling, dizziness or trouble breathing. If you notice other effects not listed above, contact your doctor or pharmacist.

How should I take it?
Celecoxib comes as a capsule to take by mouth. It is usually taken one or two times a day as needed for pain. Follow the directions on the prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take celecoxib exactly as directed. Do not take more or less of it or take it more often that prescribed by you doctor.

Dietary Considerations
Celecoxib may be taken with or without food. If celecoxib causes an upset stomach, take it with food.

What happens if I miss a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Where should I keep it?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

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Patient Monograph for CELEBREX®

(Celecoxib Capsules 100 mg and 200 mg)

THERAPEUTIC CLASSIFICATION

Anti-inflammatory Analgesic Agent

ACTION AND CLINICAL PHARMACOLOGY

CELEBREX (celecoxib) is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and anti-pyretic activities in animals. The mechanism of action of CELEBREX 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 AND ADMINISTRATION) 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 (Cmax) and area under the curve (AUC) are roughly dose proportional across the clinical dose range of 100-200 mg studied. Under fasting conditions, at higher doses, there is a less than proportional increase in Cmax 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.

Table 1: Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects1
Mean (%CV) Pharmacokinetic (PK) Parameter Values
(95% Confidence Interval)
Cmax, ng/mL Tmax, hr Effective t1/2, hr Vss/F, L CL/F, L/hr
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)
1Subjects under fasting conditions (n=36, 19-52 yrs.)

Food Effects: When CELEBREX (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 CELEBREX 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. CELEBREX capsules can be administered without regard to the timing of meals.

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 (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 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 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, CELEBREX 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 CELEBREX 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 35-60 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: The clinical effectiveness of CELEBREX (celecoxib) in the treatment of the signs and the symptoms of osteoarthritis (OA) of the knee and hip was demonstrated in placebo- and active-controlled clinical trials of up to 12 weeks duration, involving approximately 4,200 patients. CELEBREX 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 CELEBREX. Doses of 200 mg BID provided no additional efficacy above that seen with 100 mg BID. In the repeated dose OA studies with 100 mg BID of CELEBREX, 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 BID, diclofenac 75 mg BID, and ibuprofen 800 mg TID.

A total daily dose of 200 mg has been shown to be equally effective when administered as 100 mg BID or 200 mg QD. Response to CELEBREX was independent of age, gender, severity, or duration of OA. CELEBREX 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 2,500 patients.

In patients with OA, treatment with CELEBREX 100 mg BID or 200 mg QD 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: The clinical effectiveness of CELEBREX in the treatment of the signs and the symptoms of rheumatoid arthritis (RA) was demonstrated in placebo- and active-controlled clinical trials of up to 24 weeks in duration, involving approximately 2,100 patients. CELEBREX 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. CELEBREX doses of 100 mg BID and 200 mg BID were similar in efficacy and both were comparable to naproxen 500 mg BID. Although CELEBREX 100 mg BID and 200 mg BID provided similar efficacy overall, some patients derive additional benefit from the 200 mg BID dose. Doses of 400 mg BID provided no additional efficacy above that seen with 100-200 mg BID.

Additional studies demonstrated that CELEBREX 200 mg BID was comparable to diclofenac 75 mg BID and ibuprofen 800 mg TID. Response to CELEBREX was independent of age, gender, severity, or duration of RA. In an open label study of up to 12 months in approximately 1,900 RA patients, CELEBREX has shown continued efficacy.

In patients with RA, treatment with CELEBREX 200 mg BID 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 CELEBREX 100 mg BID, CELEBREX 200 mg BID 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 CELEBREX 400 mg BID (4-fold and 2-fold greater than the daily recommended 200 mg OA and 400 mg RA doses, respectively), ibuprofen 800 mg TID or diclofenac 75 mg BID (common therapeutic doses for OA and RA) for a median exposure of 9 months for CELEBREX and diclofenac, and 6 months for ibuprofen. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal 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 CELEBREX 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 four times that of patients not taking ASA (see Drug Interactions - Use With ASA or other NSAIDs).

CELEBREX at the doses studied had a significantly lower incidence of GI intolerability compared to diclofenac, but not ibuprofen (see ADVERSE REACTIONS).

Table 2
Complicated and Symptomatic Ulcers in OA and RA Patients
(Incidence rates at 12 months [%], events/patients)
Higher-than-therapeutic
Dose (4X OA; 2X RA) Common Therapeutic Dose
CELEBREX
400 mg BID Ibuprofen
800 mg TID Diclofenac
75 mg BID

All Patients (Exposure)
2320 Pt-years
1112 Pt-years
1081 Pt-years
Complicated ulcers 0.43 0.55 0.50
(17/3987) (11/1985) (10/1996)
Complicated and symptomatic ulcers 1.05* 1.76 1.30
(42/3987) (35/1985) (26/1996)

Patients without ASA (Exposure) 1803 Pt-years 874 Pt-years 841 Pt-years
Complicated ulcers 0.26† 0.64 0.26
(8/3105) (10/1573) (4/1551)
Complicated and symptomatic ulcers 0.68‡ 1.72 0.64
(21/3105) (27/1573) (10/1551)

Patients with ASA (Exposure) 517 Pt-years 248 Pt-years 240 Pt-years
Complicated ulcers 1.02 0.24 1.35
(9/882) (1/412) (6/445)
Complicated and symptomatic ulcers 2.38 1.94 3.60
(21/882) (8/412) (16/445)
*p=0.017 vs. ibuprofen
†p=0.037 vs. ibuprofen
‡p<0.001 vs. ibuprofen

In a prospective long-term outcome study, Celebrex (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 (> 10 points) 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 the doses up to 400mg BID. Similar significant differences were seen in the absence of bleeding ulcers, in patients not on ASA, and in OA and RA patients.

*P<0.05 vs. ibuprofen and diclofenac

Endoscopic studies: Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in five controlled randomized 12-24 week trials using active comparators, two of which also included placebo controls. Twelve-week endoscopic ulcer data are available on approximately 1,400 patients and 24 week endoscopic ulcer data are available on 184 patients on CELEBREX at doses ranging from 50-400 mg BID. NSAID comparators included naproxen 500 mg BID, diclofenac 75 mg BID, and ibuprofen 800 mg TID.
In active-controlled studies, the endoscopic gastroduodenal ulceration rate observed with all doses of CELEBREX was less than what was seen with the NSAID comparator (see Tables 3-5) 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 BID were evaluated, and demonstrated that with supratherapeutic doses (2-4 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 three studies that included naproxen 500 mg BID, and in the study that included ibuprofen 800 mg TID, CELEBREX was associated with a statistically significantly lower incidence of endoscopic ulcers over the study period. Two studies compared CELEBREX with diclofenac 75 mg BID; one study revealed a statistically significantly higher prevalence of endoscopic ulcers in the diclofenac group at the study endpoint (6 months on treatment), and one study revealed no statistically significant difference between cumulative endoscopic ulcer incidence rates in the diclofenac and CELEBREX groups after 1, 2, and 3 months of treatment. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of CELEBREX 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.

Table 3
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 BID 3.4% (8/233) ---
Celebrex 100 mg BID 3.1% (7/227) 4.0% (9/223)
Celebrex 200 mg BID 5.9% (13/221) 2.7% (6/219)
Celebrex 400 mg BID --- 4.1% (8/197)
Naproxen 500 mg BID 16.2% (34/210)* 17.6% (37/210)*
* 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.

Table 4
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 BID 4.0% (10/252)* 2.2% (5/227)* 1.5% (3/196)* 7.5% (20/266)*
Naproxen 500 mg BID 19.0% (47/247) 14.2% (26/182) 9.9% ( 14/141) 34.6% (89/257)

Study 4 (n=1062)
Celebrex 200 mg BID 3.9% (13/337)† 2.4% (7/296)† 1.8%(5/274)† 7.0% (25/356)†
Diclofenac 75 mg BID 5.1% (18/350) 3.3% (10/306) 2.9%(8/278) 9.7% (36/372)
Ibuprofen 800 mg TID 13.0% (42/323) 6.2% (15/241) 9.6% (21/219) 23.3% (78/334)
*p 0.05 Celebrex vs. naproxen based on interval and cumulative analyses
† 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.


Table 5
Incidence of Gastroduodenal Ulcers from a 6-month
Endoscopy Study in RA Patients
6 months
Study 5 (n = 430)
Celecoxib 200 mg BID 4% (8/212)
Diclofenac 75 mg BID 15% (33/218)*
* 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 System).

Use with acetylsalicylic acid (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 REACTIONS). 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 CELEBREX patients was higher in ASA users as opposed to non-ASA users (see Special Studies - Long Term Outcome Study).

Approximately 11% of patients (440/4,000) enrolled in 4 of the 5 endoscopic studies were taking ASA (325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in subjects taking both CELEBREX and ASA than in subjects taking only CELEBREX. 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 four clinical trials involving 118 subjects, celecoxib did not affect platelet function. CELEBREX at single doses up to 800 mg and multiple doses of 600 mg BID for up to seven days duration (i.e., three 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 BID, ibuprofen 800 mg TID, and diclofenac 75 mg BID significantly reduced platelet aggregation and prolonged bleeding time.

INDICATIONS AND CLINICAL USE

CELEBREX (celecoxib) is indicated for acute and chronic use in the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults.

CONTRAINDICATIONS

CELEBREX (celecoxib) is contraindicated in:

patients with known hypersensitivity to celecoxib.

patients who have demonstrated allergic-type reactions to sulfonamides.

patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or other nonsteroidal anti-inflammatory drugs. Severe, rarely fatal, anaphylactic-like reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients (see WARNINGS - Anaphylactoid Reactions, and PRECAUTIONS - Hypersensitivity Reactions).

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

patients with significant liver impairment or active liver disease.

patients with severe renal impairment (creatinine clearance < 0.5 mL/sec: 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).

CELEBREX is not recommended for use with other nonsteroidal anti-inflammatory drugs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

WARNINGS

Gastrointestinal system (GI): CELEBREX (celecoxib) exhibited a low incidence of gastroduodenal ulceration and serious clinically significant GI events within clinical trials. Among 5,285 patients who received CELEBREX 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 5,285 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 CELEBREX (400 mg BID) demonstrated ulcer complications (perforation, obstruction, or bleeding) over 12 months, in the absence of low-dose ASA use the rate was 0.26% (see CLINICAL STUDIES-Special Studies -Long term Outcome Study).

The following general warnings for nonsteroidal anti-inflammatory drugs 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 nonsteroidal anti-inflammatory drugs. 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 nonsteroidal anti-inflammatory drugs, 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 one in five 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 one 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 (See CONTRAINDICATIONS).

For elderly patients of less than 50kg 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 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. 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.

Anaphylactoid reactions: As with nonsteroidal anti-inflammatory drugs in general, anaphylactoid reactions may occur in patients without known prior exposure to CELEBREX. In post-marketing experience, very 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 ASA or other nonsteroidal anti-inflammatory drugs (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 from controlled clinical studies regarding the use of CELEBREX in patients with advanced kidney disease. In post-marketing experience, serious renal failure, including the need for dialysis, and fatalities have been reported in patients with impaired renal function. Therefore, treatment with CELEBREX, 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 nonsteroidal anti-inflammatory drugs 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 pre-disposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Pregnancy: There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. No studies to evaluate the effect of CELEBREX on the closure of the ductus arteriosus in humans have been carried out, therefore use of CELEBREX during the third trimester of pregnancy should be avoided (see TOXICOLOGY, Reproduction and Teratology).

Nursing mothers: 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 CELEBREX treatment in nursing mothers should be weighed against the potential risk to the newborn.

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

PRECAUTIONS

General: CELEBREX (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 system: There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of CELEBREX 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 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 CELEBREX have shown renal effects similar to those observed with comparator nonsteroidal anti-inflammatory drugs (see CONTRAINDICATIONS and WARNINGS-Advanced Renal Disease).

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

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 CELEBREX 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 three 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 CELEBREX, the incidence of borderline elevations of liver tests 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 CELEBREX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CELEBREX should be discontinued. (see CONTRAINDICATIONS)

Fluid and electrolyte balance: Fluid retention and edema have been observed in some patients taking CELEBREX (see ADVERSE REACTIONS). In the CLASS study,the rates of hypertension in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended doses for OA and RA), and common therapeutic doses of ibuprofen (800 mg TID) and diclofenac (75 mg BID) 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 nonsteroidal anti-inflammatory drugs known to inhibit prostaglandin synthesis, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. CELEBREX 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 CELEBREX. In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long-term treatment with CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. CELEBREX 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 - Long Term Outcome Study and Platelets).

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

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

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

Central Nervous System: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of nonsteroidal anti-inflammatory drugs. 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 nonsteroidal anti-inflammatory drugs has been reported in such ASA-sensitive patients, CELEBREX should not be administered to patients with this form of ASA sensitivity and should be used with caution in patients with preexisting 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 tolbutemide). 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 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.
Acetylsalicylic acid (ASA) or other NSAIDs:

Because of its lack of platelet effects, CELEBREX is not a substitute for ASA for cardiovascular prophylaxis. Therefore, in CELEBREX 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 CELEBREX results in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone (see 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 CELEBREX and comparator groups in patients taking ASA. Concomitant low dose ASA use increased the rate of complicated ulcers to four times that of patients not taking ASA. Resulting incidence rate for complicated ulcers in patients taking CELEBREX and ASA was 1.02%.

Anticoagulants: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX 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 2-5 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 post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX 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 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. Although prospective studies of CELEBREX 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 CELEBREX concurrently with diuretics (n=485). No adverse reactions indicative of sodium retention or renal impairment were seen in clinical trials in patients taking CELEBREX concurrently with diuretics.

Anti-hypertensives: 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 CELEBREX 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 CELEBREX 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 CELEBREX 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.

Methotrexate: CELEBREX 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 BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn.

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.

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

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

Other drug interactions: No drug interaction data are available for CELEBREX and the co-administration of the following products: acetaminophen, alcohol, aminoglycosides, bone marrow depressants, butemide, cholestyramine, colchicine, corticosteroids, cyclosporine, digoxin, gold compounds, indapamide, insulin, nephrotoxic agents, nonsteroidal anti-inflammatory agents, oral contraceptives, potassium supplements, probenicid, 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 REACTIONS

Of the CELEBREX (celecoxib) treated patients in controlled 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 3,900 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.

CELEBREX has been extensively studied in elderly patients. Of the total number of patients who received CELEBREX in clinical trials, more than 3,300 patients were 65-74 years of age, while approximately 1,300 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 CELEBREX from 12 controlled studies conducted in patients with osteoarthritis and rheumatoid arthritis that included a placebo and/or a positive control group.

In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX 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 CELEBREX 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 CELEBREX 400mg BID and NSAID comparators (see 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 (ie, 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).

Table 7
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


All Patients Celecoxib
400 mg BID
(n=3987) Diclofenac
75 mg BID
(n=1996) Ibuprofen 800 mg TID
(n=1985)
All withdrawals 22.4 26.5* 23.0
Withdrawals for GI
Symptoms 12.2 16.6* 13.4
Serious adverse events 6.8 5.6 6.0
Myocardial infarction (fatal and non-fatal)
Deep Vein Thrombosis
Cardiac Failure
Unstable Angina
Cerebrovascular disorder

0.5
0.2
0.2
0.2
0.1

0.2
0.3
0.1
0.2
0.3

0.5
0.0
0.5
0.0
0.3

Patients without ASA (n=3105) (n=1551) (n=1573)
All withdrawals 21.2 25.4* 22.5
Withdrawals for GI
Symptoms 11.5 15.4* 13.2
Serious adverse events 5.0 4.2 4.3
Myocardial infarction (fatal and non-fatal)
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
*p<0.05 vs. celecoxib

The following adverse events occurred in 0.1 - 1.9% of patients regardless of causality:

CELEBREX
(100 - 200 mg BID or 200 mg QD)
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 system 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 system 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 CELEBREX. Cases reported only in the post-marketing 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 Cholelithiiasis, 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

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No overdoses of CELEBREX 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 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 AND ADMINISTRATION

Osteoarthritis: The recommended daily dose of CELEBREX (celecoxib) is 200 mg administered as a single dose or as two divided doses, with or without food.

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

PHARMACEUTICAL INFORMATION

Drug Substance

Structural Formula:

CELEBREX (celecoxib) is a diarylsubstituted pyrazole and has the following structural formula:

Common Name: Celecoxib (INN, USAN)

Chemical Formula: C17H14F3N3O2S

Chemical Name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide.

Molecular Weight: 381.38

Description: Celecoxib is a white powder.
Melting Range: The melting range of celecoxib is 160-164 C.

pH/Solubility: Celecoxib is a neutral molecule at physiologic pH. Celecoxib is defined as “practically insoluble” in water according to the USP classification system (with an n-octanol/water partition coefficient of 10,000 at physiologic pH (7.0)).

pKa: Celecoxib is weakly acidic with a pKa of 11.1.

Chirality: Celecoxib does not contain a chiral center; therefore stereoisomer-dependent pharmacology is not relevant.

AVAILABILITY AND STORAGE

CELEBREX (celecoxib) 100 mg capsules are white with printed blue markings of 7767 on the cap and 100 on the body, supplied in bottles of 100 and 500.

CELEBREX 200 mg capsules are white with printed gold markings of 7767 on the cap and 200 on the body, supplied in bottles of 100 and 500.

Stability and Storage Recommendations: Store at room temperature (15-30° C).

Composition: The inactive ingredients in CELEBREX 100 mg and 200 mg capsules include: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, sodium lauryl sulfate. The capsules are made of gelatin and contain titanium dioxide (E171) and edible inks (ferric oxide (E172) for 200 mg capsules and indigotine (E132) for 100 mg capsules).

INFORMATION TO THE PATIENT

Your doctor and pharmacist are your primary sources of information about your health and the medicine you take. Consult with your doctor or pharmacist if you have questions about your health, any medication you take, or the information given here.

CELEBREX (celecoxib) is a nonsteroidal anti-inflammatory drug (NSAID) which reduces the joint swelling, redness and pain of arthritis. Your body produces chemicals called prostaglandins. Some of these prostaglandins help line the stomach with a protective layer. In arthritis, other prostaglandins cause pain and swelling. CELEBREX reduces the type that causes pain and swelling. At prescribed doses, CELEBREX does not affect the type that helps maintain the protective layer of the stomach, and reduces the chances of bleeding.

This medicine does not cure arthritis, but promotes suppression of the inflammation and tissue damaging effects resulting from this inflammation. Celebrex will help you only as long as you continue to take it.

You should take CELEBREX only as directed by your doctor. Do not take more of it, do not take it more often and do not take it for a longer period of time than your doctor ordered. Taking too much of any NSAID may increase the chance of unwanted effects, especially if you are an elderly patient, this. It is unclear at this time, whether this also applies to the use of CELEBREX in elderly patients. Therefore, elderly patients should continue to be cautious.

Be sure to take CELEBREX regularly as prescribed. In some types of arthritis, up to two weeks may pass before you feel the full effects of this medicine. During treatment, your doctor may decide to adjust the dosage according to your response to the medication.

Your doctor may prescribe low dose ASA as a blood thinner for cardiovascular prophylaxis while you are taking CELEBREX. Take only the amount of ASA prescribed by your doctor and do not discontinue it while taking CELEBREX unless directed to do so by your physician. Do not take additional ASA or ASA-containing medications or other drugs used to relieve symptoms of arthritis while taking CELEBREX unless directed to do so by your physician. Since even a low dose ASA may upset or damage your stomach, combination of CELEBREX with ASA has a greater potential for these side effects compared to CELEBREX alone.

CELEBREX is usually taken once or twice a day. CELEBREX may be taken with or without food. If you are prescribed this medication for use over a long period of time, your doctor will check your health during regular visits to assess your progress and to ensure that this medicine is not causing unwanted effects.

BEFORE TAKING THIS MEDICATION TELL YOUR DOCTOR AND PHARMACISTS IF YOU:

- or a family member are allergic to or have had a reaction to CELEBREX, sulfonamide drugs or other anti-inflammatory drugs (such as acetylsalicylic acid (ASA), diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, sulindac, tiaprofenic acid, tolmetin, nabumetone or tenoxicam) manifesting itself by increased sinusitis, hives, the initiating or worsening of asthma or anaphylaxis (sudden collapse);

- or a family member has had asthma, nasal polyps, chronic sinusitis, or chronic urticaria (hives);

- have a history of stomach upset, ulcers, liver or kidney diseases;

- are taking any other medication (either prescription or non-prescription) such as NSAIDs, high blood pressure medication, blood thinners, corticosteroids, fluconazole, or lithium;

- are pregnant or intend to become pregnant while taking this medication;

- are breast feeding or intend to breast feed while taking this medication;

- have blood or urine abnormalities;

- have high blood pressure;

- are on any special diet, such as a low-sodium or low-sugar diet;

- have diabetes;

- have any other medical problem(s) such as alcohol abuse, bleeding problems, etc.

WHILE TAKING THIS MEDICATION:

- tell any other doctor, dentist or pharmacist that you consult or see, that you are taking this medication;

- some NSAIDs may cause drowsiness or fatigue in some people taking them. Be cautious about driving or participating in activities that require alertness if you are drowsy, dizzy or lightheaded after taking this medication;

- check with your doctor if you are not getting any relief of your arthritis or if any problems develop;

- report any untoward reactions to your doctor. This is very important as it will aid in the early detection and prevention of potential complications;

- stomach problems may be more likely to occur if you drink alcoholic beverages. Therefore, do not drink alcoholic beverages while taking this medication;

- check with your doctor immediately if you experience unexpected weakness while taking this medication, or if you vomit any blood or have dark or bloody stools;

- some people may become more sensitive to sunlight than they are normally. Exposure to sunlight or sunlamps, even for brief periods of time, may cause sunburn, blisters on the skin, skin rash, redness, itching or discoloration, or vision changes. If you have a reaction from the sun, check with your doctor;

- check with your doctor immediately if chills, fever, muscle aches or pains, or other flu-like symptoms occur, especially if they occur shortly before, or together with, a skin rash. Very rarely, these effects may be the first signs of a serious reaction to this medication;

- YOUR REGULAR MEDICAL CHECKUPS ARE ESSENTIAL.

SIDE EFFECTS OF THIS MEDICATION:

Along with its beneficial effects, CELEBREX may occasionally cause some undesirable reactions, especially when used for a long time or in large doses.

Elderly, frail or debilitated patients often seem to experience more frequent or more severe side effects. Although these side effects are not common, when they do occur they may require medical attention. No substantial differences in safety and effectiveness of CELEBREX were observed between elderly and younger subjects. However, greater sensitivity of some older patients cannot be ruled out.

CHECK WITH YOUR DOCTOR IMMEDIATELY IF ANY OF THE FOLLOWING ARE NOTED:

- bloody or black tarry stools;
- shortness of breath, wheezing, any trouble in breathing or tightness in the chest;
- skin rash, hives or swelling, itching;
- vomiting or persistent indigestion, nausea, stomach pain or diarrhea;
- yellow discoloration of the skin or eyes;
- any change in the amount of or colour of your urine (dark red or brown);
- any pain or difficulty experienced while urinating;
- swelling of the feet or lower legs;
- malaise, fatigue, loss of appetite;
- blurred vision or any visual disturbance;
- mental confusion, depression, dizziness, lightheadedness;
- hearing problems.

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

DOSING:

Usual adult dose:

Rheumatoid arthritis: Initially 100 mg twice per day. Dose may be increased depending on patient's response to 200 mg twice per day. Take with or without food.

Osteoarthritis: 200 mg once daily or 100 mg twice daily. Take with or without food.

WHAT TO DO IF YOU MISS A DOSE

Take the dose as soon as you remember then take the next dose at the scheduled time.
STORAGE:

Store at room temperature, between 15-30oC.

CELEBREX IS NOT RECOMMENDED FOR PATIENTS UNDER 18 YEARS OF AGE SINCE SAFETY AND EFFECTIVENESS HAVE NOT BEEN ESTABLISHED.
DO NOT TAKE CELEBREX DURING PREGNANCY UNLESS SPECIFICALLY PRESCRIBED BY A PHYSICIAN.

DO NOT KEEP OUTDATED MEDICINE OR MEDICINE NO LONGER NEEDED.

KEEP OUT OF THE REACH OF CHILDREN.

THIS MEDICINE HAS BEEN PRESCRIBED FOR YOUR MEDICAL PROBLEM. DO NOT GIVE IT TO ANYONE ELSE.

IF YOU REQUIRE MORE INFORMATION ON THIS DRUG, CONSULT YOUR DOCTOR OR PHARMACIST.

Non-medicinal ingredients present in celecoxib capsules include croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. The capsules are made of gelatin and contain titanium dioxide (E171) and edible inks (ferric oxide (E172) for 200 mg capsules and indigotine (E132) for 100 mg capsules).

PHARMACOLOGY

ANIMAL PHARMACOLOGY

Celecoxib was evaluated in a series of preclinical pharmacology studies: 1) to examine its inhibitory kinetics and mechanism of action; 2) to determine its anti-inflammatory, analgesic and antipyretic actions in vivo; 3) to specifically evaluate its propensity to cause GI tract injury and to explore its potential for action on a variety of physiological systems that are targets of NSAIDs. A major goal of these studies was to understand the pharmacological action of celecoxib in relation to its ability to produce differential inhibition of COX isoforms in vivo, ex vivo and in vitro. Selective inhibition of COX-2 vs COX-1 by celecoxib was shown in a number of systems in vivo and in vitro, providing a mechanistic basis for the novel pharmacological profile of this agent. Based on these studies, celecoxib is expected to be an effective anti-inflammatory, analgesic, anti-pyretic and anti-proliferative agent in humans with a diminished potential for adverse GI, platelet and renal effects.

The analgesic actions of celecoxib were demonstrated using the rat carrageenan footpad hyperalgesia model with a thermal stimulus. Celecoxib also showed analgesic activity in the irritant dorsoflexion mouse model using two different irritants but it did not affect the CNS component of the dorsoflexion pain response. Naloxone did not reverse the analgesic actions of celecoxib, indicting an analgesic mechanism not involving the opioid receptor. The absence of an opiate receptor-mediated mechanism was suggested by the lack of activity in the mouse tail pinch model, which normally responds only to opiates such as morphine and local anaesthetics. Celecoxib was shown to achieve concentrations in brain tissue greater than 2-fold higher than those found in the plasma at the time points used for analgesic testing, demonstrating penetration of this agent into the CNS. When given intrathecally (to the lumbar spinal cord) to rats prior to injection of carrageenan into the foot pad, celecoxib prevented elevations of CSF levels of PGE2, decreased the inflammatory foot edema and elicited analgesia to a thermal stimulus, indicating that a portion of the analgesic efficacy of celecoxib could be at the level of the spinal cord.

HUMAN PHARMACOLOGY

Upper gastrointestinal mucosal effect: - See ACTION AND CLINICAL PHARMACOLOGY - Special Studies

Platelet function: Four studies were conducted to investigate the effects of celecoxib on platelet function. A principal feature of these studies is that celecoxib was evaluated at doses exceeding the recommended therapeutic clinical dose range for anti-inflammatory and analgesic efficacy.

Absence of platelet effect was demonstrated by evaluation of platelet aggregation, bleeding time and measurement of blood or serum thromboxane levels. The studies showed consistently that celecoxib, after single or multiple doses up to three-fold higher than the highest recommended dose, did not consistently or significantly reduce platelet aggregation in response to collagen or arachidonate. In contrast, the NSAIDs naproxen, ibuprofen, diclofenac and ASA all significantly reduced platelet aggregation.

Bleeding time was also evaluated in these studies and the results confirmed the findings of platelet aggregation assays. Celecoxib did not significantly increase bleeding time, whereas NSAIDs studied increased bleeding time compared to placebo.
Serum TxB2 levels were reduced by the above comparator NSAIDs, but not consistently by celecoxib. When reductions in serum TxB2 levels were seen with celecoxib, they were not of sufficient magnitude to affect platelet function. Linear regression analysis of celecoxib plasma concentrations did not demonstrate a pattern of correlation between plasma concentrations and platelet function in these studies.

Renal function: Specific studies assessed the effects of celecoxib on renal function in groups of individuals deemed most at risk of adverse renal hemodynamic effects associated with NSAID treatment. Renal effects of celecoxib were assessed in healthy elderly subjects, in subjects with chronic stable renal insufficiency, and in patients undergoing sodium and volume restriction. Celecoxib was not associated with deleterious changes in glomerular filtration rate (GFR) in subgroups that are considered to be susceptible to the adverse renal hemodynamic effects of NSAIDs. Celecoxib 200 mg BID and 400 mg BID did not have a measurable effect on GFR in healthy elderly subjects, in patients with moderate renal insufficiency, or in mildly sodium-depleted patients. Celecoxib was associated with transient reductions in urinary sodium excretion. However, the effect was not reproducibly observed, the magnitude of the observed changes was small, and dietary sodium intake was often not strictly controlled.

Celecoxib was associated with a reduction in urinary 6-keto-PGF1 excretion and decreased urinary PGE2 excretion but did not affect serum TxB2 levels and urinary 11-dehydroTxB2 excretion in contrast to naproxen. These results are consistent with a lack of COX-1 inhibitory activity with celecoxib in contrast to the mixed, non-specific COX inhibitory activity of naproxen.
Analgesic Activity: See CLINICAL STUDIES - Osteoarthritis and Rheumatoid arthritis
TOXICOLOGY

All of the findings seen in animals treated with celecoxib are consistent with the known pharmacological action of the compound (i.e., inhibition of PG synthesis) and/or occurred at exposures and maximal plasma concentrations of the active moiety (i.e., celecoxib) that are greater than projected for therapeutic effect. Celecoxib is not mutagenic and is not carcinogenic in rodents. GI injury is seen with celecoxib only at exposures that are greater than needed for therapeutic use. Significant departures from the comparator NSAIDs are seen with celecoxib in animals, including: 1) greater margins of safety for GI injury in sensitive animal species, 2) absence of injury to the fundic stomach and large intestine when administered by gavage or capsule, 3) no effect on hemostasis, 4) absence of renal papillary necrosis in chronic rodent studies, and 5) absence of dystocia. Based on these findings, celecoxib is considered safe for use in humans.

No evidence of toxicity or adverse pharmacological effect was produced by celecoxib in animals at the expected exposures and maximal plasma concentrations of the clinical doses (200 and 400 mg/day).

No sign of GI injury was seen in 6-month chronic studies with rats at exposures that are 3 to 6-fold greater than the expected exposures with the clinical doses, or at maximal plasma concentrations that are also 3 to 6-fold the Cmax of the clinical doses. Similarly, no sign of GI injury was seen in dogs after 12 months of dosing at mean exposures and maximal plasma concentrations that are 2 to 5-fold greater than the respective exposures and Cmax produced by the clinical doses.

Higher exposures produced dose-limiting GI injury in rats and dogs. The morphological appearance of the GI injury produced by celecoxib is similar to that seen with NSAIDs and thus, is not a novel form of injury. Exposures in rats in the chronic toxicity study that are 6 to 12-fold greater than the exposures at the range of clinical doses produced GI injury and death. The injury was seen more frequently in females due to higher exposures associated with the dimorphism seen in rats. Exposures approximately 4 to 9-fold greater than the exposures at the clinical dose range produced GI injury and death in dogs in a 4-week subchronic study. The mucosal injury is reversible in dogs with cessation of dosing with celecoxib. GI injury is an expected consequence of COX-1 inhibition, however the requirement for high exposures of celecoxib to produce injury is consistent with the pharmacological concept of COX-2 specific inhibition within the therapeutic dosage range.
No adverse pharmacological effect of celecoxib on central nervous system or pulmonary function were seen at plasma levels of celecoxib that are 2 to 5-fold and 3 to 6-fold, respectively, greater than the maximal plasma concentrations at the clinical dose range. No effect on template bleeding time was seen in dogs at exposures sufficient to produce GI injury and death. A few cardiovascular changes were observed in anesthetized animals given celecoxib intravenously, and included small sporadic increases in left ventricular end-diastolic pressure in dogs at plasma concentrations 3 to 7-fold greater than the Cmax produced by the clinical doses, and increases in mean arterial, systolic and diastolic blood pressures in guinea pigs at plasma concentrations that are 3 to 6-fold greater than the Cmax produced by the range of clinical doses. These changes are not suggestive of a clinically significant effect and are not expected at clinically relevant exposures in patients.

Decreased urinary sodium concentration (antinatriuresis) was seen in male and female rats at plasma concentrations at least 3-fold higher than the maximal plasma concentration produced by the clinical doses. Antinatriuresis is an expected pharmacological consequence of prostaglandin inhibition in the kidney. In studies of longer duration in rats, antinatriuresis was seen after 6 weeks of dosing at exposures that are 2 to 4-fold greater than the exposures at the range of clinical doses. No evidence of antinatriuresis was seen after 13 or 26 weeks at exposures that are 6- and 9-fold greater, respectively, than the exposure at the maximum daily clinical dose (400 mg/day).

Carcinogenicity: Carcinogenicity evaluations in rats and mice revealed no evidence of carcinogenicity or increases in the incidence of background tumors after at least 104 weeks of dosing. The carcinogenicity assessment of celecoxib was made in rats in which the average exposures throughout the study were as high as 4 to 9-fold greater in males and 5 to 10-fold greater in females than the exposures produced by the range of clinical doses. Evidence that the Maximum Tolerated Dose (MTD) was exceeded was seen in both males and females as GI injury and death. The frequency of this injury was greater in females which were exposed to higher levels of celecoxib due to the dimorphism in rats. Significant reductions in survival were seen in the two highest male dose groups and all treated female groups as a result of the GI injury. A NOEL (No-Observed-Effect Level) for the GI injury was established in males at exposures that are 1 to 2-fold the exposures at the range of clinical doses. A NOEL could not be established in females because exposures in these animals were generally higher than the no-effect exposure in males throughout the study.

The carcinogenicity evaluation in mice was made at average exposures throughout the study which were approximately 1 to 2.5-fold greater in males and 1 to 2-fold greater in females than the exposures at the clinical dose range. Evidence that the MTD was exceeded was seen in all treated groups as injury in all segments of the GI tract resulting in significant decreases in survival in all but the lowest dose groups. The frequency of injury was comparable in males and females because differential dosages were used to compensate for the dimorphism seen in mice. The use of diet admixture to expose the animals to celecoxib may have produced direct topical exposure of the GI tract which explains the appearance of the injury throughout the GI tract and the lower systemic exposures associated with injury in mice.

No other form of toxicity or irreversible injury was seen in rats, mice or dogs treated with celecoxib. Renal papillary necrosis was not seen in rats or mice, and occurred in two dogs with severe GI injury and hemorrhage. The GI injury seen in these dogs produced septicemia, bacterial emboli and volume depletion (due to hemorrhage) which are factors that predispose the renal papilla to injury.
Reproduction and Teratology: Celecoxib does not produce any effect on male or female fertility or male reproductive function in rats at exposures that are estimated to be 3.5 to 7-fold greater in males and 19 to 38-fold greater in females than the exposures associated with the range of clinical doses. No reproducible effect on ovulation was seen, but decreased embryonic viability reflected as pre- and post-implantation loss occurred in females treated with celecoxib at exposures that are 5 to 11-fold greater than the exposures at the clinical dose range. This effect was not seen after a recovery period during which treatment was ceased. Thus, this effect is the likely consequence of disruption of PG-dependent processes critical for implantation and maintenance of pregnancy and is not the result of permanent alteration of female reproductive function. A NOEL for all effects on early reproductive function in rats was established at exposures that are 4 to 8-fold greater than the exposures at the range of clinical doses.

Teratology evaluations conducted in rats and rabbits treated with celecoxib revealed no evidence of teratogenicity at exposures that are ~ 3-fold greater than exposures at the range of clinical doses. Diaphragmatic hernias appeared at high dosages in 3 of 4 teratology studies in rats at exposures that are 6 to 12-fold greater than clinical exposures. This malformation was also seen at a lower incidence in live offspring in the perinatal evaluation. An increase in the frequency of wavy ribs was observed in one rat teratology study but was not reproduced in a second study. Wavy ribs are reversible and are not regarded as an adverse finding of significance for humans. In rabbit teratology studies, a low incidence of ventricular septal defects (VSD) and other related anomalies, including enlarged aorta and pulmonary stenosis, was observed at systemic exposures approximately 5-fold the clinical exposures. The low incidence of VSD in celecoxib studies cannot be clearly distinguished from the background historical control data thus its relationship to treatment with celecoxib is uncertain. The NOELs for teratology evaluations in rats (10 mg/kg/day) and in rabbits (60 mg/kg/day) are associated with exposures that are ~ 3-fold greater than the clinical exposures.

Slight prolongation of gestation was seen in a perinatal evaluation in rats treated with celecoxib but was not dose-dependent and was within historical control data ranges. No evidence of dystocia or increased parturition time was seen in this study. There was no effect of celecoxib on the physical appearance of the pups with the exception of the diaphragmatic hernias previously discussed. There was no evidence of adverse effect on the survival, physical development, behavior and reproductive performance of the F1 generation, or on the development and survival of the F2 generation pups resulting from treatment of the F0 females with celecoxib. The highest plasma levels measured in treated dams are approximately 1 to 2-fold the Cmax of the clinical doses, while the highest plasma levels measured in neonates are approximately 5 to 10-fold greater than maximal plasma concentration of the clinical doses.

Mutagenicity: Celecoxib is not mutagenic in bacteria (Ames assay) or mammalian cells. No evidence of clastogenicity or disruption of the mitotic apparatus was seen in vitro, or rats in vivo at exposures that are 6 to 12-fold greater in males and 16 to 33-fold greater in females than the exposures produced by the clinical doses. These results are consistent with the absence of carcinogenicity in the cancer bioassays conducted with celecoxib.

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