CELECOXIB- celecoxib capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CELECOXIB (UNII: JCX84Q7J1L) (CELECOXIB - UNII:JCX84Q7J1L)
Available from:
REMEDYREPACK INC.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Celecoxib capsules are indicated For the management of the signs and symptoms of OA [ see Clinical Studies ( 14.1) ] For the management of the signs and symptoms of RA [ see Clinical Studies ( 14.2) ] For the management of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies ( 14.3) ] For the management of the signs and symptoms of AS [ see Clinical Studies ( 14.4) ] For the management of acute pain in adults [ see Clinical Studies ( 14.5) ] For the management of primary dysmenorrhea [see Clinical Studies ( 14.5) ] Celecoxib capsules are contraindicated in the following patients: -   Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [see Warnings and Precautions ( 5.7, 5.9) ]. -   History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see Warnings and Pr
Product summary:
Celecoxib Capsules are available in the following strengths and configurations: Storage:   Store at 25°C (77°F) excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
70518-2233-0

REMEDYREPACK INC.

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Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

What is the most important information I should know about medicines called Non-Steroidal Anti-

Inflammatory Drugs (NSAIDs)?

NSAID can cause serious side effects, including:

Increased risk of a heart attack or stroke that can lead to death . This risk may happen early in

treatment and may increase :

with increasing doses of NSAIDs

with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have

an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the

mouth to the stomach), stomach and intestines :

anytime during use

without warming symptoms

that may cause death

o The risk of getting an ulcer or bleeding increases with :

o past history of stomach ulcers, or stomach or intestinal bleeding with use

o of NSAIDs taking medicines called "corticosteroids", "antiplatelet

o drugs", "anticoagulants", "SSRIs" or "SNRIs"

o increasing doses of NSAIDs

o longer use of NSAIDs

o smoking

o drinking alcohol

o older age

o poor health

o advanced liver disease

o bleeding problems

NSAIDs should only be used :

exactly as prescribed

at the lowest dose possible for your treatment

for the shortest time needed

What are NSAIDs?

NSAID are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as

different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDs:

if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.

right before or after heart bypass surgery.

Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:

had liver or kidney problems

have high blood pressure

have asthma

are pregnant or plan to become pregnant Talk to your healthcare provider if you are considering

taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy

are breastfeeding or plan to breast feed

Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter

medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other

and cause serious side effects. Do not start taking any new medicine without talking to your healthcare

provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called Nonsteroidal Anti-

inflammatory Drugs (NSAIDs)?

new or worse high blood pressure

heart failure

liver problems including liver failure

kidney problems including kidney failure

low red blood cells (anemia)

life-threatening skin reactions

life-threatening allergic reactions

Other side effects of NSAIDs include : stomach pain, constipation, diarrhea, gas, heartburn, nausea,

vomiting, and dizziness.

Get emergency help right away if you get any of the following symptoms:

shortness of breath or trouble breathing

slurred speech

chest pain

swelling of the face or throat

weakness in one part or side of your body

Stop taking your NSAID and call your healthcare provider right away if you get any of the following

symptoms:

nausea

vomit blood

more tired or weaker than usual

there is blood in your bowel movement or it is

black and sticky like tar

diarrhea

unusual weight gain

itching

skin rash or blisters with fever

your skin or eyes look yellow

swelling of the arms, legs, hands and feet

indigestion or stomach pain

flu-like symptoms

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or

pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

Other information about NSAIDs

Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding

in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

Some NSAIDs are sold in lower doses without a prescription (over -the counter). Talk to your

healthcare provider before using over -the -counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they

have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your

pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

For more information, call 1-866-604-3268.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Cipla Ltd,

Kurkumbh, India

Manufactured for:

Cipla USA, Inc.

1560 Sawgrass Corporate Parkway,

Suite 130, Sunrise, FL 33323

Revised: 5/2019

Revised: 7/2019

Document Id: 8e78d2d2-d974-5013-e053-2a95a90a5320

34391-3

Set id: 27f17ae7-939b-402e-9498-3b6611104089

Version: 1

Effective Time: 20190724

REMEDYREPACK INC.

CELECOXIB- celecoxib capsule

REMEDYREPACK INC.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use CELECOXIB CAPSULES safely and

effectively. See full prescribing information for CELECOXIB CAPSULES.

CELECOXIB capsules, for oral use

Initial U.S. Approval:1998

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND

GASTROINTESTINAL EVENTS

See full prescribing information for complete boxed warning

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular

thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur

early in the treatment and may increase with duration of use.( 5.1)

Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. ( 4, 5.1)

NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history

of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. ( 5.2)

RECENT MAJOR CHANGES

Warnings and Precautions (5.1, 5.4) 6/2018

Warnings and Precautions (5.2) 5/2019

INDICATIONS AND USAGE

Celecoxib is a non-steroidal anti-inflammatory drug indicated for:

Osteoarthritis (OA) ( 1.1)

Rheumatoid Arthritis (RA) ( 1.2)

Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older ( 1.3)

Ankylosing Spondylitis (AS) ( 1.4)

Acute Pain (AP) ( 1.5)

Primary Dysmenorrhea (PD) ( 1.6)

DOSAGE AND ADMINISTRATION

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2.1)

OA: 200 mg once daily or 100 mg twice daily ( 2.2, 14.1)

RA: 100 mg to 200 mg twice daily ( 2.3, 14.2)

JRA: 50 mg twice daily in patients 10 kg to 25 kg. 100 mg twice daily in patients more than 25 kg ( 2.4, 14.3)

AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg

(single or divided doses) may be of benefit ( 2.5, 14.4)

AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily

as needed ( 2.6, 14.5)

Hepatic Impairment: Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.7,

8.6, 12.3)

Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in

patients who are known or suspected to be CYP2C9 poor metabolizers, ( 2.7, 8.8, 12.3).

DOSAGE FORMS AND STRENGTHS

Celecoxib capsules: 50 mg, 100 mg, 200 mg and 400 mg ( 3)

CONTRAINDICATIONS

Known hypersensitivity to celecoxib, or any components of the drug product or sulfonamides ( 4)

History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4)

In the setting of CABG surgery ( 4)

WARNINGS AND PRECAUTIONS

Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests

persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3)

Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies

when taking NSAIDs. Monitor blood pressure ( 5.4, 7)

Heart Failure and Edema : Avoid use of celecoxib capsules in patients with severe heart failure unless benefits are

expected to outweigh risk of worsening heart failure ( 5.5)

Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or

hypovolemia. Avoid use of celecoxib capsules in patients with advanced renal disease unless benefits are expected to

outweigh risk of worsening renal function ( 5.6)

Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7)

Exacerbation of Asthma Related to Aspirin Sensitivity : Celecoxib capsules is contraindicated in patients with aspirin-

sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8)

Serious Skin Reactions : Discontinue celecoxib capsules at first appearance of skin rash or other signs of

hypersensitivity ( 5.9)

Premature Closure of Fetal Ductus Arteriosus : Avoid use in pregnant women starting at 30 weeks of gestation ( 5.10,

8.1)

Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11, 7)

ADVERSE REACTIONS

Most common adverse reactions in arthritis trials (>2% and >placebo) are: abdominal pain, diarrhea, dyspepsia, flatulence,

peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd, at 1-866-604-3268 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Drugs that Interfere with Hemostasis (e.g., warfarin aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin

norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking celecoxib

capsules with drugs that interfere with hemostasis. Concomitant use of celecoxib capsules and analgesic doses of

aspirin is not generally recommended ( 7)

Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers :

Concomitant use with celecoxib capsules may diminish the antihypertensive effect of these drugs. Monitor blood

pressure ( 7)

ACE Inhibitors and ARBs : Concomitant use with celecoxib capsules in elderly, volume depleted, or those with renal

impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal

function ( 7)

Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure

diuretic efficacy including antihypertensive effects ( 7)

Digoxin : Concomitant use with celecoxib capsules can increase serum concentration and prolong half-life of digoxin.

Monitor serum digoxin levels ( 7)

USE IN SPECIFIC POPULATIONS

Pregnancy : Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal

ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation ( 5.10, 8.1)

Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of celecoxib capsules in women who

have difficulties conceiving ( 8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

1 INDICATIONS AND USAGE

1.1 Osteoarthritis

1.2 Rheumatoid Arthritis

1.3 Juvenile Rheumatoid Arthritis

1.4 Ankylosing Spondylitis

1.5 Acute Pain

1.6 Primary Dysmenorrhea

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Instructions

2.2 Osteoarthritis

2.3 Rheumatoid Arthritis

2.4 Juvenile Rheumatoid Arthritis

2.5 Ankylosing Spondylitis

2.6 Management of Acute Pain and Treatment of Primary Dysmenorrhea

2.7 Special Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Thrombotic Events

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

5.3 Hepatotoxicity

5.4 Hypertension

5.5 Heart Failure and Edema

5.6 Renal Toxicity and Hyperkalemia

5.7 Anaphylactic Reactions

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity

5.9 Serious Skin Reactions

5.10 Premature Closure of Fetal Ductus Arteriosus

5.11 Hematological Toxicity

5.12 Masking of Inflammation and Fever

5.13 Laboratory Monitoring

5.14 Disseminated Intravascular Coagulation (DIC)

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

8.8 Poor Metabolizers of CYP2C9 Substrates

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology

14 CLINICAL STUDIES

14.1 Osteoarthritis

14.2 Rheumatoid Arthritis

14.3 Juvenile Rheumatoid Arthritis(NCT00652925)

14.4 Ankylosing Spondylitis

14.5 Analgesia, including Primary Dysmenorrhea

14.6 Cardiovascular Outcomes Trial

14.7 Special Studies

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL

EVENTS

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious

cardiovascular thrombotic events, including myocardial infarction, and stroke, which

can be fatal. This risk may occur early in the treatment and may increase with duration

of use. [see Warnings and Precautions ( 5.1)]

Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG)

surgery. [ see Contraindications ( 4) and Warnings and Precautions ( 5.1) ]

NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI

bleeding are at greater risk for serious GI events. [ see Warnings and Precautions ( 5.2) ]

1 INDICATIONS AND USAGE

Celecoxib capsules are indicated

1.1 Osteoarthritis

For the management of the signs and symptoms of OA [ see Clinical Studies ( 14.1) ]

1.2 Rheumatoid Arthritis

For the management of the signs and symptoms of RA [ see Clinical Studies ( 14.2) ]

1.3 Juvenile Rheumatoid Arthritis

For the management of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies

( 14.3) ]

1.4 Ankylosing Spondylitis

For the management of the signs and symptoms of AS [ see Clinical Studies ( 14.4) ]

1.5 Acute Pain

For the management of acute pain in adults [ see Clinical Studies ( 14.5) ]

1.6 Primary Dysmenorrhea

For the management of primary dysmenorrhea [see Clinical Studies ( 14.5) ]

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Instructions

Carefully consider the potential benefits and risks of celecoxib capsules and other treatment options

before deciding to use celecoxib capsules. Use the lowest effective dosage for the shortest duration

consistent with individual patient treatment goals [ see Warnings and Precautions ( 5) ].

These doses can be given without regard to timing of meals.

2.2 Osteoarthritis

For OA, the dosage is 200 mg per day administered as a single dose or as 100 mg twice daily.

2.3 Rheumatoid Arthritis

For RA, the dosage is 100 mg to 200 mg twice daily.

2.4 Juvenile Rheumatoid Arthritis

Sections or subsections omitted from the full prescribing information are not listed.

Cardiovascular Thrombotic Events

Gastrointestinal Bleeding, Ulceration, and Perforation

For JRA, the dosage for pediatric patients (age 2 years and older) is based on weight. For patients ≥10

kg to

25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is

100 mg twice daily.

For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added

to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room

temperature applesauce and ingested immediately with water. The sprinkled capsule contents on

applesauce are stable for up to 6 hours under refrigerated conditions (2°C to 8°C/35°F to 45°F).

2.5 Ankylosing Spondylitis

For AS, the dosage of celecoxib capsules is 200 mg daily in single (once per day) or divided (twice

per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no

effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be

given to alternate treatment options.

2.6 Management of Acute Pain and Treatment of Primary Dysmenorrhea

For management of Acute Pain and Treatment of Primary Dysmenorrhea, the dosage is 400 mg initially,

followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended

dose is 200 mg twice daily as needed.

2.7 Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh Class B), reduce the dose by 50%. The use of

celecoxib capsules in patients with severe hepatic impairment is not recommended [see Warnings and

Precautions ( 5.3), Use in Specific Populations ( 8.6), and Clinical Pharmacology ( 12.3)].

Poor Metabolizers of CYP2C9 Substrates

In adult patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or

previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin), initiate

treatment with half of the lowest recommended dose.

In patients with JRA who are known or suspected to be poor CYP2C9 metabolizers, consider using

alternative treatments [see Use in Specific populations ( 8.8) and Clinical Pharmacology ( 12.5)].

3 DOSAGE FORMS AND STRENGTHS

Celecoxib capsules:

50 mg

white to off white colored granules filled in size 2 hard gelatin white capsule, axially printed with 'Cipla' on cap & '423' over '50 mg' on body in red ink.

100 mg

White to off white colored granules filled in size 2 hard gelatin white capsule,axially printed with 'Cipla' on cap & '422' over '100 mg' on body in blue ink.

200 mg

White to off white colored granules filled in size 1 hard gelatin white capsule,axially printed with 'Cipla' on cap & '421' over '200 mg' on body in gold ink.

400 mg

White to off white colored granules filled in size 0el hard gelatin white capsule,axially printed with 'Cipla' on cap & '420' over '400 mg' on body in green ink.

4 CONTRAINDICATIONS

Celecoxib capsules are contraindicated in the following patients:

Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any

components of the drug product [see Warnings and Precautions ( 5.7, 5.9) ].

History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs.

Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see

Warnings and Precautions ( 5.7, 5.8)].

In the setting of CABG surgery [see Warnings and Precautions ( 5.1)].

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

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Thrombotic Events

Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three

years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,

including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear

that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV

thrombotic events over baseline conferred by NSAID use appears to be similar in those with and

without known CV disease or risk factors for CV disease. However, patients with known CV disease or

risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their

increased baseline rate. Some observational studies found that this increased risk of serious CV

thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has

been observed most consistently at higher doses.Clinical trials of several cyclooxygenase-2 (COX-2)

selective and nonselective NSAIDs of up to three years duration have shown an increased risk of

serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which

can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all

NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID

use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess

serious CV thrombotic events, due to their increased baseline rate. Some observational studies found

that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the

composite endpoint of cardiovascular death, MI, or stroke for the celecoxib capsules 400mg twice

daily and celecoxib capsules 200 mg twice daily treatment arms compared to placebo. The increases in

both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence

of myocardial infarction [see Clinical Studies ( 14.7)].

A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated

Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular

thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and

ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and

ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists'

Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal

myocardial infarction, and non-fatal stroke [ See Clinical Studies ( 14.6) ].

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest

effective dose for the shortest duration possible. Physicians and patients should remain alert for the

development of such events, throughout the entire treatment course, even in the absence of previous CV

symptoms. Patients should be informed about the symptoms of serious CV events 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 an NSAID, such

as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (

5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first

10 to14 days following CABG surgery found an increased incidence of myocardial infarction and

stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications ( 4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated

with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-

cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the

first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100

person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat

after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least

the next four years of follow-up.

Avoid the use of celecoxib capsules in patients with a recent MI unless the benefits are expected to

outweigh the risk of recurrent CV thrombotic events. If celecoxib capsules are used in patients with a

recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation,

bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine,

which can be fatal. These serious adverse events can occur at any time, with or without warning

symptoms, in patients treated with celecoxib capsules. Only one in five patients who develop a serious

upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or

perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and

in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not

without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater

than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer

duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin),

anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age;

and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or

debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at

increased risk for GI bleeding.Patients with a prior history of peptic ulcer disease and/or GI bleeding

who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to

patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated

with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids,

antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs);

smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal

GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease

and/or coagulopathy are at increased risk for GI bleeding.

Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial,

and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of

1.40% at nine months, 3.06% when also taking ASA [ ]. Complicated and symptomatic ulcer rates were

0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA.

Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking

ASA [ see Clinical Studies (14.7)].

Strategies to Minimize the GI Risks in NSAID-treated patients:

Use the lowest effective dosage for the shortest possible duration.

Avoid administration of more than one NSAID at a time.

Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of

bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies

other than NSAIDs.

Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and

discontinue celecoxib capsules until a serious GI adverse event is ruled out.

In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients

more closely for evidence of GI bleeding [ see Drug Interactions ( 7) ].

5.3 Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in

approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases

of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been

reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with

NSAIDs including celecoxib.

In controlled clinical trials of celecoxib capsules, the incidence of borderline elevations (greater than

or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was

6% for celecoxib capsules and 5% for placebo, and approximately 0.2% of patients taking celecoxib

capsules and 0.3% of patients taking placebo had notable elevations of ALT and AST.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,

diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs

and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,

eosinophilia, rash), discontinue celecoxib capsules immediately, and perform a clinical evaluation of

the patient.

5.4 Hypertension

NSAIDs, including celecoxib capsules can lead to new onset of hypertension or worsening of

preexisting hypertension, either of which may contribute to the increased incidence of CV events.

Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may

have impaired response to these therapies when taking NSAIDs [ ]. NSAIDs, including celecoxib

capsules can lead to new onset of hypertension or worsening of preexisting hypertension, either of

which may contribute to the increased incidence of CV events. Patients taking angiotensin converting

enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these

therapies when taking NSAIDs [ see Drug Interactions ( 7) ].

See Clinical Studies ( 14.6, 14.7) for additional blood pressure data for celecoxib capsules.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of

therapy.Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the

course of therapy.

5.5 Heart Failure and Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials

demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2

selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI,

hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use

of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical

conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug

Interactions ( 7) ].

In the CLASS study [see Clinical Studies ( 14.7)], the Kaplan-Meier cumulative rates at 9 months of

peripheral edema in patients on celecoxib capsules 400 mg twice daily (4-fold and 2-fold the

recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75

mg twice daily were 4.5%, 6.9% and 4.7%, respectively.

Avoid the use of celecoxib capsules in patients with severe heart failure unless the benefits are

expected to outweigh the risk of worsening heart failure. If celecoxib capsules are used in patients with

severe heart failure, monitor patients for signs of worsening heart failure.

5.6 Renal Toxicity and Hyperkalemia

Renal Toxicity

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, dehydration, hypovolemia , heart failure, liver dysfunction, those taking diuretics, ACE

inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by

recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of celecoxib capsules in

patients with advanced renal disease. The renal effects of celecoxib may hasten the progression of

renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating celecoxib capsules.

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or

hypovolemia during use of celecoxib capsules [ see Drug Interactions ( 7) ] . Avoid the use of

celecoxib capsules in patients with advanced renal disease unless the benefits are expected to outweigh

the risk of worsening renal function. If celecoxib capsules are used in patients with advanced renal

disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of

NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these

effects have been attributed to a hyporeninemic- hypoaldosteronism state.

5.7 Anaphylactic Reactions

Celecoxib has been associated with anaphylactic reactions in patients with and without known

hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide

and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms

and life-threatening or less severe asthmatic episodes in certain susceptible people [see

Contraindications ( 4) and Warnings and Precautions ( 5.8) ].

Seek emergency help if any anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic

rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to

aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been

reported in such aspirin-sensitive patients, celecoxib capsules are contraindicated in patients with this

form of aspirin sensitivity [ see Contraindications ( 4) ]. When celecoxib capsules are used in patients

with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and

symptoms of asthma.

5.9 Serious Skin Reactions

Serious skin reactions have occurred following treatment with celecoxib capsules, including erythema

multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN),

drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous

pustulosis (AGEP). These serious events may occur without warning and can be fatal.

Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of

celecoxib capsules at the first appearance of skin rash or any other sign of hypersensitivity. Celecoxib

capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [ see

Contraindications ( 4) ].

5.10 Premature Closure of Fetal Ductus Arteriosus

Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including

celecoxib capsules, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in

Specific Populations ( 8.1) ].

5.11 Hematological Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid

retention, or an incompletely described effect on erythropoiesis. If a patient treated with celecoxib

capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

In controlled clinical trials the incidence of anemia was 0.6% with celecoxib capsules and 0.4% with

placebo. Patients on long-term treatment with celecoxib capsules should have their hemoglobin or

hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs, including celecoxib capsules, may increase the risk of bleeding events. Co-morbid conditions

such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs

(e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk.

Monitor these patients for signs of bleeding [ see Drug Interactions ( 7) ].

5.12 Masking of Inflammation and Fever

The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish

the utility of diagnostic signs in detecting infections.

5.13 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or

signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile

periodically [ see Warnings and Precautions ( 5.2, 5.3, 5.6) ].

In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib

capsules 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.

5.14 Disseminated Intravascular Coagulation (DIC)

Because of the risk of disseminated intravascular coagulation with use of celecoxib capsules in

pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting

or bleeding, and inform patients and their caregivers to report symptoms as soon as possible.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labelling:

Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1) ]

GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2) ]

Hepatotoxicity [ see Warnings and Precautions ( 5.3) ]

Hypertension [ see Warnings and Precautions ( 5.4) ]

Heart Failure and Edema [ see Warnings and Precautions ( 5.5) ]

Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6) ]

Anaphylactic Reactions [ see Warnings and Precautions ( 5.7) ]

Serious Skin Reactions [ see Warnings and Precautions ( 5.9) ]

Hematologic Toxicity [ see Warnings and Precautions ( 5.11) ]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice. The adverse reaction information from clinical trials

does, however, provide a basis for identifying the adverse events that appear to be related to drug use

and for approximating rates.

Of the celecoxib-treated patients in the pre-marketing 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 received a total daily dose of celecoxib

capsules of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400

treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib capsules 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.

Pre-marketing Controlled Arthritis Trials

Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving

celecoxib capsules 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 1: Adverse Events Occurring in ≥2% of Celecoxib Patients from Pre-marketing

Controlled Arthritis Trials

Celecoxib = Celecoxib capsules 100 mg to 200 mg twice daily or 200 mg once daily;

NAP = Naproxen 500 mg twice daily;

DCF = Diclofenac 75 mg twice daily;

IBU = Ibuprofen 800 mg three times daily.

Celecoxib

(N=4146)

Placebo

(N=1864)

NAP

(N=1366)

DCF (N=387) IBU (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,

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%

Psychatric

Insomnia

2.3%

2.3%

2.9%

1.3%

1.4%

Respiratory

Pharyngitis

2.3%

1.1%

1.7%

1.6%

2.6%

Rhinitis

2.0%

1.3%

2.4%

2.3%

0.6%

Sinusitis

5.0%

4.3%

4.0%

5.4%

5.8%

Upper

Respiratory

Infection

8.1%

6.7%

9.9%

9.8%

9.9%

Skin

Rash

2.2%

2.1%

2.1%

1.3%

1.2%

In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1%

for patients receiving celecoxib capsules and 6.1% for patients receiving placebo. Among the most

common reasons for discontinuation due to adverse events in the celecoxib capsules treatment groups

were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib

patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and

0.6% withdrew due to abdominal pain.

The following adverse reactions occurred in 0.1% to 1.9% of patients treated with celecoxib Capsules

(100 mg to 200 mg twice daily or 200 mg once daily):

Gastrointestinal:

Constipation, diverticulitis, dysphagia, eructation,

esophagitis, gastritis, gastroenteritis, gastroesophageal

reflux, hemorrhoids, hiatal hernia, melena, dry mouth,

stomatitis, tenesmus, vomiting

Cardiovascular:

Aggravated hypertension, angina pectoris, coronary artery

disorder, myocardial infarction Allergy

General:

Hypersensitivity, allergic reaction, chest pain, cyst NOS,

edema generalized, face edema, fatigue, fever, hot flushes,

influenza-like symptoms, pain, peripheral pain

Central, peripheral

nervous system:

Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia,

vertigo

Hearing and vestibular:

Deafness, tinnitus

Heart rate and rhythm:

Palpitation, tachycardia

Liver and biliary:

Hepatic function abnormal, SGOT increased, SGPT increased

Metabolic and nutritional:

blood urea nitrogen (BUN) increased, creatine phosphokinase

(CPK) increased, hypercholesterolemia, hyperglycemia,

hypokalemia, NPN increased, creatinine increased, alkaline

phosphatase increased, weight increased

Musculoskeletal:

Arthralgia, arthrosis, myalgia, 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, photosensitivity reaction, pruritus, rash

erythematous, rash maculopapular, skin disorder, skin dry,

sweating increased, urticaria

Application site disorders:

Cellulitis, dermatitis contact

Urinary:

Albuminuria, cystitis, dysuria, hematuria, micturition

frequency, renal calculus

The following serious adverse events (causality not evaluated) occurred in <0.1% of patients:

Cardiovascular:

Syncope, congestive heart failure, ventricular fibrillation, pulmonary

embolism, cerebrovascular accident, peripheral gangrene,

thrombophlebitis

Gastrointestinal:

Intestinal obstruction, intestinal perforation, gastrointestinal

bleeding, colitis with bleeding, esophageal perforation, pancreatitis

ileus

General:

Sepsis, sudden death

Liver and biliary:

Cholelithiasis,

Hemic and

lymphatic:

Thrombocytopenia

Nervous:

Ataxia, suicide [ see Drug Interactions ( 7.1) ]

Renal:

Acute renal failure

The Celecoxib Long-Term Arthritis Safety Study [ see Special Studies ( 14.7)]

Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was

lower in patients on celecoxib capsules 400 mg twice daily (0.5%) compared to patients on either

diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence

of events with celecoxib capsules was maintained with or without aspirin use [see Clinical

Pharmacology ( 12.2)].

Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to

adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates

for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise

medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and

8%, respectively).

Juvenile Rheumatoid Arthritis Study

In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were

treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily,

82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen

7.5 mg/kg twice daily. The most commonly occurring (≥5%) adverse events in celecoxib treated patients

were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea,

arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for

naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea,

cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6

mg/kg twice daily had no observable deleterious effect on growth and development during the course

of the 12-week double-blind study. There was no substantial difference in the number of clinical

exacerbations of uveitis or systemic features of JRA among treatment groups.

In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were

treated with celecoxib 6 mg/kg twice daily. The incidence of adverse events was similar to that

observed during the double-blind study; no unexpected adverse events of clinical importance emerged.

$ Table 2: Adverse Events Occurring in ≥5% of JRA Patients in Any

Treatment Group, by System Organ Class (% of patients with events)

Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time,

Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive,

Blood glucose increased, Blood pressure increased, Blood uric acid increased,

Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests

NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis

abnormal NOS

All Doses Twice

Daily

System Organ Class

Preferred Term

Celecoxib

3 mg/kg

N=77

Celecoxib

6 mg/kg

N=82

Naproxen

7.5 mg/kg

N=83

Any Event

64

70

72

Eye Disorders

5

5

5

Gastrointestinal

26

24

36

Abdominal pain NOS

Abdominal pain upper

Vomiting NOS

Diarrhea NOS

Nausea

General

13

11

18

Pyrexia

Infections

25

20

27

Nasopharyngitis

Injury and Poisoning

4

6

5

Investigations*

3

11

7

Musculoskeletal

8

10

17

Arthralgia

Nervous System

17

11

21

Headache NOS

Dizziness (excl

vertigo)

Respiratory

8

15

15

Cough

Skin & Subcutaneous

10

7

18

Other Pre-Approval Studies

Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib

capsules in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied.

The types of adverse events reported in the AS studies were similar to those reported in the OA/RA

studies.

Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated

with celecoxib capsules in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain

studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib capsules

were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse

events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The

only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the

post-oral surgery pain studies.

The APC and PreSAP Trials

Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to celecoxib

capsules in the APC and PreSAP trials was 400 mg to 800 mg daily for up to 3 years [see Special

Studies Adenomatous Polyp Prevention Studies ( 14.7)].

Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing

trials (treatment durations up to 12 weeks; see Adverse events from celecoxib capsules pre-marketing

controlled arthritis trials, above). The adverse reactions for which these differences in patients treated

with celecoxib capsules were greater as compared to the arthritis pre-marketing trials were as follows:

Celecoxib Capsules

(400 to 800 mg daily)

Placebo

N=1303

N = 2285

N=1303

Diarrhea

10.5%

7.0%

Gastroesophageal reflux

disease

4.7%

3.1%

Nausea

6.8%

5.3%

Vomiting

3.2%

2.1%

Dyspnea

2.8%

1.6%

Hypertension

12.5%

9.8%

Nephrolithiasis

2.1%

0.8%

The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib

capsules, at an incidence greater than placebo in the long-term polyp prevention studies, and were either

not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in

the long-term, placebo-controlled polyp prevention studies:

Nervous system disorders:

Cerebral infarction

Eye disorders:

Vitreous floaters, conjunctival hemorrhage

Ear and labyrinth:

Labyrinthitis

Cardiac disorders:

Angina unstable, aortic valve incompetence,

coronary artery atherosclerosis, sinus

bradycardia, ventricular hypertrophy

Vascular disorders:

Deep vein thrombosis

Reproductive system and breast

disorders:

Ovarian cyst

Investigations:

Blood potassium increased, blood sodium

increased, blood testosterone decreased

Injury, poisoning and procedural

complications:

Epicondylitis, tendon rupture

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of celecoxib capsules.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Cardiovascular:

Vasculitis, deep venous thrombosis

General:

Anaphylactoid reaction, angioedema

Liver and biliary:

Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic

Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic:

Hypoglycemia, hyponatremia

Nervous:

Aseptic meningitis, ageusia, anosmia, fatal intracranial

hemorrhage

Renal

Interstitial nephritis

7 DRUG INTERACTIONS

See Table 3 for clinically drug interactions with celecoxib.

Table 3: Clinically Significant drug interactions with Celecoxib

Drugs That Interfere with Hemostasis

Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect

on bleeding. The concomitant use of Celecoxib and anticoagulants have an

increased risk of serious bleeding compared to the use of either drug

alone.

Serotonin release by platelets plays an important role in hemostasis.

Case-control and cohort epidemiological studies showed that concomitant

use of drugs that interfere with serotonin reuptake and an NSAID may

potentiate the risk of bleeding more than an NSAID alone.

Intervention:

Monitor patients with concomitant use of celecoxib capsules with

anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs,

and SNRIs for signs of bleeding [ see Warnings and Precautions ( 5.11) ] .

Aspirin

Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs

and analgesic doses of aspirin does not produce any greater therapeutic

effect than the use of NSAIDs alone. In a clinical study, the concomitant

use of an NSAID and aspirin was associated with a significantly increased

incidence of GI adverse reactions as compared to use of the NSAID alone

[ see Warnings and Precautions ( 5.2) ].

In two studies in healthy volunteers, and in patients with osteoarthritis and

established heart disease respectively, celecoxib (200 mg to 400 mg

daily) has demonstrated a lack of interference with the cardioprotective

antiplatelet effect of aspirin (100 mg to 325 mg).

Intervention:

Concomitant use of celecoxib capsules and analgesic doses of aspirin is

not generally recommended because of the increased risk of bleeding [ see

Warnings and Precautions ( 5.11) ].

Celecoxib capsules are not a substitute for low dose aspirin for

cardiovascular protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers

Clinical Impact: NSAIDs may diminish the antihypertensive effect of ACE inhibitors,

ARBs, or beta-blockers (including propranolol).

In patients who are elderly, volume-depleted (including those on

diuretic therapy), or have renal impairment, co-administration of an NSAID

with ACE inhibitors or ARBs may result in deterioration of renal function,

including possible acute renal failure. These effects are usually

reversible.

Intervention:

During concomitant use of celecoxib capsules and ACE inhibitors,

ARBs, or beta-blockers, monitor blood pressure to ensure that the desired

blood pressure is obtained.

During concomitant use of celecoxib capsules and ACE inhibitors or

ARBs in patients who are elderly, volume-depleted, or have impaired

renal function, monitor for signs of worsening renal function [ see

Warnings and Precautions ( 5.6) ].

When these drugs are administered concomitantly, patients should be

adequately hydrated. Assess renal function at the beginning of the

concomitant treatment and periodically thereafter.

Diuretics

Clinical Impact: Clinical studies, as well as post-marketing observations, showed that

NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide)

and thiazide diuretics in some patients. This effect has been attributed to

the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of celecoxib capsules with diuretics, observe

patients for signs of worsening renal function, in addition to assuring

diuretic efficacy including antihypertensive effects [ see Warnings and

Precautions ( 5.6) ].

Digoxin

Clinical Impact: The concomitant use of Celecoxib with digoxin has been reported to

increase the serum concentration and prolong the half-life of digoxin.

Intervention:

During concomitant use of celecoxib capsules and digoxin, monitor serum

digoxin levels.

Lithium

Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions

in renal lithium clearance. The mean minimum lithium concentration

increased 15%, and the renal clearance decreased by approximately 20%.

This effect has been attributed to NSAID inhibition of renal prostaglandin

synthesis.

Intervention:

During concomitant use of celecoxib capsules and lithium, monitor

patients for signs of lithium toxicity.

Methotrexate

Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for

methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal

dysfunction).

Celecoxib has no effect on methotrexate pharmacokinetics.

Intervention:

During concomitant use of celecoxib capsules and methotrexate, monitor

patients for methotrexate toxicity.

Cyclosporine

Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase

cyclosporine's nephrotoxicity.

Intervention:

During concomitant use of celecoxib capsules and cyclosporine, monitor

patients for signs of worsening renal function.

NSAIDs and Salicylates

Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g.,

diflunisal, salsalate) increases the risk of GI toxicity, with little or no

increase in efficacy [ see Warnings and Precautions ( 5.2) ] .

Intervention:

The concomitant use of Celecoxib with other NSAIDs or salicylates is

not recommended.

Pemetrexed

Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the

risk of pemetrexed-associated myelosuppression, renal, and GI toxicity

(see the pemetrexed prescribing information).

Intervention:

During concomitant use of celecoxib capsules and pemetrexed, in patients

with renal impairment whose creatinine clearance ranges from 45 to 79

mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin)

should be avoided for a period of two days before, the day of, and two

days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed

and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients

taking these NSAIDs should interrupt dosing for at least five days before,

the day of, and two days following pemetrexed administration.

CYP2C9 Inhibitors or inducers

Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450

(CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are

known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure

and toxicity of celecoxib whereas co-administration with CYP2C9

inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib.

Intervention:

Evaluate each patient's medical history when consideration is given to

prescribing celecoxib. A dosage adjustment may be warranted when

celecoxib is administered with CYP2C9 inhibitors or inducers. [ see

Clinical Pharmacology ( 12.3) ].

CYP2D6 substrates

Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an

inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug

interaction with drugs that are metabolized by CYP2D6 (e.g.,

atomoxetine), and celecoxib may enhance the exposure and toxicity of

these drugs.

Intervention:

Evaluate each patient's medical history when consideration is given to

prescribing celecoxib. A dosage adjustment may be warranted when

celecoxib is administered with CYP2D6 substrates. [ see Clinical

Pharmacology ( 12.3) ].

Corticosteroids

Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase

the risk of GI ulceration or bleeding.

Intervention:

Monitor patients with concomitant use of celecoxib capsules with

corticosteroids for signs of bleeding [ see Warnings and Precautions ( 5.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.

Risk Summary

Use of NSAIDs, including celecoxib capsules, during the third trimester of pregnancy increases the

risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including celecoxib

capsules, in pregnant women starting at 30 weeks of gestation.

There are no adequate and well-controlled studies of celecoxib capsules in pregnant women. Data from

observational studies regarding potential embryofetal risks of NSAID use in women in the first or

second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths

and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the

period of organogenesis at oral doses approximately 6 times the maximum recommended human dose

(MRHD) of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused,

sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of

celecoxib during the period of organogenesis at approximately 2 times the MRHD [see Data]. Based on

animal data, prostaglandins have been shown to have an important role in endometrial vascular

permeability, blastocyst implantation, and decidualization. In animal studies, administration of

prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation

loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a

background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of celecoxib capsules during labor or delivery. In animal studies,

NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase

the incidence of stillbirth.

Data

Human Data

The available data do not establish the presence or absence of developmental toxicity related to the use

of celecoxib capsules.

Animal Data

Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice

daily as measured by AUC

), caused an increased incidence of ventricular septal defects, a rare

event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits

were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was

observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human

exposure based on the AUC

at 200 mg twice daily for RA) throughout organogenesis. In rats,

exposure to celecoxib during early embryonic development resulted in pre-implantation and post-

implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the

at 200 mg twice daily for RA).

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Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats

(approximately 7-fold human exposure as measured by the AUC

at 200 mg twice daily). The effects

of celecoxib capsules on labor and delivery in pregnant women are unknown.

8.2 Lactation

Risk Summary

Limited data from 3 published reports that included a total of 12 breastfeeding women showed low

levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day,

less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed

infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when

celecoxib capsules are administered to a nursing woman. The developmental and health benefits of

breastfeeding should be considered along with the mother's clinical need for celecoxib capsules and

any potential adverse effects on the breastfed infant from the celecoxib capsules or from the underlying

maternal condition.

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib

capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible

infertility in some women. Published animal studies have shown that administration of prostaglandin

synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for

ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in

ovulation. Consider withdrawal of NSAIDs, including celecoxib capsules, in women who have

difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

Celecoxib capsules are 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 celecoxib capsules has not been evaluated

and it is unknown if long-term risks may be similar to that seen in adults exposed to celecoxib capsules

or other COX-2 selective and non-selective NSAIDs [see Boxed Warning, Warnings and Precautions (

5.12), and Clinical Studies ( 14.3)].

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). When NSAIDs including

celecoxib are used in patients with systemic onset JRA, monitor patients for signs and symptoms of

abnormal clotting or bleeding, due to the risk of disseminated intravascular coagulation. Patients with

systemic onset JRA should be monitored for the development of abnormal coagulation tests [see

Dosage and Administration ( 2.4), Warnings and Precautions ( 5.14), Adverse Reactions ( 6.1), Animal

Toxicology ( 13.2), Clinical Studies ( 14.3)].

Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be

CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 substrates ( 8.8)].

8.5 Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious

cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly

patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor

patients for adverse effects [ see Warnings and Precautions ( 5.1, 5.2, 5.3, 5.6, 5.13)].

Of the total number of patients who received celecoxib capsules in pre-approval 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 and Precautions ( 5.2, 5.6) ].

8.6 Hepatic Impairment

The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment

(Child-Pugh Class B) should be reduced by 50%. The use of celecoxib capsules in patients with severe

hepatic impairment is not recommended [see Dosage and Administration ( 2.7) and Clinical

Pharmacology ( 12.3)].

8.7 Renal Impairment

Celecoxib capsules is not recommended in patients with severe renal insufficiency [ see Warnings and

Precautions ( 5.6) and Clinical Pharmacology ( 12.3)].

8.8 Poor Metabolizers of CYP2C9 Substrates

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In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on

genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin)

administer celecoxib capsules starting with half the lowest recommended dose. Alternative management

should be considered in JRA patients identified to be CYP2C9 poor metabolizers [ see Dosage and

Administration (2.7) and Clinical Pharmacology (12.5)].

10 OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness,

nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care.

Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and

coma have occurred, but were rare [ see Warnings and Precautions ( 5.1, 5.2, 5.4, 5.6) ].

No overdoses of celecoxib capsules 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. 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.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no

specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams

per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within

four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage).

Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high

protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-

1222).

11 DESCRIPTION

Celecoxib is a nonsteroidal anti-inflammatory drug, available as capsules containing 50 mg, 100 mg,

200 mg and 400 mg celecoxib for oral administration. The chemical name is 4-[5-(4-methylphenyl)- 3-

(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The

molecular weight is 381.38. Its molecular formula is C

S, and it has the following

chemical structure:

Celecoxib is a white to off-white powder with a pKa of 11.1 (sulfonamide moiety). Celecoxib is

hydrophobic (log P is 3.5) and is practically insoluble in aqueous media at physiological pH range.

The inactive ingredients in celecoxib capsules include: croscarmellose sodium, edible inks, gelatin,

lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

CELECOXIB has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis,

primarily via inhibition of COX-2.

Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations reached

during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the

action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation.

Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease

of prostaglandins in peripheral tissues.

12.2 Pharmacodynamics

Platelets

In clinical trials using normal volunteers, celecoxib capsules 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, celecoxib capsules are not a substitute for aspirin for cardiovascular prophylaxis. It is

not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of

serious cardiovascular thrombotic adverse events associated with the use of celecoxib capsules.

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.

12.3 Pharmacokinetics

Celecoxib exhibits dose-proportional increase in exposure after oral administration up to 200 mg twice

daily and less than proportional increase at higher doses. It has extensive distribution and high protein

binding. It is primarily metabolized by CYP2C9 with a half-life of approximately 11 hours.

Absorption

Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Under fasting

conditions, both peak plasma levels (C

) and area under the curve (AUC) are roughly dose-

proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in C

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 4.

$ Table 4: Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in

Healthy Subjects

Subjects under fasting conditions (n=36, 19-52 yrs.)

Mean (%CV) PK Parameter Values

Cmax, ng/mL

Tmax, hr

Effective t1/2, hr

Vss/F, L

CL/F, L/hr

705 (38)

2.8 (37)

11.2 (31)

429 (34)

27.7 (28)

Food Effects

When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1

to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses

above 200 mg, there is less than a proportional increase in C

and AUC, which is thought to be due

to the low solubility of the drug in aqueous media.

Coadministration of celecoxib capsules with an aluminum- and magnesium-containing antacids resulted

in a reduction in plasma celecoxib concentrations with a decrease of 37% in C

and 10% in AUC.

Celecoxib capsules, at doses up to 200 mg twice daily, can be administered without regard to timing of

meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.

In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when

celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were

no significant alterations in C

or t

after administration of capsule contents on applesauce

[see Dosage and Administration ( 2)].

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, a

-acid glycoprotein.

The apparent volume of distribution at steady state (V

/F) is approximately 400 L, suggesting

extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.

Elimination

Metabolism

Celecoxib metabolism is primarily mediated via CYP2C9. 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.

Excretion

Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug

recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately

57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite

in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the

glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the

absorption process making terminal half-life (t

) 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.

Specific Population

Geriatric

At steady state, elderly subjects (over 65 years old) had a 40% higher C

and a 50% higher AUC

compared to the young subjects. In elderly females, celecoxib C

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 [see Dosage and Administration ( 2.7) and Use

in Specific Populations ( 8.5)].

Pediatric

The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was

evaluated in 152 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%

1

1

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 ( 2.4)]. 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 Impairment

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

celecoxib 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 celecoxib capsules in patients with severe hepatic impairment is not

recommended [see Dosage and Administration ( 2.6) and Use in Specific Populations ( 8.6)].

Renal Impairment

In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic

renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No

significant relationship was found between GFR and celecoxib clearance. Patients with severe renal

insufficiency have not been studied. Similar to other NSAIDs, celecoxib capsules are not recommended

in patients with severe renal insufficiency [see Warnings and Precautions ( 5.6)].

Drug Interaction Studies

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

In vivo studies have shown the following:

Aspirin

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although

the clearance of free NSAID was not altered. The clinical significance of this interaction is not known.

See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions (

7) ] .

Lithium

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased

approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib capsules 200 mg

twice daily as compared to subjects receiving lithium alone [see Drug Interactions ( 7)].

Fluconazole

Concomitant administration of fluconazole at 200 mg once daily 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 Drug Interactions ( 7)].

Other Drugs

The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide,

ketoconazole, [see Drug Interactions ( 7)], phenytoin, and tolbutamide have been studied in vivo and

clinically important interactions have not been found.

12.5 Pharmacogenomics

CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme

activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data

from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3

genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to

subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been

evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated

that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups [ see

Dosage and Administration ( 2.7), Use in Specific Populations ( 8.8)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males

and 10 mg/kg for females (approximately 2-to 4-times the human exposure as measured by the AUC

at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females

(approximately equal to human exposure as measured by the AUC

at 200 mg twice daily) for two

years.

Mutagenesis

Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO)

cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test

in rat bone marrow.

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in rat bone marrow.

Impairment of Fertility

Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses

up to 600 mg/kg/day (approximately 11-times human exposure at 200 mg twice daily based on the AUC

). At ≥50 mg/kg/day (approximately 6-times human exposure based on the AUC

at 200 mg twice

daily) there was increased preimplantation loss.

13.2 Animal Toxicology

An increase in the incidence of background findings of spermatocele with or without secondary

changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous

tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did

not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous

condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in

adult rats treated with celecoxib. The clinical significance of this observation is unknown.

14 CLINICAL STUDIES

14.1 Osteoarthritis

Celecoxib capsules have demonstrated significant reduction in joint pain compared to placebo.

Celecoxib capsules were 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 celecoxib capsules 100 mg twice daily or 200 mg once daily resulted in improvement in

WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain,

stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare,

celecoxib capsules doses of 100 mg twice daily and 200 mg twice daily provided significant reduction

of pain within 24 to 48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice

daily the effectiveness of celecoxib capsules was shown to be similar to that of naproxen 500 mg twice

daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice

daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100

mg twice daily or 200 mg once daily.

14.2 Rheumatoid Arthritis

Celecoxib capsules have demonstrated significant reduction in joint tenderness/pain and joint swelling

compared to placebo. Celecoxib capsules were evaluated for treatment of the signs and symptoms of

RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Celecoxib capsules

were shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite

of clinical, laboratory, and functional measures in RA. Celecoxib capsules doses of 100 mg twice daily

and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg

twice daily.

Although celecoxib capsules 100 mg twice daily and 200 mg twice daily provided similar overall

effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400

mg twice daily provided no additional benefit above that seen with 100 mg to 200 mg twice daily.

14.3 Juvenile Rheumatoid Arthritis(NCT00652925)

In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority

study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or

systemic onset JRA (with currently inactive systemic features), received one of the following

treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum

of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response

rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30)

criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI

30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg twice daily, celecoxib

6 mg/kg twice daily, and naproxen 7.5 mg/kg twice daily treatment groups, respectively.

The efficacy and safety of celecoxib capsules for JRA have not been studied beyond six months. The

long-term cardiovascular toxicity in children exposed to celecoxib capsules have not been evaluated

and it is unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib

capsules or other COX-2 selective and non-selective NSAIDs [see Boxed Warning, Warnings and

Precautions ( 5.12)].

14.4 Ankylosing Spondylitis

Celecoxib capsules were evaluated in AS patients in two placebo- and active-controlled clinical trials

of 6 and 12 weeks duration. Celecoxib capsules at doses of 100 mg twice daily, 200 mg once daily and

400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-

primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease

activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional

Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg

and 400 mg celecoxib capsules doses in a comparison of mean change from baseline, but there was a

greater percentage of patients who responded to celecoxib capsules 400 mg, 53%, than to celecoxib

capsules 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20).

The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute

improvement of at least 10 mm, on a 0 mm to 100 mm scale, in at least three of the four following

domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The

responder analysis also demonstrated no change in the responder rates beyond 6 weeks.

14.5 Analgesia, including Primary Dysmenorrhea

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In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary

dysmenorrhea, celecoxib capsules relieved pain that was rated by patients as moderate to severe. Single

doses [see Dosage and Administration ( 2.6)] of celecoxib capsules provided pain relief within 60

minutes.

14.6 Cardiovascular Outcomes Trial

Cardiovascular Outcomes Trial: Prospective Randomized Evaluation of Celecoxib Integrated

Safety vs. Ibuprofen Or Naproxen(PRECISION; NCT00346216)

Design

The PRECISION trial was a double-blind randomized controlled trial of cardiovascular safety in OA

and RA patients with or at high risk for cardiovascular disease comparing celecoxib with naproxen and

ibuprofen. Patients were randomized to a starting dose of 100 mg twice daily of celecoxib, 600 mg

three times daily of ibuprofen, or 375 mg twice daily of naproxen, with the option of escalating the dose

as needed for pain management. Based on labeled doses, OA patients randomized to celecoxib could not

dose escalate.

The primary endpoint, the Antiplatelet Trialists' Collaboration (APTC) composite, was an independently

adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial

infarction, and non-fatal stroke with 80% power to evaluate non-inferiority. All patients were

prescribed open-label esomeprazole (20-40 mg) for gastroprotection. Treatment randomization was

stratified by baseline low-dose aspirin use.

Additionally, there was a 4-month substudy assessing the effects of the three drugs on blood pressure

as measured by ambulatory monitoring.

Results

Among subjects with OA, only 0.2% (17/7259) escalated celecoxib to the 200 mg twice daily dose,

whereas 54.7% (3946/7208) escalated ibuprofen to 800 mg three times daily, and 54.8% (3937/7178)

escalated naproxen to the 500 mg twice daily dose. Among subjects with RA, 55.7% (453/813)

escalated celecoxib to the 200 mg twice daily dose, 56.5% (470/832) escalated ibuprofen to 800 mg

three times daily, and 54.6% (432/791) escalated naproxen to the 500 mg twice daily dose; however, the

RA population accounted for only 10% of the trial population.

Because relatively few celecoxib patients overall (5.8% [470/8072]) dose-escalated to 200 mg twice

daily, the results of the PRECISION trial are not suitable for determining the relative CV safety of

celecoxib at 200 mg twice daily compared to ibuprofen and naproxen at the doses taken.

Primary Endpoint

The trial had two prespecified analysis populations:

Intent-to-treat population (ITT): Comprised of all randomized subjects followed for a maximum of

30 months

Modified Intent-to-treat population (mITT): Comprised of all randomized subjects who received at

least one dose of study medication and had at least one post-baseline visit followed until the earlier

of treatment discontinuation plus 30 days, or 43 months

Celecoxib, at the 100 mg twice daily dose, as compared with either naproxen or ibuprofen at the doses

taken, met all four prespecified non-inferiority criteria (p<0.001 for non-inferiority in both

comparisons) for the APTC endpoint, a composite of cardiovascular death (including hemorrhagic

death), non-fatal myocardial infarction, and non-fatal stroke [ See Table 5]. Non-inferiority was

prespecified as a hazard ratio (HR) of ≤1.12 in both ITT and mITT analyses, and upper 95% CI of ≤1.33

for ITT analysis and ≤1.40 for mITT analysis. The primary analysis results for ITT and mITT are

described in Table 5.

Table 5. Primary Analysis of the Adjudicated APTC Composite Endpoint

Intent-To-Treat Analysis (ITT, through month 30)

Celecoxib

Ibuprofen

Naproxen

8,072

8,040

7,969

Subjects with Events

188 (2.3%)

218 (2.7%)

201 (2.5%)

Pairwise Comparison

Celecoxib vs.

Naproxen

Celecoxib vs.

Ibuprofen

Ibuprofen vs.

Naproxen

HR (95% CI)

0.93 (0.76, 1.13)

0.86 (0.70, 1.04)

1.08 (0.89, 1.31)

Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43)

Celecoxib

Ibuprofen

Naproxen

8,030

7,990

7,933

Subjects with Events

134 (1.7%)

155 (1.9%)

144 (1.8%)

Pairwise Comparison

Celecoxib vs.

Naproxen

Celecoxib vs.

Ibuprofen

Ibuprofen vs.

Naproxen

HR (95% CI)

0.90 (0.72, 1.14)

0.81 (0.64, 1.02)

1.12 (0.89, 1.40)

Table 6. Summary of the Adjudicated APTC Components*

Intent-To-Treat Analysis (ITT, through month 30)

Celecoxib

Ibuprofen

Naproxen

8,072

8,040

7,969

CV Death

68 (0.8%)

80 (1.0%)

86 (1.1%)

Non-Fatal MI

76 (0.9%)

92 (1.1%)

66 (0.8%)

*A patient may have experienced more than one component; therefore, the sum of the components

is larger than the number of patients who experienced the composite outcome

Non-Fatal Stroke

51 (0.6%)

53 (0.7%)

57 (0.7%)

Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43)

8,030

7,990

7,933

CV Death

35 (0.4%)

51 (0.6%)

49 (0.6%)

Non-fatal MI

58 (0.7%)

76 (1.0%)

53 (0.7%)

Non-fatal Stroke

43 (0.5%)

32 (0.4%)

45 (0.6%)

In the ITT analysis population through 30 months, all-cause mortality was 1.6% in the celecoxib group,

1.8% in the ibuprofen group, and 2.0% in the naproxen group.

Ambulatory Blood Pressure Monitoring (ABPM) Substudy

In the PRECISION-ABPM substudy, among the total of 444 analyzable patients at Month 4, celecoxib

dosed at 100 mg twice daily decreased mean 24-hour systolic blood pressure (SBP) by 0.3 mmHg,

whereas ibuprofen and naproxen at the doses taken increased mean 24-hour SBP by 3.7 and 1.6 mmHg,

respectively. These changes resulted in a statistically significant and clinically meaningful difference

of 3.9 mmHg (p=0.0009) between celecoxib and ibuprofen and a non-statistically significant difference

of 1.8 (p=0.119) mmHg between celecoxib and naproxen.

14.7 Special Studies

Adenomatous Polyp Prevention Studies (NCT00005094 and NCT00141193)

Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year

studies involving patients with Sporadic Adenomatous Polyps treated with celecoxib capsules: the APC

trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous

Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint

(adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to

placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant

increased risk for the same composite endpoint (adjudicated):

In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of

cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 - 8.5) with celecoxib

400 mg twice daily and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily. Cumulative rates

for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects),

respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both

celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of

myocardial infarction.

In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95%

CI 0.6 - 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this

composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects),

respectively.

Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have

shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke,

which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk.

Celecoxib Long-Term Arthritis Safety Study (CLASS)

This was a prospective, long-term, safety outcome study conducted post-marketing in approximately

5,800 OA patients and 2,200 RA patients. Patients received celecoxib capsules 400 mg twice daily (4-

fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily

or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for celecoxib capsules

(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: celecoxib capsules, n = 882;

diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between

celecoxib capsules and the combined group of ibuprofen and diclofenac were not statistically

significant.

Patients on celecoxib capsules 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 and Precautions ( 5.4)].

The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated

with celecoxib capsules 400 mg twice daily are described in Table 7. Table 7 also displays results for

patients less than or greater than 65 years of age. The difference in rates between celecoxib capsules

alone and celecoxib capsules with ASA groups may be due to the higher risk for GI events in ASA

users.

Table 7: Complicated and Symptomatic Ulcer Rates in Patients

Taking Celecoxib Capsules 400 mg Twice Daily (Kaplan-Meier

Rates at 9 months [%]) Based on Risk Factors

All Patients

Celecoxib alone (n=3105)

0.78

Celecoxib with ASA (n=882)

2.19

Patients <65 Years

Celecoxib alone (n=2025)

0.47

Celecoxib with ASA (n=403)

1.26

Patients ≥ 65 Years

Celecoxib alone (n=1080)

1.40

Celecoxib with ASA (n=479)

3.06

In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer

rates in patients taking celecoxib capsules alone or celecoxib capsules 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 and Precautions ( 5.4) and Adverse Reactions ( 6.1)].

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 celecoxib, diclofenac, or

ibuprofen treatment groups. The cumulative rates in all patients at nine months for celecoxib,

diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA

users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for

myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less

than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine

whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a

similar degree. In the CLASS study, the Kaplan-Meier cumulative rates at 9 months of peripheral edema

in patients on celecoxib capsules 400 mg twice daily (4-fold and 2-fold the recommended OA and RA

doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%,

6.9% and 4.7%, respectively. The rates of hypertension from the CLASS trial in the celecoxib

capsules, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively.

Endoscopic Studies

The correlation between findings of short-term endoscopic studies with celecoxib capsules and the

relative incidence of clinically significant serious upper GI events with long-term use has not been

established. Serious clinically significant upper GI bleeding has been observed in patients receiving

celecoxib capsules in controlled and open-labeled trials [see Warnings and Precautions ( 5.4) and

Clinical Studies ( 14.7)].

A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic

examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking

celecoxib capsules 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice

daily. However, celecoxib capsules was not statistically different than diclofenac for clinically relevant

GI outcomes in the CLASS trial [see Clinical Studies ( 14.7)]

The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled 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 celecoxib capsules (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 celecoxib capsules the incidence ranged between

2.7%-5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI

outcomes with celecoxib and naproxen.

In the endoscopic studies, approximately 11% of patients were taking aspirin ( 325 mg/day). In the

celecoxib capsule 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Celecoxib Capsules are available in the following strengths and configurations:

Product Name

Description

Size

NDC number

Celecoxib

Capsules 50 mg

White to off white colored

granules filled in size 2 hard

gelatin white capsule,

axially printed with 'Cipla' on cap

& '423' over '50 mg' on body in red

ink.

Bottle of 30 capsules

Bottle of 60 capsules

69097-423-02

69097-423-03

Celecoxib

Capsules 100

White to off white colored

granules filled in size 2 hard

gelatin white capsule,

axially printed with 'Cipla' on cap

& '422' over '100 mg' on body in

blue ink.

Bottle of 30 capsules

Bottle of 100 capsules

Bottle of 500 capsules

10's Blister

Carton of 100 (10 x 10)

Unit-

dose Capsules

69097-422-02

69097-422-07

69097-422-12

69097-422-19

69097-422-21

Celecoxib

Capsules 200

White to off white colored

granules filled in size 1 hard

gelatin white capsule,

axially printed with 'Cipla' on cap

& '421' over '200 mg' on body in

gold ink.

Bottle of 30 capsules

Bottle of 100 capsules

Bottle of 500 capsules

10's Blister

Carton of 100 (10 x 10)

Unit-

dose Capsules

69097-421-02

69097-421-07

69097-421-12

69097-421-19

69097-421-21

Celecoxib

Capsules 400

White to off white colored

granules filled in size 0el hard

Bottle of 30 capsules

Bottle of 60 capsules

69097-420-02

69097-420-03

gelatin white capsule,

axially printed with 'Cipla' on cap

& '420' over '400 mg' on body in

green ink.

Bottle of 480 capsules

10's Blister

Carton of 100 (10 x 10)

Unit-

dose Capsules

69097-420-11

69097-420-19

69097-420-21

Storage:

Store at 25°C (77°F) excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room

Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each

prescription dispensed. Inform patients, families, or their caregivers of the following information

before initiating therapy with celecoxib capsules and periodically during the course of ongoing

therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain,

shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health

care provider immediately [see Warnings and Precautions ( 5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia,

melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose

aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of

GI bleeding [ see Warnings and Precautions ( 5.2) ].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,

pruritus, diarrhea jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur,

instruct patients to stop celecoxib capsules and seek immediate medical therapy [ see Warnings and

Precautions ( 5.3), Use in Specific Populations ( 8.6) ].

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath,

unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see

Warnings and Precautions ( 5.5) ].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face

or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications ( 4)

and Warnings and Precautions ( 5.7)].

Serious Skin Reactions

Advise patients to stop celecoxib capsules immediately if they develop any type of rash and to contact

their healthcare provider as soon as possible [see Warnings and Precautions ( 5.9)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including celecoxib

capsules, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3) ].

Fetal Toxicity

Inform pregnant women to avoid use of celecoxib capsules and other NSAIDs starting at 30 weeks of

gestation because of the risk of the premature closing of the fetal ductus arteriosus [ see Warnings and

Precautions ( 5.10) and Use in Specific Populations ( 8.1) ].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of celecoxib capsules with other NSAIDs or salicylates (e.g.,

diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little

or no increase in efficacy [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7) ]. Alert patients

that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or

insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with celecoxib capsules until they talk to their

healthcare provider [see Drug Interactions ( 7) ].

Manufactured by:

Cipla Ltd,

Kurkumbh, India

Manufactured for:

Cipla USA, Inc.

1560 Sawgrass Corporate Parkway,

Suite 130, Sunrise, FL 33323

Revised: 5/2019

Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

What is the most important information I should know about medicines called Non-Steroidal

Anti-Inflammatory Drugs (NSAIDs)?

NSAID can cause serious side effects, including:

Increased risk of a heart attack or stroke that can lead to death . This risk may happen early in

treatment and may increase :

with increasing doses of NSAIDs

with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft

(CABG)."

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to.

You may have an increased risk of another heart attack if you take NSAIDs after a recent heart

attack.

Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading

from the mouth to the stomach), stomach and intestines :

anytime during use

without warming symptoms

that may cause death

o The risk of getting an ulcer or bleeding increases with :

o past history of stomach ulcers, or stomach or intestinal bleeding with use

o of NSAIDs taking medicines called "corticosteroids", "antiplatelet

o drugs", "anticoagulants", "SSRIs" or "SNRIs"

o increasing doses of NSAIDs

o longer use of NSAIDs

o smoking

o drinking alcohol

o older age

o poor health

o advanced liver disease

o bleeding problems

NSAIDs should only be used :

exactly as prescribed

at the lowest dose possible for your treatment

for the shortest time needed

What are NSAIDs?

NSAID are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions

such as different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDs:

if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other

NSAIDs.

right before or after heart bypass surgery.

Before taking NSAIDs, tell your healthcare provider about all of your medical conditions,

including if you:

had liver or kidney problems

have high blood pressure

have asthma

are pregnant or plan to become pregnant Talk to your healthcare provider if you are considering

taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy

are breastfeeding or plan to breast feed

Tell your healthcare provider about all of the medicines you take, including prescription or over-

the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can

interact with each other and cause serious side effects. Do not start taking any new medicine without

talking to your healthcare provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called Nonsteroidal

Anti-inflammatory Drugs (NSAIDs)?

new or worse high blood pressure

heart failure

liver problems including liver failure

kidney problems including kidney failure

low red blood cells (anemia)

life-threatening skin reactions

life-threatening allergic reactions

Other side effects of NSAIDs include : stomach pain, constipation, diarrhea, gas, heartburn,

nausea, vomiting, and dizziness.

Get emergency help right away if you get any of the following symptoms:

shortness of breath or trouble breathing

slurred speech

chest pain

swelling of the face or throat

weakness in one part or side of your body

Stop taking your NSAID and call your healthcare provider right away if you get any of the

following symptoms:

nausea

vomit blood

more tired or weaker than usual there is blood in your bowel movement or it is

black and sticky like tar

diarrhea

unusual weight gain

itching

skin rash or blisters with fever

your skin or eyes look yellow

swelling of the arms, legs, hands and feet

indigestion or stomach pain

flu-like symptoms

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare

provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

Other information about NSAIDs

Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding

in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

Some NSAIDs are sold in lower doses without a prescription (over -the counter). Talk to your

healthcare provider before using over -the -counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people,

even if they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your

pharmacist or healthcare provider for information about NSAIDs that is written for health

professionals.

For more information, call 1-866-604-3268.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Cipla Ltd,

Kurkumbh, India

Manufactured for:

Cipla USA, Inc.

1560 Sawgrass Corporate Parkway,

Suite 130, Sunrise, FL 33323

Revised: 5/2019

DRUG: CELECOXIB

GENERIC: CELECOXIB

DOSAGE: CAPSULE

ADMINSTRATION: ORAL

NDC: 70518-2233-0

COLOR: white

SHAPE: CAPSULE

SCORE: No score

SIZE: 19 mm

IMPRINT: Cipla;421;200

PACKAGING: 30 in 1 BOTTLE, PLASTIC

ACTIVE INGREDIENT(S):

CELECOXIB 200mg in 1

INACTIVE INGREDIENT(S):

CROSCARMELLOSE SODIUM

POVIDONE

SODIUM LAURYL SULFATE

GELATIN

LACTOSE MONOHYDRATE

MAGNESIUM STEARATE

CELECOXIB

celecoxib capsule

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:70 518 -2233(NDC:6 9 0 9 7-421)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CELECO XIB (UNII: JCX8 4Q7J1L) (CELECOXIB - UNII:JCX8 4Q7J1L)

CELECOXIB

20 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

GELATIN (UNII: 2G8 6 QN327L)

Product Characteristics

Color

white

S core

no sco re

S hap e

CAPSULE

S iz e

19 mm

Flavor

Imprint Code

Cipla ;421;20 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:70 518 -2233-

30 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 7/24/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

REMEDYREPACK INC.

ANDA

ANDA20 7446

0 7/24/20 19

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 7/2019

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