Celebrex

Before taking celecoxib,

• tell your doctor and pharmacist if you are allergic to celecoxib, aspirin or other NSAIDs such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn), sulfa medications, any other medications, or any of the inactive ingredients in celecoxib capsules. Ask your pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril, enalapril (Vasotec, in Vaseretic), fosinopril, lisinopril (in Zestoretic), moexipril (Univasc), perindopril (Aceon, in Prestalia), quinapril (Accupril, in Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); angiotensin receptor blockers such as candesartan (Atacand, in Atacand HCT), eprosartan (Teveten), irbesartan (Avapro, in Avalide), losartan (Cozaar, in Hyzaar), olmesartan (Benicar, in Azor, in Benicar HCT, in Tribenzor), telmisartan (Micardis, in Micardis HCT, in Twynsta), and valsartan (in Exforge HCT); beta blockers such as atenolol (Tenormin, in Tenoretic), labetalol (Trandate), metoprolol (Lopressor, Toprol XL, in Dutoprol), nadolol (Corgard, in Corzide), and propranolol (Hemangeol, Inderal, Innopran); diuretics ('water pills'); fluconazole (Diflucan); and lithium (Lithobid). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section or asthma, especially if you also have frequent stuffed or runny nose or nasal polyps (swelling of the lining of the nose); swelling of the hands, arms, feet, ankles, or lower legs; heart failure; or liver or kidney disease.
• tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, you plan to become pregnant, or you are breast-feeding. If you become pregnant while taking celecoxib, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking celecoxib.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• lack of energy
• drowsiness
• nausea
• vomiting
• stomach pain
• vomiting material that is bloody or looks like coffee grounds
• bloody or black, tarry stools
• loss of consciousness
• hives
• rash
• swelling of the eyes, face, tongue, lips, throat, arms, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing

CELEBREX is indicated

Osteoarthritis (OA)

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

Rheumatoid Arthritis (RA)

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

Juvenile Rheumatoid Arthritis (JRA)

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

Ankylosing Spondylitis (AS)

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

Acute Pain

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

Primary Dysmenorrhea

For the management of primary dysmenorrhea [see Clinical Studies]

Celebrex is a prescription medication used to treat pain, arthritis, and painful menstrual periods. Celebrex belongs to a group of medications called nonsteroidal anti-inflammatory drugs (NSAIDs). These work by blocking chemicals in the body that cause pain and inflammation.

Celebrex comes in capsule form and is taken by mouth, once or twice daily, with or without food.

Common side effects include stomach pain, upset stomach, and diarrhea.

Celebrex can cause serious side effects. See "Drug Precautions" section.

Common Celebrex side effects include:

• abdominal pain
• diarrhea
• upset stomach
• gas or bloating
• nausea
• cough
• upper respiratory infection

This is not a complete list of Celebrex side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you are breastfeeding or plan to breastfeed. Celebrex may be excreted in human milk in low amounts. The manufacturer recommends breastfeeding women use caution when taking Celebrex. You and your doctor will need to decide it is safe for you to take Celebrex while breastfeeding.

NSAIA1 2 3 4 5 8 11 41 that is a selective inhibitor of cyclooxygenase-2 (COX-2);1 2 8 diaryl-substituted pyrazole derivative containing a sulfonamide substituent.1 2 3 4 5 8 11 41

Consider potential benefits and risks of celecoxib therapy as well as alternative therapies before initiating therapy with the drug.1 Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1

Osteoarthritis

Symptomatic treatment of osteoarthritis.1 2 3 28 29 64 Effect comparable to that of prototypical NSAIAs (naproxen).1 2 3 28 29 64

Lower incidence of endoscopically confirmed GI ulcer and serious adverse GI effects than prototypical NSAIAs.1 28 29 33 79

Rheumatoid Arthritis in Adults

Symptomatic treatment of rheumatoid arthritis in adults.1 2 3 9 10 21 23 24 28 65 66 99 Effect comparable to that of prototypical NSAIAs (naproxen, diclofenac).1 2 3 9 10 21 23 24 28 65 66 99

Lower incidence of endoscopically confirmed GI ulcer and serious adverse GI effects than prototypical NSAIAs.1 3 9 10 21 23 24 28 33 65 66 79

Juvenile Arthritis

Symptomatic management of pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis in children ≥2 years of age.1 Effect comparable to that of naproxen.1

Ankylosing Spondylitis

Management of the signs and symptoms of ankylosing spondylitis.1 132

Colorectal Polyps

Reduction of the number of adenomatous colorectal polyps (colorectal adenomas) in adults with familial adenomatous polyposis (FAP); used as an adjunct to usual care.1 60 Not known whether celecoxib reduces the risk of colorectal, duodenal, or other FAP-related cancers.1

Has been investigated for the prevention of colorectal adenomas in patients without a history of FAP†.149 150 Use of celecoxib reduces the risk of recurrent colorectal adenomas;149 150 not known whether celecoxib reduces the risk of colorectal cancer.149 150 Routine use not recommended because of the potential for serious cardiovascular events.149

Pain

Management of acute pain, including postoperative (e.g., dental, orthopedic) pain, in adults.1 8 42 43

Dysmenorrhea

Symptomatic management of primary dysmenorrhea in adults.1 2

Cardiovascular Risk Reduction

Not a substitute for aspirin in the prevention of adverse cardiovascular events (MI).1 (See Cardiovascular Thrombotic Effects under Cautions.)

Metabolized by CYP2C9.77

Inhibits CYP2D6; does not inhibit CYP2C9, CYP2C19, or CYP3A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma celecoxib concentrations) with drugs that inhibit CYP2C9.1 Caution is advised.1

Potential pharmacokinetic interaction (increased plasma concentrations of CYP2D6 substrate) with drugs metabolized by CYP2D6.1 3 6 44

Specific Drugs

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentration usually attained within 3 hours in fasting individuals.1 2 23

Onset

Single doses provide pain relief within 60 minutes.1

Food

Bioavailability increased 10–20% and time to reach peak plasma concentration delayed 1–2 hours when 200-mg capsule is administered with a high-fat meal.1 2 Administration of dosages of 400 mg twice daily with food improves absorption.1

Administration as mixture in applesauce does not alter AUC, peak plasma concentration, or time to peak plasma concentration.1

Special Populations

In geriatric patients, peak plasma concentration and AUC increased by 40 and 50%, respectively.1 2

In patients with mild or moderate hepatic impairment, AUC increased by 40 or 180%, respectively.1 2

In patients with chronic renal impairment (GFR 35–60 mL/minute), AUC decreased by 40%; pharmacokinetics not studied in patients with severe renal impairment.1 2

Distribution

Extent

Not well characterized.1

Plasma Protein Binding

97% (principally albumin; α1-acid glycoprotein to a lesser extent).1 2 23

Elimination

Metabolism

Metabolized in the liver to inactive metabolites, mainly by CYP2C9.1 2 23

Elimination Route

Excreted in urine and feces principally as metabolites.1 2 23

Pediatric patients: Oral clearance increases in less-than-proportional manner with increasing weight; clearance predicted to be 40 or 24% lower in pediatric patients weighing 10 or 25 kg, respectively, than in a 70-kg adult.1

Half-life

11 hours under fasting conditions.1

In the U.S.

• CeleBREX

Available Dosage Forms:

• Capsule

Therapeutic Class: Analgesic

Pharmacologic Class: Cyclooxygenase-2 Inhibitor

For safe and effective use of this medicine, do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Taking too much of this medicine may increase the chance of unwanted effects.

This medicine should come with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

You may take this medicine with or without food.

If you cannot swallow the capsule, you may open it and pour the medicine to a teaspoon of cool or room temperature applesauce. This mixture must be swallowed right away without chewing and followed with a glass of water to make sure all of the mixture is swallowed.

Any medicine that has been mixed with applesauce may be stored in a refrigerator and used within 6 hours.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For acute pain or pain during menstruation:
    • Adults—At first, 400 milligrams (mg). A second dose of 200 mg can be taken if needed on the first day. Then, 200 mg two times a day as needed.
    • Children—Use and dose must be determined by your doctor.
  • For ankylosing spondylitis or osteoarthritis:
    • Adults—200 milligrams (mg) once a day or 100 mg two times a day. Your doctor may increase your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For rheumatoid arthritis or juvenile rheumatoid arthritis:
    • Adults—100 to 200 milligrams (mg) two times a day.
    • Children 2 years of age and older and weighing more than 25 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The dose is usually 100 milligrams (mg) two times a day.
    • Children 2 years of age and older and weighing less than 25 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The dose is usually 50 milligrams (mg) two times a day.
    • Children younger than 2 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• If you have an allergy to celecoxib or any other part of CeleBREX.
• If you have an allergy to aspirin or NSAIDs.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a sulfa (sulfonamide) allergy, talk with your doctor.
• If you have any of these health problems: Kidney disease or liver disease.
• If you have GI (gastrointestinal) bleeding.
• If you are having trouble getting pregnant or you are having your fertility checked.
• If you are pregnant or may be pregnant. Do not take this medicine if you are in the third trimester of pregnancy. You may also need to avoid CeleBREX at other times during pregnancy. Talk with your doctor to see when you need to avoid taking this medicine during pregnancy.
• If you are taking any other NSAID.
• If you are taking a salicylate drug like aspirin.
• If you are taking pemetrexed.

This is not a list of all drugs or health problems that interact with CeleBREX.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time CeleBREX is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take CeleBREX or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to CeleBREX. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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

• 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)]

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 Celebrex-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 Celebrex 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 Celebrex at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Pre-marketing Controlled Arthritis Trials

Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving Celebrex from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.

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

The following adverse reactions occurred in 0.1 – 1.9% of patients treated with Celebrex (100 – 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

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 enzyme increased (including SGOT increased, SGPT increased)

Metabolic and nutritional: BUN increased, 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, cough, 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 (14.6)]

Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on Celebrex 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 Celebrex 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 Celebrex, 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)

Other Pre-Approval Studies

Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with Celebrex 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 Celebrex 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 Celebrex 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 Celebrex in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [see Special Studies Adenomatous Polyp Prevention Studies (14.6)].

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 Celebrex pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with Celebrex were greater as compared to the arthritis pre-marketing trials were as follows:

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

Postmarketing Experience

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

Pregnancy

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

Risk Summary

Use of NSAIDs, including Celebrex, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Celebrex, in pregnant women starting at 30 weeks of gestation.

There are no adequate and well-controlled studies of Celebrex 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 the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. 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 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.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of Celebrex 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 Celebrex.

Animal data

Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC0–24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the AUC0–24 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 AUC0–24 at 200 mg twice daily for RA).

Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0–24 at 200 mg twice daily). The effects of Celebrex on labor and delivery in pregnant women are unknown.

Lactation

Risk Summary

Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celebrex in breast milk. The calculated average daily infant dose was 10–40 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 Celebrex is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Celebrex and any potential adverse effects on the breastfed infant from the Celebrex or from the underlying maternal condition.

Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Celebrex, 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 Celebrex, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Celebrex is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to Celebrex has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to Celebrex 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 (5.12), Adverse Reactions (6.3), 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)].

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 Celebrex 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 (5.4, 5.6)].

Hepatic Impairment

The daily recommended dose of Celebrex capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Celebrex in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Renal Impairment

Celebrex is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Poor Metabolizers of CYP2C9 Substrates

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 Celebrex 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 (2.6) and Clinical Pharmacology (12.5)].

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Celebrex®
celecoxib capsules

50 mg

60 Capsules
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Pfizer

Celebrex®
celecoxib capsules

400 mg

60 Capsules
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PRINCIPAL DISPLAY PANEL - 400 mg Blister Pack

Celebrex®
celecoxib capsules

400 mg

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MADE IN SINGAPORE

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Celebrex®
celecoxib capsules

400 mg

For in-institution use only

100 Capsules
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Celebrex can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Celebrex may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using Celebrex, especially in older adults. You should not take this medicine if you already have bleeding in your stomach or intestines.

Avoid drinking alcohol. It may increase your risk of stomach bleeding.

Avoid taking aspirin or other NSAIDs while you are taking Celebrex.

Ask a doctor or pharmacist before using any cold, allergy, or pain medication. Many medicines available over the counter contain aspirin or other medicines similar to celecoxib. Taking certain products together can cause you to get too much of this type of medication. Check the label to see if a medicine contains aspirin, ibuprofen, ketoprofen, or naproxen.

Ask your doctor before using Celebrex if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with an NSAID may cause you to bruise or bleed easily.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• fluconazole;

• lithium;

• a blood thinner (warfarin, Coumadin, Jantoven);

• heart or blood pressure medication, including a diuretic or "water pill"; or

• steroid medicine (such as prednisone).

This list is not complete. Other drugs may interact with celecoxib, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Effective for the relief of pain and inflammation associated with arthritis, Ankylosing Spondylitis, menstruation, and for the relief of acute pain.
• NSAIDs (including Celebrex) are considered first-line options for mild-to-moderate acute pain because at correct dosages they are effective, do not cause dependence and are readily available.
• Celebrex relieves pain, decreases inflammation, and lowers temperature.
• Celebrex is less likely to cause stomach ulcers at higher dosages than other NSAIDs. Advantages are negated when Celebrex is given with aspirin.
• Celebrex is available as a generic under the name celecoxib.

Celebrex is effective for the short-term relief of acute pain, and pain and inflammation associated with arthritis, menstruation, and Ankylosing Spondylitis. Risk of symptomatic ulcers is lower with higher dosages compared to other NSAIDs.

Summary of Use during Lactation

Because of the low levels of celecoxib in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.[1][2] No special precautions are required.

Drug Levels

Maternal Levels. Milk celecoxib levels were measured in one mother taking 100 mg orally twice daily. At 4.75 hours after the fourth dose, milk levels were 101 and 133 mcg/L from her right and left breasts, respectively. A second peak level of about 30 mcg/L occurred in milk from the right breast about 35 hours after the last dose. The average half-life in the milk was 5.1 hours. The authors estimated that a fully breastfed infant would receive a maximum dose of 40 mcg/kg daily.[3]

Three mothers, averaging 12 months postpartum, who had been taking oral celecoxib 200 mg daily (average 3.27 mg/kg daily) for several weeks had milk celecoxib levels measured at several times during a 24-hour period. Peak milk levels averaged 139 mcg/L at 2 hours after the dose. By 12 hours after the dose, celecoxib was undetectable (<10 mcg/L) in milk. Two other mothers were given a single oral dose of celecoxib 200 mg. Breastmilk and maternal serum were collected periodically over an 8-hour period. Peak milk levels were 170 mcg/L at 4 hours after the dose in one woman and 269 mcg/L at 2 hours after the dose in the other.[4] Based on data from these 5 women, an exclusively breastfed infant would receive an estimated 9.8 mcg/kg daily or 0.3% of the maternal weight-adjusted dosage.

Six women averaging 11 months postpartum (range 6.5 to 15 months) were given a single 200 mg dose of celecoxib orally. Milk samples were collected for 48 hours after the dose. A median peak milk level of 200 mcg/L (range 70 to 330 mcg/L) occurred 2 to 4 hours after the dose. The authors calculated that a fully breastfed infant would receive a median daily dosage of 13 mcg/kg (range 11 to 210 mcg/kg) or 0.23% of the maternal weight-adjusted dosage.[5]

Thirteen nonlactating women took celecoxib 200 or 400 mg twice daily for 2 weeks followed by collection of nipple aspirate fluid. Two women taking 200 mg twice daily had celecoxib concentrations of 1.2 and 1.5 mg/L; 2 women taking 400 mg twice daily had celecoxib concentrations of 0.53 and 8.4 mg/L in the aspirate. Celecoxib was undetectable (lower limit of assay not stated) in the in nipple aspirate fluid of the other 9 women. Collection times with respect to the doses were not stated.[6]

Infant Levels. Two breastfed infants whose mothers had been taking celecoxib 200 mg orally twice daily for many weeks, had blood samples taken 4 hours after a maternal dose. The infants were 17 and 22 months of age and were being breastfed on demand every 3 to 4 hours during the day and once at night. Celecoxib was undetectable (<10 mcg/L) in the plasma of these infants.[4]

Effects in Breastfed Infants

No infant side effects were noted by the mothers of 2 infants aged 17 and 22 months who were breastfed during long-term maternal use of celecoxib 200 mg daily.[4]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Acetaminophen, Flurbiprofen, Ibuprofen, Indomethacin, Piroxicam

References

1. Montgomery A, Hale TW. ABM clinical protocol #15: analgesia and anesthesia for the breastfeeding mother, revised 2012. Breastfeed Med. 2012;7:547-53.

2. Gotestam Skorpen C, Hoeltzenbein M, Tincani A et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795-810. PMID: 26888948

3. Knoppert DC, Stempak D, Baruchel S et al. Celecoxib in human milk: a case report. Pharmacotherapy. 2003;23(1):97-100. PMID: 12523466

4. Hale TW, McDonald R, Boger J. Transfer of celecoxib into human milk. J Hum Lact. 2004;20(4):397-403. PMID: 15479658

5. Gardiner SJ, Doogue MP, Zhang M, Begg EJ. Quantification of infant exposure to celecoxib through breast milk. Br J Clin Pharmacol. 2006;61:101-4. PMID: 16390357

6. Ruhlen RL, Chen YC, Rottinghaus GE, Sauter ER. RE: "Transfer of celecoxib into human milk". J Hum Lact. 2007;23:13-4. PMID: 17293545

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID). Celecoxib works by reducing hormones that cause inflammation and pain in the body.

Celecoxib is used to treat pain or inflammation caused by many conditions such as arthritis, ankylosing spondylitis, and menstrual pain. Celecoxib is used to treat juvenile rheumatoid arthritis in children who are at least 2 years old. Celecoxib is also used in the treatment of hereditary polyps in the colon.

Celecoxib may also be used for purposes not listed in this medication guide.