CELEBREX

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is a nonsteroidal anti-inflammatory drug (NSAID) which is known for its decreased risk of causing gastrointestinal bleeding compared to other NSAIDS.

It is used to manage symptoms of various types of arthritis pain and in familial adenomatous polyposis (FAP) to reduce precancerous polyps in the colon.

It is marketed by Pfizer under the brand name Celebrex, and was initially granted FDA approval in 1998.

Interestingly, selective COX-2 inhibitors (especially celecoxib), have been evaluated as potential cancer chemopreventive and therapeutic drugs in clinical trials for a variety of malignancies.

Celecoxib is indicated for symptomatic treatment of adult osteoarthritis (OA) and adult rheumatoid arthritis (RA).

Celecoxib is not a substitute for aspirin for cardiovascular event prophylaxis.

It may be also be used to treat acute pain from various sources, juvenile rheumatoid arthritis in children over 2, ankylosing spondylitis, and primary dysmenorrhea.

Celecoxib, in combination with tramadol, is indicated for the management of acute pain in adults severe enough to require an opioid analgesic and in whom alternative treatments are inadequate.

Celecoxib inhibits cyclooxygenase 2 (COX-2) enzyme, reducing pain and inflammation.

It is important to note that though the risk of bleeding with celecoxib is lower than with certain other NSAIDS, it exists nonetheless and caution must be observed when it is administered to those with a high risk of gastrointestinal bleeding.

A note on the risk of cardiovascular events Significant concerns regarding the safety of COX-2 selective NSAIDs emerged in the early 2000s.

Rofecoxib, another member of the COX-2 inhibitor drug class, also known as Vioxx, was withdrawn from the market due to prothrombotic cardiovascular risks.

Committee meeting in 2005, in which data from large clinical outcome trials were evaluated, the FDA concluded that the risk for cardiovascular thrombotic events for both COX-2 selective NSAIDs and nonselective NSAIDs was evident.

It was determined that the benefits of celecoxib treatment, however, outweighed the risks.

Postmarketing cardiovascular outcomes trial (PRECISION) revealed that the lowest possible dose of celecoxib was similar in cardiovascular safety to moderate strength doses of both naproxen and ibuprofen.

Patients who had previous cardiovascular events including acute MI, coronary revascularization, or coronary stent insertion were not evaluated in the trial.

It is not advisable to administer

NSAIDS to these groups of patients.

Celecoxib is absorbed rapidly in the gastrointestinal tract.

When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. 7, 31 The Cmax is 705 ng/mL.

When multiple doses are given, steady-state concentrations are reached on or before day 5.

When taken with a high-fat meal, peak plasma levels are delayed for about 1-2 hours with an increase in total absorption (AUC) of 10% to 20%.

AUC of celecoxib has been shown to be significantly lower in patients with chronic renal impairment. 12, 31 A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC (area under the curve) of celecoxib in black patients compared to Caucasians for unknown reasons.

The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429 L 25, which suggests wide distribution into various tissues.

Celecoxib is not preferentially bound to red blood cells.

Another resource reports a volume of distribution of 455 ± 166 L.

A large part of celecoxib metabolism is mediated by cytochrome P450 2C9 in the liver with some contribution from CYP3A4 and CYP2C8 and possible contributions from CYP2D6. 7, 21, 20, 22 It is metabolized by biotransformation to carboxylic acid and glucuronide metabolites.

Three metabolites, a primary alcohol, a carboxylic acid, and a glucuronide conjugate, have been found in human plasma after celecoxib administration.

These are considered inactive metabolites in regards to COX enzyme inhibition.

Patients who are known or suspected to have decreased cytochrome P450 2C9 activity or function, based on their previous history, should be administered celecoxib with caution as they may have abnormally high serum concentrations resulting from decreased metabolism celecoxib.

Hover over products below to view reaction partners Celecoxib Hydroxycelecoxib Carboxycelecoxib Celecoxib glucuronide.

Celecoxib is primarily eliminated by hepatic metabolism with small amounts (<3%) of the unchanged drug found in both the urine and feces.

About 57% of an oral dose of celecoxib is excreted in the feces and 27% is found to be excreted into the urine in the form of metabolites.

The main metabolite in urine and feces is identified as the carboxylic acid metabolite (73%).

The amount of glucuronide in the urine is reported to be low.

The effective half-life of celecoxib is approximately 11 hours when a single 200 mg dose is given to healthy subjects. 25, 31 The terminal half-life of celecoxib varies because of its low solubility, which prolongs absorption.

Apparent clearance (CL/F), single oral 200 mg dose, healthy subjects = 27.7 L/hr.

Clearance may be decreased by about 47% in patients with chronic renal insufficiency, according to a pharmacokinetic study.

Studies have not been performed in patients with severe renal impairment.

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The oral

TDLo in humans 5.71 mg/kg.

It is not advisable to administer celecoxib in patients with renal impairment or advanced hepatic impairment, as this may lead to increased serum concentrations, causing toxicity.

Symptoms of overdose may include breathing difficulties, coma, drowsiness, gastrointestinal bleeding, high blood pressure, kidney failure, nausea, sluggishness, stomach pain, and vomiting.

Because serious gastrointestinal tract ulceration and bleeding can occur without preceding symptoms, patients should be monitored for signs/symptoms of gastrointestinal bleeding.

Symptomatic and supportive measures should be taken in a celecoxib overdose.

The induction of emesis or administration of active charcoal should take place if the patient is seen within 4 hours of celecoxib ingestion.

Diuresis, urinary alkalinization, hemodialysis, or hemoperfusion may not be useful in a celecoxib overdose due to its high level of protein binding.

Celecoxib is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product.

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.

In the setting of

CABG surgery.

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

Known hypersensitivity to celecoxib, or any components of the drug product or sulphonamides.

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

OA: 200 mg once daily or 100 mg twice daily.

RA: 100 mg to 200 mg twice daily.

JRA: 50 mg twice daily in patients 10 kg to 25 kg. 100 mg twice daily in patients more than 25 kg. 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.

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.

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

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. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of celecoxib and other treatment options before deciding to use celecoxib.

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

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 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 capsule 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 in patients with severe hepatic impairment is not recommended.

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.

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Risk Summary Use of

NSAIDs, including celecoxib, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

Because of these risks, limit dose and duration of celecoxib use between about and 30 weeks of gestation and avoid celecoxib use at about 30 weeks of gestation and later in pregnancy.

Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including celecoxib, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other 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.

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.

Prostaglandins also have been shown to have an important role in fetal kidney development.

In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

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

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions Premature closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including celecoxib, can cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

If celecoxib treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios.

If oligohydramnios occurs, discontinue celecoxib and follow up according to clinical practice.

There are no studies on the effects of celecoxib during labor or delivery.

In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

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

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug.

There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible.

Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications.

These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use.

Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

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 to 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 AUC to 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 AUC to 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 AUC to 24 at 200 mg twice daily).

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

Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib, 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, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Celecoxib 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 celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to celecoxib or other COX-2 selective and non.

• selective NSAIDs.

The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension.

Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features.

Patients with systemic onset

JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests.

In some patients with systemic onset

JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT).

NSAIDs including celecoxib 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.

JRA should be monitored for the development of abnormal coagulation tests.

Alternative therapies for treatment of

JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers.

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.

Of the total number of patients who received celecoxib in pre-approval clinical trials, more than were 65 to 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.