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Celecoxib

Pronunciation

Pronunciation: SEL-e-KOX-ib
Class: Selective COX-2 inhibitor

Trade Names

Celebrex
- Capsules, oral 50 mg
- Capsules, oral 100 mg
- Capsules, oral 200 mg
- Capsules, oral 400 mg

Pharmacology

Reduces inflammation, fever, and pain by inhibiting prostaglandin synthesis, primarily via inhibition of cyclooxygenase 2 (COX-2) isoenzyme.

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Pharmacokinetics

Absorption

C max is 705 ng/mL and T max is approximately 3 h. Steady state is reached on or before day 5 with multiple dosing.

Food

T max increased approximately 1 to 2 h and AUC increased 10% to 20% when taken with a high-fat meal.

Distribution

Approximately 97% protein bound. Vd is approximately 400 L.

Metabolism

Metabolized in the liver via CYP2C9 to inactive metabolites.

Elimination

Less than 3% is excreted unchanged in the urine and feces. Approximately 57% is excreted in feces and 27% in urine. The half-life is approximately 11 h. Cl is approximately 500 mL/min.

Special Populations

Renal Function Impairment

AUC is approximately 40% lower in patients with a CrCl of 35 to 60 mL/min.

Hepatic Function Impairment

AUC is increased approximately 40% in patients with mild impairment and 180% in patients with moderate impairment.

Elderly

C max is 40% higher and AUC is 50% higher.

Children

10 and 25 kg children are predicted to have 40% and 24% lower Cl, respectively, compared with a 70 kg adult.

Race

AUC is approximately 40% higher in black compared with white patients.

Indications and Usage

Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis (RA), and ankylosing spondylitis; management of acute pain in adults; treatment of primary dysmenorrhea; relief of signs and symptoms of juvenile RA in patients 2 y and older.

Unlabeled Uses

Adjunctive therapy in the treatment of schizophrenia; prevention of colorectal cancer; prevention of lung cancer.

Contraindications

Hypersensitivity to celecoxib, aspirin, or other NSAIDs; allergy to sulfonamides; previous allergic reactions following aspirin or other NSAID use (eg, asthma, hives, rash); treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Dosage and Administration

Acute Pain, Primary Dysmenorrhea
Adults

PO 400 mg initially followed by an additional 200 mg dose on day 1, if needed, then 200 mg twice daily as needed.

Ankylosing Spondylitis
Adults

PO 200 mg once daily or 100 mg twice daily. If no response after 6 wk, attempt dosage increase to 400 mg/day; if no response after 6 wk at 400 mg/day, discontinue and consider alternate treatment.

Juvenile Rheumatoid Arthritis
Children 2 y and older

PO Children weighing 10 to 25 kg, 50 mg twice daily. Children weighing more than 25 kg, 100 mg twice daily.

Osteoarthritis
Adults

PO 200 mg once daily or as 100 mg twice daily.

Rheumatoid Arthritis
Adults

PO 100 to 200 mg twice daily.

Hepatic Function Impairment

Reduce dose by 50% in patients with moderate hepatic impairment. Not recommended in patients with severe hepatic impairment.

Poor Metabolizers of CYP2C9 Substrates

Use with caution. Consider starting treatment at half the lowest recommended dose. In patients with juvenile RA who are poor metabolizers, consider using alternative treatment.

Elderly

Dosage adjustment is generally not necessary. However, for patients less than 50 kg, initiate therapy at the lowest recommended dose.

General Advice

  • Dosages of up to 200 mg twice daily can be given without regard to meals. Administer high doses (400 mg twice daily) with food.
  • Use lowest effective dose for the shortest duration.
  • Capsules may be opened and added to 1 level tablespoon of cool or room temperature applesauce, and ingested immediately with water.

Storage/Stability

Store between 59° and 86°F. The sprinkled capsule contents on applesauce are stable for up to 6 h in the refrigerator.

Drug Interactions

ACE inhibitors, angiotensin II antagonists

NSAIDs may diminish the antihypertensive effect of these drugs. Risk of renal impairment may be increased. Monitor BP closely.

Alcohol

May increase risk of GI bleeding.

Antacids (containing aluminum or magnesium)

Coadministration may decrease celecoxib plasma levels.

Antiplatelets (eg, clopidogrel, prasugrel)

Risk of hemorrhage may be increased. Use with caution.

Aspirin

Coadministration may result in an increased rate of GI ulceration or other complications. Celecoxib can be used with low-dose aspirin. Close clinical monitoring is warranted.

Azole antifungals (eg, fluconazole, voriconazole)

Increase in celecoxib plasma concentration may occur. Start celecoxib at the lowest recommended dose.

Corticosteroids (eg, prednisone)

Use with caution. Concomitant use may increase the risk of GI bleeding.

CYP2C9 inhibitors (eg, amiodarone, ritonavir, zafirlukast)

Celecoxib metabolism is predominantly mediated via CYP2C9. Use with caution with CYP2C9 inhibitors.

CYP2D6 substrates (eg, carvedilol, mexiletine, tramadol)

In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.

Diuretics (eg, loop diuretics [eg, furosemide], thiazides [eg, hydrochlorothiazide])

Patients taking thiazides or loop diuretics may have an impaired response to therapy. Risk of renal impairment may be increased. Closely observe patients for diuretic efficacy and signs of renal failure.

Heparin, low molecular weight heparin (eg, enoxaparin)

Risk of hemorrhagic adverse reactions may be increased. Monitor closely.

Lithium

Mean steady-state lithium plasma levels increased approximately 17% when coadministered. Monitor lithium concentrations and for signs of lithium toxicity, especially when celecoxib is started or stopped.

Methotrexate

Plasma concentrations and toxic effects of methotrexate may be increased. Severe toxicity characterized by bone marrow suppression, nephrotoxicity, and mucositis has occurred in patients receiving celecoxib and high-dose methotrexate chemotherapy. Fatal toxicity has occurred. Avoid coadministration of high doses of methotrexate and celecoxib. Use of low-dose methotrexate for RA, commonly used in conjunction with NSAIDs, is considerably less likely to result in a clinically important interaction.

NSAIDs (eg, ibuprofen)

Avoid concomitant use because of the potential for increased risk of adverse reactions.

Smoking

Smoking may increase the risk of GI bleeding.

Warfarin

There have been postmarketing reports of serious bleeding events (some fatal), predominantly in elderly patients taking warfarin and celecoxib. Monitor anticoagulant activity, particularly in the first few days, after initiating or changing celecoxib therapy in patients receiving warfarin or similar agents.

Adverse Reactions

Cardiovascular

Hypertension (13%); aggravated hypertension, angina pectoris, coronary artery disorder, MI, palpitations, tachycardia (less than 2%); deep vein thrombosis, vasculitis (postmarketing).

CNS

Headache (16%); dizziness, insomnia (2%); anxiety, depression, fatigue, hypertonia, hypoesthesia, migraine, nervousness, paresthesia, somnolence, vertigo (less than 2%); ageusia, anosmia, aseptic meningitis, fatal intracranial hemorrhage (postmarketing).

Dermatologic

Rash (2%); alopecia, cellulitis, contact dermatitis, dermatitis, dry skin, erythematous rash, increased sweating, maculopapular rash, photosensitivity reaction, pruritus, skin disorder, urticaria (less than 2%); erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, TEN (postmarketing).

EENT

Nasopharyngitis (6%); sinusitis (5%); rhinitis (2%); deafness, laryngitis, tinnitus (less than 2%).

GI

Diarrhea (11%); dyspepsia (9%); upper abdominal pain (8%); abdominal pain (6%); nausea (7%); vomiting (6%); gastroesophageal reflux (5%); flatulence (2%); anorexia, constipation, diverticulitis, dry mouth, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, hemorrhoids, hiatal hernia, increased appetite, melena, stomatitis, tenesmus (less than 2%).

Genitourinary

Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus (less than 2%); interstitial nephritis (postmarketing).

Hematologic

Anemia, ecchymosis, epistaxis, thrombocythemia (less than 2%); agranulocytosis, aplastic anemia, leukopenia, pancytopenia (postmarketing).

Hepatic

Abnormal hepatic function, elevated ALT, elevated AST (less than 2%); hepatitis, jaundice, liver failure (postmarketing).

Metabolic

Hypercholesterolemia, hyperglycemia, hypokalemia, increased alkaline phosphatase, increased BUN, increased CPK, increased creatinine, increased nonprotein nitrogen, weight gain (less than 2%); hypoglycemia, hyponatremia (postmarketing).

Musculoskeletal

Arthralgia (7%); back pain (3%); arthrosis, leg cramps, myalgia, synovitis, tendinitis (less than 2%).

Respiratory

Upper respiratory tract infection (8%); cough (7%); dyspnea (3%); pharyngitis (2%); aggravated bronchospasm, bronchitis, bronchospasm, coughing, pneumonia (less than 2%).

Miscellaneous

Infections (25%); pyrexia (9%); injury and poisoning (6%); peripheral edema (2%); aggravated allergy, allergic reaction, chest pain, cyst, facial edema, flu-like symptoms, generalized edema, hot flushes, pain, peripheral pain (less than 2%); anaphylactoid reaction, angioedema (postmarketing).

Precautions

Warnings

CV risk

May cause an increased risk of serious CV thrombotic events, MI, and stroke, which may be fatal. This risk may increase with duration of use. Patients with CV disease or risk factors for CV disease may be at higher risk. Celecoxib is contraindicated for the treatment of perioperative pain in the setting of CABG surgery.

GI risk

NSAIDs, including celecoxib, caused an increase in serious GI adverse reactions, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These reactions can occur at any time during use and without warning symptoms. Elderly patients are at higher risk of serious GI events.


Monitor

Monitor BP closely during initiation and throughout therapy. Monitor CBC and chemistry profile periodically during long-term use. Monitor for signs and symptoms of GI bleeding. Monitor renal function in patients with advanced renal disease. Monitor liver function in patients with signs and symptoms of liver dysfunction. Monitor for the development of abnormal coagulation tests in patients with juvenile RA. Remain alert for the development of CV thrombotic events, even in the absence of previous CV symptoms.


Pregnancy

Category C . Category D from 30 weeks' gestation onward. Because celecoxib may cause premature closure of the patent ductus arteriosus, avoid use in late pregnancy.

Lactation

Excreted in breast milk.

Children

For the treatment of juvenile RA, safety and efficacy have not been established in pediatric patients younger than 2 y, in patients less than 10 kg, or in patients with systemic features. For other indications, safety and efficacy not established in patients younger than 18 y.

Elderly

There have been more spontaneous reports of fatal GI events and acute renal failure in elderly patients.

Hypersensitivity

Severe anaphylactoid reactions, some fatal, and angioedema have occurred.

Renal Function

Not recommended in patients with severe renal impairment.

Hepatic Function

Not recommended in patients with severe hepatic impairment.

Anemia

May occur.

Aspirin triad

Use not recommended.

Asthma

Use with caution in patients with preexisting asthma.

CHF and edema

Fluid retention and edema have been observed. Use with caution in patients with fluid retention or heart failure.

CYP2D6 poor metabolizers

Use with caution in patients who are known or suspected to be poor CYP2C9 metabolizers based on history/experience with other CYP2C9 substrates (eg, phenytoin, warfarin). Consider reduced doses. Consider alternative therapy in patients with juvenile RA identified to be poor metabolizers.

Dermatologic

Can cause serious skin reactions, which may be fatal (eg, exfoliative dermatitis, Stevens-Johnson syndrome, TEN).

GI effects

Use with extreme caution in patients with history of ulcer disease or GI bleeding.

Hepatic effects

Elevated liver enzymes may occur. Rare cases of severe hepatic reactions (eg, jaundice, hepatic failure), some with fatal outcomes, have occurred. Discontinue use if liver disease develops or if systematic manifestations occur (eg, eosinophilia, rash).

Hypertension

Use with caution. Can lead to onset of new hypertension or worsening of preexisting hypertension.

Infection

May mask the usual signs and symptoms of infection.

Lab test abnormalities

Elevated BUN may occur.

Renal effects

Long-term use of NSAIDs has resulted in renal papillary necrosis and other renal injury. Those at greater risk are patients with impaired renal function, heart failure, or liver dysfunction; those taking diuretics, angiotensin II receptor antagonists, or ACE inhibitors; and elderly patients.

Sulfa allergy

Do not use in patients with a sulfa allergy.

Systemic-onset juvenile rheumatoid arthritis

Use with caution because of risk of serious adverse reactions, including DIC.

Overdosage

Symptoms

Acute renal failure, anaphylactoid reactions, coma, drowsiness, epigastric pain, GI bleeding, hypertension, lethargy, nausea, respiratory depression, vomiting.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Inform patients that celecoxib may cause serious CV events, such as MI or stroke, which may result in hospitalization and even death. Instruct patients to report chest pain, shortness of breath, slurring of speech, weakness, or any unusual reaction or concern to their health care provider.
  • Inform patients that celecoxib can lead to new-onset hypertension or worsening of preexisting hypertension, and that it may impair the response to some antihypertensives. Instruct patients on the proper follow-up for monitoring of BP.
  • Inform patients that celecoxib can cause GI discomfort and more serious adverse reactions, such as ulcers and bleeding, which may result in hospitalization and even death. Instruct patients to promptly report signs or symptoms of GI ulceration or bleeding to their health care provider.
  • Inform patients of the warning signs and symptoms of hepatotoxicity (eg, fatigue, flu-like symptoms, jaundice, lethargy, nausea, pruritus, right upper quadrant tenderness) and to stop therapy and contact their health care provider if any of these occur.
  • Inform patients that celecoxib can cause serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and TEN, which may result in hospitalization or even death. Advise patients that these reactions may occur without warning, but they should be alert for signs and symptoms such as skin rash and blisters, fever, and itching, and seek immediate medical care if they occur.
  • Instruct patients to report signs or symptoms of unexplained weight gain or edema to their health care provider.
  • Advise patients that long-term administration of celecoxib has resulted in renal injury.
  • Instruct patients to seek immediate emergency help in case of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat).
  • Advise patients to stop celecoxib immediately if they develop any type of rash and to contact their health care provider as soon as possible.
  • Advise patents with a history of sulfa allergy not to take celecoxib.
  • Inform patients to avoid celecoxib in late pregnancy because it may cause premature closure of the ductus arteriosus.
  • Inform patients with aspirin-sensitive asthma that the use of NSAIDs has been associated with severe bronchospasm, which can be fatal. Instruct patients with this form of aspirin sensitivity not to take celecoxib.

Copyright © 2009 Wolters Kluwer Health.

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