Celecoxib

Introduction

Celecoxib is a nonsteroidal anti-inflammatory drug, an NSAID, selectively inhibit cyclo-oxygenase-2 (COX-2). As an NSAID, celecoxib is an analgesic, anti-inflammatory and antipyretic.

Clinical indications for indomethacin include:

• rheumatoid arthritis
• alkylosing spondylitis
• osteoarthritis
• gouty arthritis
• acute painful shoulder bursitis or tendinitis

It is also be used in menstrual pain, headaches, dental pain, postoperative and postpartum pain.

FAQ

How should I take the tablet?

Should always be taken with food. Nearly all patients benefit from an ulcer protective drug (e.g. antacids, or famotidine 20mg or omeprazole 20 mg at bedtime).

Mechanism of Action

• Anti-inflammatory agent
• Non-steroidal anti-inflammatory drug (NSAID)
• Highly selective COX-2 inhibitor

Dosage

Osteoarthritis	Oral: 200 mg daily given as a single dose or in 2 divided doses. If necessary a dose of 200 mg twice daily may be used.
Rheumatoid arthritis	Oral: 100 to 200 mg given twice daily.
Ankylosing Spondylitis	Oral: an initial dose of 200 mg daily, as a single or in 2 divided doses. In the USA, the dose may be increased to 400 mg daily after 6 weeks, although if no response is seen at this dose a further 6 weeks, alternative treatments should be considered.
Pain and Dysmenorrhea	Oral: an initial dose of 400 mg followed by an additional dose of 200 mg, if necessary, is recommended on the first day; thereafter the dose is 200mg twice daily. In patients with hepatic impairment and in those also taking fluconazole, a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9, the dose of celecoxib should be reduced to half the recommended dose.

Administration in children

For the treatment of juvenile idiopathic arthritis in children aged 2 years and over, the recommended oral doses, based on body-weight, are:

• 10 to 25 kg: 50 mg twice daily
• Over 25 kg: 100 mg twice daily

It is recommended that children who are deficient in the cytochrome P450 isoenzyme CYP2C9 and hence poor metabolizers of celecoxib should be given alternative treatment. The contents of a celecoxib capsule may be sprinkled onto pureed meal if a patient has difficulty swallowing the capsules. The sprinkled capsule should be taken immediately; it remains stable at a temperature of between 2 degrees to 8 degrees for up to 6 hours.

Pharmacokinetics

Peak plasma concentrations occur after 3 hours of an oral dose. Plasma protein binding is about 97%. Celecoxib is metabolized in the liver mainly by the cytochrome P450 isoenzyme CYP2C9. It is eliminated mainly as metabolites in the faeces and urine. The plasma elimination half-life is about 11 hours. Celecoxib is distributed into breast milk.

Side Effects

Common side effects include:

• Abdominal pain, nausea and diarrhea.

Serious side effects may include:

• Heart attacks
• Strokes
• Gastrointestinal perforation
• Gastrointestinal bleeding
• Kidney failure
• anaphylaxis

It is generally accepted that COX-2 inhibitor may cause less gastrotoxicity than that seen with the non-selective inhibition of the traditional NSAIDs. However, reports that upper gastrointestinal perforation, ulceration and bleeds have occurred with celecoxib treatment and should not be used in patients with active gastrointestinal ulceration or bleeding.

Drug Management

Monitoring

• Regular physical examination to detect edema and signs of central nervous side effects.
• Blood pressure checks will reveal development of hypertension.
• Periodic serum electrolyte (sodium, potassium, chloride) measurements,
• complete blood counts and
• assessment of liver enzymes as well as creatinine (renal function) should be performed.

This is particularly important if Indomethacin is given together with an ACE inhibitor or with potassium-sparing diuretic (e.g. spironolactone), because these combinations can lead to hyperkalemia and/or serious kidney failure.

Drug Interaction

• the metabolism of celecoxib is mediated by the cytochrome P450 isoenzyme CYP2C9. Use of other drugs that inhibit or induce by this isoenzyme may result in changes in plasma concentration of celecoxib. Fluconazole has increased plasma concentrations of celecoxib and it is recommended that the dose of celecoxib should be halved when given with fluconazole.
• Increases the blood thinning effects of warfarin by displacing them from their plasma protein binding and increases their free concentrations in the bloodstream, so increases the risk of bleeding
• Increase the risk of adverse effects of lithium, methotrexate and cardiac glycosides by lowering their excretion via the kidneys.
• Increase risk of kidney failure if given with ACE inhibitors such as lisinopril, ciclosporin, tacrolimus and diuretics, such as hydrochlorothiazide.
• Increase risk of hyperkalaemia with ACE inhibitors and potassium-sparing diuretics such as spironolactone.
• Use of more than one NSAID together (including aspirin) should be avoided because of the increased risk of adverse effects.
• It adds to the risk of gastrointestinal bleeding and ulceration when used with steroids, the SSRIs (such as sertraline or fluoxetine), the SNRI venlafaxaine, the antiplatelet clopidogrel, bisphosphonates or pentoxifylline.

Many NSAIDs, but particularly indomethacin, cause lithium retention by reducing its excretion by the kidney. Thus, indomethacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment of bipolar disorder), less toxic NSAIDs such as sulindac is preferred. All NSAIDs, including indomethacin, also increase plasma renin activity and aldosterone levels, and increase sodium and potassium retention. Vasopressin activity is also enhanced. Together these may lead to:

• Edema (swelling due to fluid retention)
• Hyperkaelemia (high potassium levels)
• Hypernatremia (high sodium levels)
• hypertension

Contraindication

• Allergy to aspirin or other NSAIDs
• Avoided by patients with a history of asthma attacks
• Contraindicated during pregnancy and in lactating women.
• Active stomach and/or duodenal ulceration or gastrointestinal bleeding, or history of peptic ulcer disease
• Inflammatory bowel disease such as Crohn’s disease or ulcerative colitis
• Severe congestive heart failure (NYHA class II to IV)
• Severe chronic kidney disease (creatinine clearance <30 mi/min)
• Caution in patients with severe, active bleeding such as cerebral hemorrhage
• Caution in patients with fluid retention or heart failure
• Caution in patients with Parkinson’s disease, epilepsy, psychotic disorders (sulindac may worsen these conditions)
• Concurrent with potassium sparing diuretics
• Can lead to onset of new hypertension or worsening of pre-existing hypertension
• Avoid in pregnancy and in breast-feeding women

Note

• Celecoxib should not be used after coronary artery bypass surgery as there may be an increased risk of adverse effects such as myocardial infarction and stroke.
• It should be used with caution, it at all, in patients with a history of ischaemic heart disease, peripheral arterial disease, or cerebrovascular disease.