Continuing Education Activity

The FDA recommends celecoxib and other NSAIDs (non-steroidal anti-inflammatory drugs), along with acetaminophen, as first-line analgesics for patients with osteoarthritis and rheumatoid arthritis. Celecoxib also has an FDA indication for the management of acute pain in adult women and primary dysmenorrhea. Furthermore, the FDA also recommends using celecoxib as an adjunct therapy in patients with familial adenomatous polyposis to reduce the number of colorectal polyps. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of celecoxib, pertinent for clinicians and other interprofessional team members to allow for appropriate utilization of celecoxib.

Objectives:

• Outline the mechanism of action of celecoxib.
• Identify the approved and off-label indications for celecoxib.
• Summarize the potential adverse effects of celecoxib.
• Explain interprofessional team strategies for improving care coordination and communication to determine the appropriateness of celecoxib in the clinical setting.

Indications

Celecoxib has numerous indications, both FDA approved, and non-FDA approved.[1]

The FDA recommends celecoxib and other NSAIDs (non-steroidal anti-inflammatory drugs), along with acetaminophen, as first-line analgesics for patients with osteoarthritis and rheumatoid arthritis. Celecoxib also has an FDA indication for the management of acute pain in adult women and primary dysmenorrhea. Furthermore, the FDA also recommends using celecoxib as an adjunct therapy in patients with familial adenomatous polyposis to reduce the number of colorectal polyps.[2]

Off-label, celecoxib can be used for a wide variety of musculoskeletal and rheumatologic conditions, including ankylosing spondylitis, juvenile idiopathic arthritis, and gout. It is also being used increasingly in hospital protocols as part of a multimodal perioperative pain management regimen, frequently given pre-operatively along with adjunct pain medications, including acetaminophen and/or pregabalin.[3]

Mechanism of Action

Celecoxib is chemically designated as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The mechanism of action of celecoxib is due to selective inhibition of cyclooxygenase-2 (COX-2), which is responsible for prostaglandin synthesis, an integral part of the pain and inflammation pathway.[4] This pharmacologic activity gives celecoxib its analgesic, anti-inflammatory, and antipyretic effects. Celecoxib weakly inhibits COX-1 and, therefore, may affect platelet function less than aspirin.

Celecoxib also has anticancer properties discussed below and exerts its anticancer properties by binding cadherin-11 (CDH11), which likely plays a significant role in the malignant progression of cancerous cells.[5]

Celecoxib is extensively metabolized through cytochrome P450 2C9 (CYP2C9) and may have interactions with other medications that are substrates of CYP2C9.[6]

Administration

Celecoxib is a medication taken orally and comes in 50, 100, 200, and 400 mg doses. In rare cases, celecoxib can also be added to customized compounds for topical administration with or without the use of iontophoresis or other topical delivery mechanisms. It is not available via any other route of administration.

Dosing for approved indications is as follows:

Osteoarthritis: 200 mg orally daily, or alternatively, 100 mg twice daily.

Rheumatoid Arthritis: 100 to 200 mg by mouth twice daily, using the lowest effective dose.

Ankylosing Spondylitis: 200 mg by mouth daily. Dosing can increase to 400 mg. Always use the lowest effective dose for the shortest possible treatment duration. Prescribers should consider discontinuing the drug if there is no response at the highest dose after six weeks.

Dysmenorrhea: 200 mg by mouth twice daily. Dosing can increase to 400 mg. Always use the lowest effective dose for the shortest possible treatment duration. Prescribers should consider discontinuing the drug if there is no response at the highest dose after six weeks.

Acute Pain: 200 mg orally twice daily; patients can start with 400 mg for a single dose on day one of therapy, with an additional 200 mg on the first day if necessary.

All doses should be given with food if GI upset occurs. In patients who are poor CYP2C9 metabolizers, consider starting at 50% of the lowest dose. Avoid use in renal impairment of creatinine clearance is less than 30 mL/s. Also, avoid use in hepatic insufficiency if the patient isChild-Pugh Class C.

Adverse Effects

Like all NSAIDs, celecoxib carries an FDA boxed warning for cardiovascular risk, including the increased risk of heart attacks and strokes. As a selective COX-2 inhibitor, celecoxib also faces scrutiny for increased cardiovascular risk since another selective COX-2 inhibitor, rofecoxib, was withdrawn from production in 2004 due to cardiovascular risk concerns. Extensive reviews have had mixed results regarding whether celecoxib carries non-inferior or increased cardiovascular risk compared to ibuprofen and naproxen.[7][8]

Also, like all NSAIDs, celecoxib carries an additional FDA boxed warning for gastrointestinal (GI) effects, including bleeding, ulceration, and perforation of the stomach and intestines. This adverse effect makes it particularly dangerous to susceptible populations such as the elderly.[9]

In addition to these, celecoxib may cause new or worsening hypertension, fluid retention in patients with congestive heart failure, renal toxicity, liver toxicity, anaphylactic reactions, and skin changes ranging from a non-severe rash to Stevens-Johnson syndrome.

Contraindications

Due to its cardiovascular risk, celecoxib is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graph (CABG) surgery.

Celecoxib also contains a sulfonamide group and is contraindicated in patients who have demonstrated severe allergic reactions to drugs with a sulfonamide group, e.g., sulfamethoxazole. Studies have shown that allergies to sulfonamide antimicrobials are indeed a risk factor for allergic reactions to the sulfonamide chemical group. Non-antimicrobial drugs that contain a sulfonamide chemical group such as celecoxib, a history of penicillin allergy is at least as strong a risk factor for an allergic reaction. Thus, providers should understand that this phenomenon is likely not solely due to cross-reactivity of sulfonamide-containing antimicrobials and non-antimicrobials and that certain patients have an increased propensity to celecoxib allergy if they are allergic to any antimicrobial drug.[10]

Since CYP2C9 metabolizes celecoxib, its use requires caution in patients taking medicines that inhibit CYP2C9, for example, fluconazole, which is an antifungal drug.[6]

Like all NSAIDs, celecoxib should not be taken after 29 weeks of pregnancy.

Monitoring

Due to the risk for celecoxib to cause new or worsening hypertension, fluid retention in patients with congestive heart failure, renal toxicity, liver toxicity, anaphylactic reactions, and skin changes ranging from a non-severe rash to more severe reactions including Stevens-Johnson syndrome, prescribers need to monitor patients for adverse drug reactions. Prescribers should monitor a patient's blood pressure, renal and liver function and monitor for signs and symptoms of GI bleeding.

Patients taking such medications as lithium or warfarin should have the concentrations of these drugs monitored more carefully as well due to celecoxib's renal toxicity and inhibition of CYP2C9, respectively. Plasma concentrations of celecoxib are not routinely part of the monitoring to determine therapeutic efficacy.

Toxicity

Unfortunately, no antidotes for celecoxib overdose are available. However, celecoxib is a relatively safe medication overall. There were no reported overdoses of celecoxib during FDA trials, and doses up to 2400 mg per day for ten days did not result in severe toxicity.

Symptoms of celecoxib overdose would likely be similar to overdoses of other NSAIDs, which include lethargy, drowsiness, nausea, vomiting, and epigastric pain. Activated charcoal may be administered for overdose treatment at the discretion of emergency medical providers if the patient presents within 4 hours of known or suspected ingestion of significant amounts of celecoxib. Due to high plasma protein binding, dialysis, urine alkalinization, or diureses are unlikely to have a significant therapeutic effect on celecoxib overdose.[9]

Enhancing Healthcare Team Outcomes

Significant opportunities are available for improved interprofessional care coordination with regard to celecoxib.

As mentioned above, in the inpatient setting, celecoxib is increasingly being used as part of pre-operative and post-operative multimodal pain management algorithms. Research has shown in several small randomized trials that administering celecoxib peri-operatively for elective procedures such as total hip arthroplasties, total knee arthroplasties, and other procedures with some success in reducing pain and improving functionality such as early ambulation. The use of non-opioid medications to improve pain and function after surgery is becoming increasingly important due to societal and political pressure to reduce overall opioid analgesic consumption as a response to increasing rates of overdose deaths. It is, therefore, important for clinicians (including MDs, DOs, PAs, and NPs), nurses, pharmacists, physical and occupational therapists, and other support staff to coordinate a concerted effort to set patient-specific goals regarding pain and function in the acute care and rehabilitative settings and to reinforce how celecoxib use can help to achieve these goals to the patient. Clinicians and the interprofessional health care team must also maintain constant and open communication while monitoring the patient for improvements in pain and function and for possible adverse effects the patient may be experiencing. This interprofessional approach will yield the best therapeutic results while minimizing the chance of adverse events. [Level 5]

In the outpatient setting, prescribers of celecoxib must also coordinate with pharmacists to prevent and monitor for unsafe drug interactions and with the patient, family members, and caregivers to monitor therapeutic benefit and possible adverse drug effects. When the caregivers function as an interprofessional team, patients can obtain maximum benefit with celecoxib with minimal adverse effects.