Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor nonsteroidal anti-inflammatory drug (NSAID), demonstrates anti-inflammatory, analgesic, and antipyretic effects through inhibiting prostaglandin synthesis, predominantly by inhibiting COX-2. Like nonselective NSAIDs, celecoxib is associated with an increased risk of potentially fatal thrombotic cardiovascular events, including myocardial infarction and stroke. Therefore, celecoxib should be used cautiously in patients with cardiovascular disease or with risk factors for cardiovascular disease. To minimize the risk of celecoxib-associated cardiovascular events, the lowest celecoxib dose for the shortest treatment duration should be utilized. Celecoxib capsules are FDA-approved to manage ankylosing spondylitis, juvenile rheumatoid arthritis, osteoarthritis, acute pain, primary dysmenorrhea, and rheumatoid arthritis1-3. Celecoxib liquid is FDA approved for the acute treatment of migraine with or without aura in adult patients1,2,4.
Maximum recommended celecoxib doses are listed in Table 1. Dosages exceeding these recommendations will be reviewed.
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| celecoxib (Celebrex®) | 50 mg, 100 mg, 200 mg, 400 mg capsules | acute pain (including primary dysmenorrhea) | 400 mg/day* |
| ankylosing spondylitis | 400 mg/day | ||
| osteoarthritis | 200 mg/day | ||
| rheumatoid arthritis | 400 mg/day | ||
| celecoxib (Elyxyb®) | 120 mg/4.8 mL (25 mg/mL) oral solution | acute migraine (with or without aura) | 120 mg/day |
* An additional 200 mg dose may be given on the first day only to manage acute pain
Celecoxib is FDA-approved for use in pediatric patients 2 years of age and older with a diagnosis of juvenile rheumatoid arthritis (JRA), now also known as juvenile arthritis (JA) or juvenile idiopathic arthritis (JIA). However, celecoxib long-term cardiovascular toxicity as well as extended treatment for greater than six months have not been evaluated in pediatric patients. Therefore, the lowest celecoxib dose for the shortest treatment duration should be employed. Celecoxib safety and efficacy have not been determined in pediatric patients younger than 2 years of age1-3. Recommended celecoxib pediatric dosages are summarized in Table 2.
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| celecoxib (Celebrex®) | 50 mg, 100 mg capsules | juvenile rheumatoid arthritis (JRA)/ juvenile arthritis (JA)/juvenile idiopathic arthritis (JIA) |
Greater than or equal to 2 years of age:
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In patients with moderate hepatic impairment (Child-Pugh Class B), the celecoxib dose should be reduced by 50%. Celecoxib is not recommended for use in patients with severe hepatic impairment.
Due to the potential for increased cardiovascular and gastrointestinal adverse events, celecoxib and amlodipine/celecoxib should be prescribed as the lowest effective dose for the shortest treatment duration that satisfies patient treatment goals.
Elderly patients are frequently prescribed a COX-2 specific NSAID like celecoxib to manage acute and chronic pain. Several issues surface with COX-2 inhibitor use in elderly patients, including potential adverse effects and drug interactions. NSAID-induced gastrointestinal toxicity is prevalent in the elderly; therefore, COX-2 inhibitors like celecoxib or nonselective NSAIDs plus proton pump inhibitors may offer safer alternatives to these patients. Renal toxicity as well as adverse central nervous system effects are more prevalent in elderly patients due to changes in metabolism, underlying disease states, and concurrent drug therapy and should be considered prior to prescribing celecoxib, especially in higher doses. The potential for increased cardiovascular risk with COX-2 inhibitor use is also a factor when evaluating NSAID therapy in elderly patients. Elderly patients prescribed celecoxib, especially those at higher risk, should be evaluated for appropriateness of therapy as well as potential for drug-drug interactions. Appropriate therapy duration and dosages should also be assessed. Preventive measures such as gastric antisecretory agents administered should be considered in some individuals to reduce GI complications. Medication profiles of elderly patients greater than 60 years of age prescribed celecoxib in high doses or in patients with increased risk factors for adverse events or drug-drug interactions will be reviewed.
Some clinical trials have shown that patients prescribed selective and nonselective NSAIDs may be at increased risk for serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, all of which can be fatal. Patients at greater risk are those with known CV disease or risk factors for CV disease. Due to the lack of long-term clinical trial data, CV risks associated with NSAID use remains controversial, especially in high-risk patients. Risk also varies between nonselective NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, as well as between individual NSAIDs. The Center for Drug Evaluation and Research has determined that the increased risk of CV events associated with NSAID use should be considered a class effect for both selective and nonselective NSAIDs until more results are available. Patients should be prescribed the lowest effective NSAID dose for the shortest possible treatment duration to minimize the potential for cardiovascular adverse events.
NSAIDs may induce new onset hypertension or worsen pre-existing hypertension in some patients, which may contribute to the development of cardiovascular adverse events. Blood pressure should be routinely monitored in patients prescribed NSAIDs.
NSAIDs may cause fluid retention or edema in some patients and should be used cautiously in patients with a history of fluid retention or heart failure.
Like nonselective NSAIDs, celecoxib use may be associated with an increased risk of serious gastrointestinal (GI) adverse events, including potentially fatal GI bleeding, ulceration, or gastric/intestinal perforation. The risk of NSAID-associated severe GI adverse events increases in patients with a history of peptic ulcer disease, GI bleeding, smoking, alcohol use, concurrent use of anticoagulants or oral corticosteroids, advanced age, poor health and prolonged NSAID use. However, celecoxib may be associated with fewer GI adverse events due to selective COX-2 inhibition. Short-term trials (3 to 6 months) have shown celecoxib to be associated with significantly fewer GI complications compared to a nonselective NSAID plus a proton pump inhibitor (PPI) (e.g., diclofenac plus omeprazole) and a Cochrane review found significantly fewer ulcer complications with COX-2 inhibitors compared to nonselective NSAIDs. Chan and cohorts, in a randomized, double-blind trial, found that celecoxib administered concurrently with the PPI, esomeprazole, was significantly better in preventing ulcer bleeding in high risk patients compared to celecoxib monotherapy. In a case-control study, Patterson et al. observed that outpatients in the United States using commonly prescribed nonselective NSAIDs and COX-2 inhibitors from 1999 to 2003 were two times more likely to be hospitalized for peptic ulcer bleeding and perforation following nonselective NSAID use compared to those receiving celecoxib. Additionally, a recent small study suggests that lower GI bleeding may occur less frequently following COX-2 inhibitor use compared to that seen with nonselective NSAIDs. This study was criticized, though, as investigators used hemoglobin decrease rather than documented lower GI bleeds to assess outcomes. Further long-term studies are necessary to substantiate the perceived lower GI risk associated with COX-2 inhibitors.
The combined use of specific COX-2 inhibitors and nonspecific COX-1, COX-2 inhibitors does not provide additional therapeutic benefit and may result in additive adverse effects, including gastrointestinal toxicity. However, because celecoxib lacks antiplatelet effects, celecoxib may be used concurrently with low-dose aspirin prescribed for cardiovascular prophylaxis. While an increased incidence of gastrointestinal adverse effects has been observed with combined celecoxib-aspirin therapy, the combination is cautiously warranted due to the potential cardiovascular benefits. Concurrent therapy with celecoxib and nonspecific COX-1, COX-2 inhibitors other than low-dose aspirin is not recommended and will be reviewed.
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically significant for celecoxib are summarized in Table 3. Only those drug-drug interactions classified as clinical significance contraindicated or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level # |
|---|---|---|---|---|
| amlodipine/celecoxib | clopidogrel | combined administration may reduce clopidogrel antiplatelet activity and increase risk of thrombotic events as both medications are metabolized by the CYP3A4 enzyme (CYP3A4 converts clopidogrel to active metabolite) | administer cautiously together and observe patients for changes in clopidogrel efficacy | moderate (CP) |
| amlodipine/celecoxib | CYP3A4 inducers (e.g., rifampin) | adjunctive administration may result in reduced amlodipine serum levels and therapeutic efficacy due to induction of amlodipine metabolism by CYP system | observe patients for sustained therapeutic effects and adjust amlodipine dosages, if needed; may consider alternate therapy that does not induce CYP3A4 | moderate (CP) |
| amlodipine/celecoxib | CYP3A4 inhibitors (e.g., clarithromycin) | co-administration may result in enhanced amlodipine pharmacologic and adverse effects, including hypotension and acute kidney injury, as amlodipine is metabolized by CYP3A4 | use cautiously together, if at all; observe patients for amplified pharmacologic/ adverse effects; adjust dosages as necessary | major (CP) |
| amlodipine/celecoxib | simvastatin | due to an unknown mechanism, combined use may cause enhanced simvastatin availability (increased area under curve, maximum concentration) and increased pharmacologic/ adverse effects including myopathy and rhabdomyolysis | avoid combined use, if possible; if combined administration necessary, simvastatin dose should not exceed 20 mg/day; patients maintained on high-dose simvastatin who require amlodipine therapy should be converted to another statin with fewer interactions | major (CP) |
| amlodipine/celecoxib | tacrolimus | increased tacrolimus serum levels with possible enhanced pharmacologic/ adverse effects may result with combined use; tacrolimus is a CYP3A4 substrate with a narrow therapeutic index and amlodipine is weak CYP3A4 inhibitor | use cautiously together; monitor patients for tacrolimus adverse effects (e.g., renal dysfunction, cholestasis, paresthesias) | moderate (CP) |
| celecoxib | ACE inhibitors, angiotensin receptor blockers | potential for decreased antihypertensive effects, increased renal impairment risk with combined therapy; NSAIDs may block production of vasodilator and natriuretic prostaglandins | monitor blood pressure and renal function, modify therapy as needed; use combination cautiously in elderly; nonacetylated salicylates, sulindac, may be alternative NSAIDS – have less inhibitory effect on prostaglandin synthesis | moderate (CP) |
| celecoxib | anticoagulants/ aspirin/ thrombolytic agents | potential for increased gastrointestinal and bleeding adverse effects most likely due to either additive effects and/or decreased platelet function | administer combination cautiously and observe for adverse bleeding events | major (CP) |
| celecoxib | corticosteroids | potential for increased gastrointestinal adverse effects with combined therapy | monitor for adverse effects; avoid prolonged concurrent administration | moderate (CP) |
| celecoxib | CYP2C9 inhibitors (e.g., fluconazole, amiodarone, delavirdine) | celecoxib metabolized by CYP2C9; combination may increase celecoxib serum levels and potential for toxicity | use cautiously together with lowest effective celecoxib dose; monitor for adverse effects | moderate (CP) |
| celecoxib | immune suppressants | celecoxib may mask infection symptoms (e.g., fever, swelling) | use combination cautiously | moderate (CP) |
| celecoxib | lithium | NSAIDs may decrease lithium clearance by blocking renal tubular prostaglandins (may contribute to lithium clearance; may result in increased lithium levels and potential for adverse effects | avoid combination, if possible; if concurrent therapy necessary, monitor lithium levels and signs/ symptoms of lithium toxicity; sulindac, aspirin do not affect lithium clearance -may be alternative NSAIDS | moderate (CP) |
| celecoxib | loop diuretics (e.g., furosemide) | potential for impaired diuretic and antihypertensive activity of loop diuretic and increased risk of renal insufficiency due to NSAID-associated decreased renal prostaglandin production | administer combination cautiously; monitor for signs/symptoms of renal dysfunction and reduced diuretic/ antihypertensive efficacy | moderate (CP) |
| celecoxib | methotrexate | adjunctive administration may lead to increased methotrexate serum levels and the potential for adverse effects (e.g., hematologic, gastrointestinal toxicity), especially with higher methotrexate doses, due to NSAID- associated reductions in renal methotrexate clearance | administer combination cautiously together; observe for enhanced methotrexate pharmacologic and adverse events | major (CP) |
| celecoxib | SNRIs/SSRIs | concurrent administration may increase risk of enhanced bleeding activity as serotonin release from platelets necessary for adequate hemostasis | monitor for signs/symptoms of bleeding with adjunctive administration | moderate (CP) |
| celecoxib | warfarin | combined therapy may result in increased INR and increased risk of gastrointestinal adverse effects, especially in elderly, most likely due to competition for metabolism through CYP2C9 | monitor anticoagulant activity, especially in first several days of combination therapy; adjust warfarin doses as necessary | major (CP) |
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