What are the potential drug interactions with celecoxib (Celebrex), especially in patients with a history of cardiovascular disease, hypertension, or impaired renal function?

Important Drug Interactions with Celecoxib

Celecoxib has critical drug interactions that significantly increase cardiovascular, renal, and bleeding risks, particularly when combined with anticoagulants, antiplatelet agents, ACE inhibitors, ARBs, diuretics, and other NSAIDs. 1

Anticoagulants and Antiplatelet Agents

Avoid combining celecoxib with warfarin, aspirin (at analgesic doses), or other antiplatelet drugs due to substantially increased bleeding risk. 1

• Concomitant use of celecoxib with anticoagulants (warfarin) or antiplatelet drugs (aspirin, clopidogrel) increases serious bleeding risk compared to either drug alone 1
• The combination of celecoxib with SSRIs or SNRIs further potentiates bleeding risk beyond celecoxib alone, as these medications interfere with serotonin-mediated platelet function 1
• Critical exception: Celecoxib does NOT interfere with low-dose aspirin's cardioprotective antiplatelet effect (unlike ibuprofen), but the combination still increases GI bleeding risk and is not generally recommended 2, 1
• If aspirin is required for cardiovascular protection, celecoxib is not a substitute and patients need both medications with appropriate gastroprotection 1

ACE Inhibitors, ARBs, and Beta-Blockers

Monitor blood pressure and renal function closely when combining celecoxib with ACE inhibitors, ARBs, or beta-blockers, as celecoxib diminishes their antihypertensive effects and increases acute renal failure risk. 1

• Celecoxib may reduce the antihypertensive efficacy of ACE inhibitors, ARBs, and beta-blockers (including propranolol) 1
• In elderly patients, those on diuretics, or those with volume depletion or renal impairment, combining celecoxib with ACE inhibitors or ARBs can cause acute renal failure 1
• The American Heart Association emphasizes that renal function and blood pressure must be monitored when celecoxib is given to patients with preexisting hypertension, renal disease, or heart failure 2
• Ensure adequate hydration and assess renal function at the beginning of concomitant treatment and periodically thereafter 1

Diuretics

Celecoxib reduces the natriuretic and antihypertensive effects of both loop and thiazide diuretics while increasing renal toxicity risk. 1

• NSAIDs including celecoxib inhibit renal prostaglandin synthesis, which reduces the effectiveness of furosemide and thiazide diuretics 1
• Monitor for signs of worsening renal function and reduced diuretic efficacy, including inadequate blood pressure control 1
• The National Kidney Foundation advises avoiding celecoxib when combining with ACE inhibitors and beta-blockers, as approximately 2% of patients develop renal complications requiring discontinuation 3

Digoxin

Monitor digoxin levels closely, as celecoxib increases serum digoxin concentration and prolongs its half-life. 1

• Concomitant use requires regular monitoring of serum digoxin levels to prevent toxicity 1

Lithium

Celecoxib increases plasma lithium levels by approximately 15% and decreases renal lithium clearance by 20%. 1

• Monitor patients for signs of lithium toxicity during concomitant use 1
• This effect results from NSAID inhibition of renal prostaglandin synthesis 1

Methotrexate

Combining celecoxib with methotrexate increases methotrexate toxicity risk, including neutropenia, thrombocytopenia, and renal dysfunction. 1

• Monitor patients for methotrexate toxicity during concomitant use, though celecoxib does not affect methotrexate pharmacokinetics 1

Cyclosporine

Celecoxib increases cyclosporine's nephrotoxicity through additive effects on renal prostaglandin inhibition. 1

• Monitor for signs of worsening renal function during concomitant use 1

Other NSAIDs and Salicylates

Never combine celecoxib with other NSAIDs or salicylates (diflunisal, salsalate), as this increases GI toxicity without improving efficacy. 1

• Concomitant use is not recommended due to increased GI bleeding and ulceration risk 1
• The American Gastroenterological Association notes that elderly patients already face 2-3.5-fold increased GI complication risk with single NSAID use, which would be amplified by dual therapy 4

Pemetrexed

In patients with creatinine clearance 45-79 mL/min, avoid celecoxib for 2 days before, the day of, and 2 days after pemetrexed administration. 1

• Concomitant use increases risk of pemetrexed-associated myelosuppression, renal, and GI toxicity 1
• Monitor for these toxicities in patients with renal impairment 1

CYP2C9 Inhibitors and Inducers

Fluconazole and other CYP2C9 inhibitors increase celecoxib exposure and toxicity, while CYP2C9 inducers (rifampin) reduce celecoxib efficacy. 1

• Celecoxib metabolism is predominantly mediated via CYP2C9 in the liver 1
• Dose adjustment may be necessary when combining with strong CYP2C9 inhibitors or inducers 1

High-Risk Patient Populations Requiring Extra Caution

Patients with cardiovascular disease, recent MI, or bypass surgery have an estimated excess mortality risk of 6 deaths per 100 person-years when treated with celecoxib. 2

• The American College of Cardiology suggests avoiding celecoxib entirely in patients with established cardiovascular disease, congestive heart failure, or elevated cardiovascular risk 3
• Use only the lowest recommended dose for the shortest duration necessary in high-risk patients 2
• Celecoxib may increase blood pressure by approximately 5 mm Hg 3, 4
• The American Geriatrics Society recommends avoiding celecoxib entirely in elderly patients with cardiovascular disease, heart failure, or renal impairment 3

Renal Monitoring Requirements

Monitor renal function in all patients with preexisting renal disease, heart failure, hepatic dysfunction, elderly patients, and those on diuretics, ACE inhibitors, or ARBs. 1, 5

• Approximately 2% of patients require NSAID discontinuation due to renal complications 3, 4
• Serious or life-threatening renal failure has been reported after short-term celecoxib therapy in patients with both normal and impaired renal function 5
• Avoid celecoxib in patients with advanced renal disease unless benefits outweigh risks 1, 5