4. Drug-Drug Interactions
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) |
Legend:
- * - Clinical Pharmacology
- ACE - angiotensin converting enzyme
- NSAIDs - nonsteroidal anti-inflammatory drugs
- SNRIs - serotonin norepinephrine reuptake inhibitors
- SSRIs - selective serotonin reuptake inhibitors