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 NSAIDs are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level # |
|---|---|---|---|---|
| NSAIDs | antihypertensive agents (e.g., ACE inhibitors, angiotensin receptor blockers, beta blockers, diuretics) | potential for decreased antihypertensive effects, increased renal impairment risk (especially in patents dependent on renal prostaglandins for perfusion), with combined therapy; increased hyperkalemia risk with potassium-sparing diuretics; NSAIDs may block production of vasodilator and natriuretic prostaglandins | monitor blood pressure, renal function; observe for hyperkalemia with potassium-sparing diuretics; modify therapy as necessary; use combination cautiously in elderly; sulindac, nonacetylated salicylates may be alternative NSAIDS – have less inhibitory effect on prostaglandin synthesis | major |
| NSAIDs | antiplatelet drugs (e.g., clopidogrel, prasugrel) | potential for increased bleeding risk due to additive inhibitory effects on platelet aggregation | administer cautiously together; monitor for increased bleeding, especially gastrointestinal (GI) bleeding | moderate |
| NSAIDs | aspirin (ASA) | combined therapy may result in reduced ASA antiplatelet/ cardioprotective effects due to competitive inhibition of COX-1 binding site | ASA should be administered at least 30 minutes before or 8 hours after NSAID; NSAID should be given at least 1 hour after enteric-coated ASA | moderate |
| NSAIDs | bisphosphonates | combined therapy may result in additive GI, renal toxicity; NSAIDs also decrease bone mineral density, may attenuate bone mineral stabilizing effects by bisphosphonates | administer combination cautiously; monitor for increased GI/renal adverse effects, reduced bone mineral density | major |
| NSAIDs | corticosteroids | potential for increased GI adverse effects with combined therapy | monitor for adverse effects; avoid prolonged concurrent administration | 3-moderate (CP) |
| NSAIDs | cardiac glycosides (e.g. digoxin) | decreased renal function, such as eGFR or tubular secretion, caused by NSAIDs | may impair digoxin excretion monitor for signs and symptoms of digoxin toxicity | moderate |
| NSAIDs | cidofovir | increased risk for nephrotoxicity with concomitant administration | discontinue NSAIDs 7 days prior to starting cidofovir | contraindicated |
| NSAIDs | cyclosporine | increased risk for additive renal dysfunction with concurrent administration; potential for reduced cyclosporine elimination/ increased pharmacologic and adverse effects due to NSAID effects on renal prostaglandins; NSAIDs may mask signs of infection (e.g., fever, swelling) | use cautiously together; monitor clinical status, renal function, serum potassium concentrations | moderate |
| NSAIDs | fluoroquinolones | increased risk for CNS stimulation and seizures | administer cautiously together; consider alternative therapy in patients with predisposition to seizures | moderate |
| NSAIDs | ketorolac | increased risk for adverse cardiovascular events | avoid combination | contraindicated |
| NSAIDs | lithium | NSAIDs may decrease lithium clearance most likely by blocking renal tubular prostaglandins; 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 |
| NSAIDs | low molecular weight heparins | potential for additive bleeding adverse effects; NSAIDs inhibit platelet aggregation and have increased GI bleeding risk, prolonged bleeding time | avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding | major |
| NSAIDs | methotrexate (MTX) | potential for increased MTX serum levels, risk of enhanced pharmacologic/toxic effects as NSAIDs can reduce MTX clearance | avoid concurrent NSAIDs within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelopsuppressive, GI adverse effects; may consider using longer leucovorin rescue | moderate |
| NSAIDs | phenytoin | NSAIDs may inhibit phenytoin metabolism, with increased risk for enhanced phenytoin pharmacologic/toxic effects (e.g., ataxia, nystagmus, hyperreflexia) | monitor for signs/symptoms of phenytoin toxicity, especially in patients with renal impairment; adjust doses as necessary | moderate |
| NSAIDs | select azole antifungals (e.g., fluconazole, voriconazole) | for NSAIDs metabolized by CYP2C9, increased risk of elevated NSAID plasma levels and potential for enhanced pharmacologic/adverse effects; select antifungals inhibit CYP2C9 | administer cautiously together; monitor for increased NSAID pharmacologic/adverse effects (e.g., bleeding, renal dysfunction); consider reduced NSAID doses, if necessary, or alternate NSAID/antifungal that does not affect metabolism | moderate |
| NSAIDs | SSRIs/SNRIs (e.g., milnacipran) | increased bleeding risk with combined therapy, especially GI bleeding; SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation | monitor for signs/symptoms of bleeding; may consider lower NSAID doses, shorter treatment durations, adding proton pump inhibitor, or substituting tricyclic antidepressant for SSRI/SNRI | moderate |
| NSAIDs | sulfonylureas | increased risk for additive hypoglycemia | monitor serum glucose concentrations; adjust doses as necessary | moderate |
| NSAIDs | tacrolimus | potential for additive nephrotoxicity with combined therapy due to NSAID inhibitory effects on renal prostaglandins | avoid combination, if possible; if concurrent therapy necessary, closely monitor renal function | moderate |
| NSAIDs | warfarin | combined therapy may result in increased INR and increased risk of GI adverse effects, especially in elderly; mechanism unknown | monitor anticoagulant activity, especially in first several days of combination therapy; adjust warfarin doses as necessary | moderate |
Legend:
- # CP = Clinical Pharmacology