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 ketorolac are summarized in Table 1. 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 # |
|---|---|---|---|---|
| ketorolac | pentoxifylline | adjunctive administration may increase bleeding risk, due to unknown mechanism | combined therapy contraindicated | severe (CP) |
| ketorolac | phenytoin | concurrent administration increases seizure risk due to unknown mechanism; ketorolac may displace phenytoin from binding sites | monitor for seizures, signs/symptoms of phenytoin toxicity; adjust phenytoin doses as necessary | moderate (CP) |
| ketorolac | probenecid | combined administration may increase ketorolac serum concentrations and potential for enhanced pharmacologic/adverse effects due to decreased ketorolac clearance | adjunctive administration contraindicated | severe (CP) |
| NSAIDs | antihypertensive agents (e.g., angiotensin converting enzyme 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 | moderate (CP) |
| 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 (CP) |
| 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 (CP) |
| NSAIDs | corticosteroids | potential for increased GI adverse effects with combined therapy | monitor for adverse effects; avoid prolonged concurrent administration | moderate (CP) |
| 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 and signs/symptoms of cyclosporine toxicity (e.g., renal dysfunction, cholestasis, paresthesias) | moderate (CP) |
| NSAIDs | fluoroquinolones | increased risk for seizures, potentially due to inhibition of gamma aminobutyric acid (GABA) which results in CNS stimulation | administer cautiously together; consider alternative therapy in patients with predisposition to seizures | moderate (CP) |
| NSAIDs | lithium | NSAIDs like ketorolac decreases lithium clearance 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 when ketorolac therapy initiated or discontinued | moderate (CP) |
| 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 (CP) |
| NSAIDs | methotrexate (MTX) | potential for increased MTX serum levels, risk of enhanced pharmacologic/toxic effects as NSAIDs like ketorolac can reduce MTX clearance | avoid concurrent NSAIDs prior to, concurrently or following intermediate or high-dose MTX; use cautiously together with low-dose MTX; monitor for increased myelopsuppressive, GI adverse effects; may consider using longer leucovorin rescue | severe (CP) |
| 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 shorter treatment duration, adding proton pump inhibitor, or substituting tricyclic antidepressant for SSRI/SNRI or acetaminophen for NSAID | moderate (CP) |
| NSAIDs | sulfonylureas | increased risk for additive hypoglycemia due to inhibition of sulfonylurea metabolism | monitor serum glucose concentrations; adjust doses as necessary | moderate (CP) |
| 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 (CP) |
| NSAIDs | warfarin | combined therapy may increase risk of GI bleeding as NSAIDs, including ketorolac, inhibit platelet aggregation and may cause gastric erosion | monitor anticoagulant activity and signs of bleeding, especially in first several days of combination therapy; adjust warfarin doses as necessary | major (CP) |
Legend:
- * Clinical Pharmacology
- NSAIDs = nonsteroidal anti-inflammatory drugs
- SNRIs = serotonin-norepinephrine reuptake inhibitors
- SSRIs = selective serotonin reuptake inhibitors