Criteria for Outpatient Use Guidelines

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[Developed, February 1995; Revised, October 1995; October 1996; September 1997; September 1998; September 1999; October 2000; September 2001; October 2002; October 2003; January 2009; May 2011 ]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Ketorolac is FDA-approved for short-term management of acute moderate to severe pain, usually in the postoperative setting, that requires pain management at the opioid level.

Oral ketorolac is only approved for use after therapy initiation with intravenous or intramuscular ketorolac. Therefore, a prescription for a parenteral form of ketorolac should precede treatment with oral ketorolac to satisfy manufacturer and FDA recommendations.

The maximum recommended dosage for oral ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), is 40 mg/24 hours given in divided doses every 4 to 6 hours. Dosages exceeding this recommendation will be reviewed.

Pediatrics
Oral ketorolac is not FDA-approved for pediatric patients younger than 17 years of age as safety and efficacy in this age group have not been established.

2.* Duration of Therapy

1. Therapy Limits
   The maximum duration of treatment for oral and parenteral ketorolac, combined, is five days due to the increased frequency and severity of adverse effects associated with extended use.  Treatment regimens exceeding these requirements will be reviewed.
   
   
2. NSAID Use and Elderly Patients
   Elderly patients frequently utilize prescription and nonprescription NSAIDs to manage acute and chronic pain. Several issues surface with NSAID use in elderly patients, including potential adverse effects and drug interactions.  NSAID-induced gastrointestinal and 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.  The potential for increased cardiovascular risk with NSAID use is also a factor when evaluating NSAID therapy in elderly patients.  Elderly patients prescribed NSAIDs, especially those at higher risk, should be evaluated for appropriateness of therapy as well as potential for drug-drug interactions.  Appropriate ketorolac therapy duration as well as appropriate dosages should also be evaluated.
   
   
3. NSAID Use and Cardiovascular Risk
   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, 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.

3.* Duplicative Therapy

The use of oral ketorolac in combination with aspirin or other NSAIDs is contraindicated as combined therapy may result in an increased risk of gastrointestinal (GI) adverse effects and may also increase serum ketorolac levels.  Therefore, concurrent use of ketorolac with these agents will be reviewed.

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:

Table 1
Ketorolac Drug-Drug Interactions

TARGET DRUG	INTERACTING DRUG	INTERACTION	RECOMMENDATIONS	CLINICAL SIGNIFICANCE
ketorolac	lithium	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 (DrugReax) 3-moderate (CP) 2 (DIF)
ketorolac	pentoxifylline	adjunctive administration may increase bleeding risk, due to unknown mechanism	combined therapy contraindicated	contraindicated (DrugReax) 1-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	major (DrugReax) 3-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	contraindicated (DrugReax) 1-severe (CP) 1 (DIF)
ketorolac	warfarin	combined therapy may increase risk of GI bleeding as ketorolac inhibits 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	moderate (DrugReax) 2-major (CP) 1 (DIF)
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  natiuretic 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 (DrugReax) 3-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	clopidogrel –major; prasugrel - moderate (DrugReax) 3-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	2-major (CP) 4 (DIF)
NSAIDs	corticosteroids	potential for increased GI adverse effects with combined therapy	monitor for adverse effects; avoid prolonged concurrent administration	3-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 (DrugReax) 3-moderate (CP) 4 (DIF)
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 (DrugReax) 3-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 (DrugReax) 2-major (CP) 2 (DIF)
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	major (DrugReax) 1-severe (CP) 1 (DIF)
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	major, moderate (DrugReax) 3-moderate (CP) 2 (DIF)
NSAIDs	sulfonylureas	increased risk for additive hypoglycemia due to inhibition of sulfonylurea metabolism	monitor serum glucose concentrations; adjust doses as necessary	moderate (DrugReax)
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	major (DrugReax) 3-moderate (CP)

 

References

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.