AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Ketorolac Tromethamine

• Ketorolac

Ketorolac is a prototypical nonsteroidal anti-inflammatory agent (NSAIA)1,2,3,21,32,33,70,91,92,93,96,140 that also exhibits analgesic and antipyretic activity.2,21,32,33,70,83

Pain

Ketorolac tromethamine is used parenterally or as a sequential regimen of parenteral followed by oral therapy for the short-term (i.e., up to 5 days) management of moderately severe, acute pain, usually in a postoperative setting, that requires analgesia at the opiate level.1,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,68,70,71,72,73,74,75,76,91,92,93,101,207,1201 Ketorolac tromethamine also is used intranasally for the short-term (i.e., up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opiate level.208 The manufacturer states that the drug is not indicated for use in minor or chronic painful conditions.1,154

The potential benefits and risks of ketorolac therapy as well as alternative therapies should be considered prior to initiating ketorolac therapy.198 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.198

Ketorolac tromethamine has been used for the symptomatic relief of moderate to severe postoperative pain, including that associated with abdominal, gynecologic, oral, ophthalmologic, orthopedic, urologic, or otolaryngologic surgery.1,47,48,49,50,51,52,54,55,56,57,58,59,60,61,68,70,71,72,73,74,75,76,91,99,101,159,161,162,165,196,197 Ketorolac tromethamine should not be used in obstetric patients as a preoperative medication or for analgesia during labor since inhibitors of prostaglandin synthesis (e.g., ketorolac tromethamine) may affect uterine contractions and fetal circulation.1,91,140 In addition, ketorolac tromethamine should not be used as a preoperative medication for support of anesthesia, since the drug does not have sedative or anxiolytic effects but may inhibit platelet aggregation and prolong bleeding time.1 Ketorolac tromethamine also has been used for the relief of acute renal colic,70,91,140,163 pain associated with trauma,70 pain associated with vaso-occlusive crisis of sickle-cell disease,155,156 and visceral pain associated with cancer.53,70,81,140,160,164 IM ketorolac tromethamine generally produces analgesia comparable to that of moderate IM doses of opiate analgesics.1,47,48,50,51,54,68,70,72,91,92,99,138 However, unlike opiate agonists,25,36 ketorolac tromethamine does not appear to cause respiratory depression1,25,26,35,140 and there is no evidence that therapy with ketorolac tromethamine results in physical dependence on the drug.1,2,56,100,103,140

When used to relieve moderate to severe pain in adults, a single 10-mg IM dose of ketorolac tromethamine has been reported to be more effective than placebo51,53 and at least as effective as a single 6-mg IM dose of morphine sulfate,1,47,48,70,91,92,140 a single 30-mg IM dose of pentazocine,51,70,91 or a single 50- or 100-mg IM dose of meperidine hydrochloride.1,72 A single 30-mg IM dose of ketorolac tromethamine has been reported to be more effective than placebo53 or a single 6-mg IM dose of morphine sulfate1,47,48,70,99,140 and at least as effective as a single 12-mg IM dose of morphine sulfate,1,47,48,50,91,92,99,140 a single 30-mg IM dose of pentazocine,51,91,140 or a single 50- to 100-mg IM dose of meperidine hydrochloride.1,54,68,72,91,92,140 The duration of analgesia produced by single IM doses of ketorolac tromethamine appears to be longer than that of single IM doses of morphine sulfate1,47,50,91,92 or meperidine hydrochloride.1,68,91

In a short-term (up to 5 days) multiple-dose study in adults with moderate to severe postoperative pain, IM ketorolac tromethamine doses of 30 mg were more effective than IM morphine sulfate doses of 6 mg and as effective as IM morphine sulfate doses of 12 mg; the drugs were administered at an average frequency of every 5-6 hours.91,134,140 When used to relieve severe sciatic pain†, IM ketorolac tromethamine dosages of 30 mg 4 times daily have been at least as effective as IM ketoprofen dosages of 100 mg twice daily.70

Parenteral ketorolac tromethamine has been used concomitantly with opiate agonist analgesics (e.g., meperidine, morphine) for the management of moderate to severe postoperative pain without apparent adverse drug interactions.1,91 Combined use of the drugs can result in reduced opiate analgesic requirements.1,49 Ketorolac tromethamine also has been administered concomitantly with non-opiate analgesics (e.g., aspirin, acetaminophen),91 but the manufacturer states that use of the drug with other NSAIAs is contraindicated because of the potential for additive adverse effects.1,91,92,154

In postoperative patients receiving morphine via patient-controlled analgesia, those receiving fixed intermittent doses of IV ketorolac tromethamine (initial dose of 30 mg, followed by 15 mg every 3 hours) required 26% less morphine and achieved superior pain relief compared with those receiving placebo.1201

Ketorolac tromethamine also is used orally in adults for the symptomatic relief of moderate to severe pain such as postpartum,83 postoperative (including that associated with oral, orthopedic, or gynecologic surgery),1,55,56,57,58,71,73,75,76 orthopedic (including musculoskeletal strains or sprains),70 or sciatic pain70 and for visceral pain associated with cancer.70 When used to relieve moderate to severe pain in adults, a single 5-mg oral dose of ketorolac tromethamine has been reported to be more effective than placebo83 and as effective as a single 500-mg or 1-g oral dose of acetaminophen.55 A single 10-mg oral dose of ketorolac tromethamine has been reported to be more effective than placebo75,76 and at least as effective as single oral doses of acetaminophen 500 mg, 600 mg, or 1 g;1,55,70,75 aspirin 650 mg;1,70,71,73,75,83 pentazocine 100 mg;58,70 dihydrocodeine 30 mg;59,70 naproxen 550 mg;1,70,76 ibuprofen 400 mg;1,70,75 acetaminophen 600 mg or 1 g with codeine phosphate 60 mg;1,56,70,75 or propoxyphene napsylate 300 mg with aspirin 700 mg and antipyrine 300 mg.57 A single 20-mg oral dose of ketorolac tromethamine was more effective than placebo,73,75 a single 500- or 600-mg oral dose of acetaminophen,1,55,75 or a single 650-mg oral dose of aspirin1,71,73 and at least as effective as a single 1-g oral dose of acetaminophen,55 a single 400-mg oral dose of ibuprofen,1,75 a single 650-mg oral dose of aspirin with 60 mg of codeine phosphate,70,71,73 or a single 600-mg oral dose of acetaminophen with 60 mg of codeine phosphate.1,75

Oral ketorolac tromethamine dosages of 560,70 or 1060 mg 4 times daily have been as effective as oral diflunisal dosages of 500 mg twice daily. Oral ketorolac tromethamine dosages of 10 mg given up to 4 times daily have been as effective as oral pentazocine dosages of 100 mg given up to 4 times daily,58,70 oral dihydrocodeine dosages of 30 mg given up to 4 times daily,59 or oral acetaminophen dosages of 1 g with oral codeine phosphate dosages of 60 mg given up to 4 times daily.56 When used to relieve orthopedic (including musculoskeletal strains or sprains) pain, oral ketorolac tromethamine dosages of 10 mg 4 times daily have been at least as effective as oral diclofenac sodium dosages of 50 mg 3 times daily, oral ibuprofen dosages of 400 mg 4 times daily, oral diflunisal dosages of 500 mg twice daily, or oral acetaminophen dosages of 600 mg with oral codeine phosphate dosages of 60 mg 4 times daily.70

Long-term† (e.g., up to 1 year)137 oral ketorolac tromethamine therapy at dosages of 10 mg given up to 4 times daily has been used in adults to relieve chronic pain, including that associated with osteoarthritis, fibromyopathies, fibromyalgias, or tension headaches,70,176 and was more effective than chronic aspirin therapy at dosages of 650 mg given up to 4 times daily.70,74,176 However, the manufacturer states that total combined duration of parenteral and oral ketorolac tromethamine therapy in adults should not exceed 5 days,1,154 and, therefore, the drug is not indicated for the management of chronic pain.

In adults undergoing elective abdominal or orthopedic surgery, postoperative therapy with ketorolac tromethamine 31.5 mg administered intranasally every 6 or 8 hours reduced postoperative pain intensity over 48 hours compared with placebo; ketorolac-treated patients required 26-36% less morphine administered via patient-controlled analgesia on an as-need basis for pain relief over the 48-hour period than did those receiving placebo.208,209,210

Ophthalmic Uses

For ophthalmic uses of ketorolac tromethamine, see 52:08.20.

Administration

The potential benefits and risks of ketorolac therapy as well as alternative therapies should be considered prior to initiating ketorolac therapy.198

Ketorolac tromethamine is administered by IM or IV injection,1,23,47,48,49,50,51,52,53,54,154,156,161,162,163,164,165 orally,1,55,56,57,58,59,60,61 or intranasally.208

Parenteral and Oral Administration

Ketorolac tromethamine is administered by IM or IV injection.1,23,47,48,49,50,51,52,53,54,154,156,161,162,163,164,165 The drug also is administered orally.1,55,56,57,58,59,60,61 Therapy should be initiated with parenteral (i.e., IV or IM) ketorolac, with the oral formulation used as continuation therapy, as required.1,154 The total duration of parenteral and oral ketorolac therapy should not exceed 5 days.1,154 Patients should be switched to alternate analgesic therapy as soon as clinically possible.1,154

IV administration of ketorolac tromethamine injection must be given over no less than 15 seconds.1 IM injection of ketorolac should be given slowly, via deep IM injection.1 While administration with food may delay and reduce peak plasma concentrations following oral administration, the extent of GI absorption of the drug is not affected.1 Concomitant administration of ketorolac tromethamine and antacids does not appear to affect oral absorption of the NSAIA.1

Parenteral solutions of ketorolac tromethamine should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.1

Intranasal Administration

Ketorolac tromethamine nasal solution is administered using a metered-dose spray pump.208 Prior to initial use, the spray pump must be primed.208 The patient instructions provided by the manufacturer should be consulted for use of the nasal spray pump.208 Because the nasal spray is not an inhalation product, the patient should be instructed not to inhale during administration.208 Contact of the solution with the eyes should be avoided; if such contact occurs, the affected eye(s) should be rinsed with water or saline, and a clinician should be consulted if ocular irritation persists for more than one hour.208

Each bottle should be used for only 24 hours and then discarded; the manufacturer states that the spray pump will not deliver the intended dose after 24 hours.208

The total duration of therapy with ketorolac nasal spray alone or sequential therapy that includes the nasal spray and oral or parenteral formulations of ketorolac should not exceed 5 days.208

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.198

Current principles of pain management indicate that analgesics, including ketorolac tromethamine, preferably should be administered at regularly scheduled intervals, although the drug also has been administered on an as-needed basis (i.e., withholding subsequent doses until pain returns).1,91,140 The manufacturer states that clinicians should manage breakthrough pain in adults receiving ketorolac tromethamine therapy with supplemental low doses of opiate analgesics (unless contraindicated) as needed rather than considering higher or more frequent dosages of ketorolac tromethamine.1,142

Because there is some evidence of dose-related adverse effects (e.g., GI bleeding), particularly in geriatric patients, the lowest possible effective ketorolac tromethamine dosage should be employed, and total duration of therapy with the drug (including parenteral, oral, and intranasal formulations) should not exceed 5 days.1,137,142,143,154,208 Particular caution and reduced dosage should be employed in geriatric patients, adults weighing less than 50 kg, and those with renal impairment (see Dosage in Renal and Hepatic Impairment under Dosage and Administration).1,137,142,143,154,207,208,1201 Elimination of the drug generally is slower and sensitivity to adverse renal effects of NSAIAs generally is increased in geriatric patients.1,154

Parenteral and Oral Dosage

For the short-term management of moderately severe, acute pain that requires analgesia at the opiate level in adults, a single IM or IV ketorolac tromethamine dose of 60 or 30 mg, respectively, is recommended by the manufacturer.1,91,92,140,154,1201 For geriatric patients (65 years of age or older) and adults weighing less than 50 kg, the manufacturer recommends a single IM or IV dose of 30 or 15 mg, respectively.1,91,92,142,154 Such single-dose parenteral ketorolac tromethamine may be followed by oral ketorolac therapy in adults.1,154

The manufacturer recommends that multiple-dose parenteral ketorolac tromethamine therapy be both initiated and continued with IM or IV dosages of 30 mg every 6 hours in adults; the maximum daily dose should not exceed 120 mg.1,154 For multiple-dose parenteral therapy in geriatric patients (65 years of age and older) and adults weighing less than 50 kg, the manufacturer recommends 15 mg of ketorolac tromethamine every 6 hours;1,154 the maximum daily dose in these patients should not exceed 60 mg.1,154

Adults receiving parenteral ketorolac tromethamine who have experienced pain relief without limiting adverse effects may be switched to oral ketorolac tromethamine therapy, if needed.1,142 The manufacturer states that oral ketorolac tromethamine should be used only as continuation therapy following parenteral ketorolac therapy.1,154 Adults 17-64 years of age who are being switched from parenteral ketorolac tromethamine to oral therapy with the drug should receive a first oral dose of 20 mg, followed by 10 mg every 4-6 hours as needed.1,154,207 Geriatric patients (65 years of age or older) or adults weighing less than 50 kg who are being switched from parenteral ketorolac tromethamine to oral therapy with the drug should receive 10 mg of ketorolac tromethamine orally every 4-6 hours as needed.1,154,207 The dosing interval should not be shorter than 4-6 hours.207 The manufacturer states that the daily oral dosage in any patient should not exceed 40 mg in a 24-hour period.1,154 Low supplemental doses of an opiate agonist may be administered concomitantly with ketorolac tromethamine if breakthrough pain occurs, unless administration of an opiate agonist is contraindicated.1

Intranasal Dosage

Ketorolac tromethamine nasal spray pump delivers 15.75 mg of ketorolac tromethamine per spray and 8 sprays per single-day bottle.208

For the short-term management of moderate to moderately severe pain that requires analgesia at the opiate level in adults, the recommended intranasal dosage of ketorolac tromethamine is 31.5 mg (one spray in each nostril) every 6-8 hours; the maximum daily dosage is 126 mg (4 doses).208 Geriatric patients (65 years of age or older) and adults who weigh less than 50 kg should receive 15.75 mg (one spray in only one nostril) every 6-8 hours; the maximum daily dosage in these patients is 63 mg (4 doses).208

Dosage in Renal and Hepatic Impairment

Renal Impairment

Since ketorolac and its metabolites are excreted mainly by the kidneys, dosage adjustment may be required in geriatric patients and in other patients with reduced renal function.1,70,91,92,142,150

When ketorolac is used parenterally in adults with renal impairment, the manufacturer recommends a single IM or IV ketorolac tromethamine dose of 30 or 15 mg, respectively.1,154 In these patients, multiple-dose parenteral ketorolac tromethamine therapy is administered at a dosage of 15 mg every 6 hours.1,154 The daily parenteral dosage in adults with renal impairment should not exceed 60 mg.1201 Subsequent oral ketorolac tromethamine therapy should be administered at a dosage of 10 mg every 4-6 hours as needed.1,154,207 The dosing interval should not be shorter than 4-6 hours.207 The manufacturer states that the daily oral dosage in any patient should not exceed 40 mg in a 24-hour period.1,154 The manufacturer also states that for breakthrough pain, supplemental doses of an opiate agonist may be administered concomitantly with these reduced doses of ketorolac tromethamine, unless opiate agonists are contraindicated.1,142

The recommended intranasal dosage of ketorolac tromethamine in adults with renal impairment is 15.75 mg (one spray in only one nostril) every 6-8 hours; the maximum daily dosage is 63 mg (4 doses).208 Ketorolac is contraindicated in patients with advanced renal disease.207,208,1201

Hepatic Impairment

Evidence from patients with liver cirrhosis suggests that modification may not be necessary.137

Ketorolac tromethamine shares the toxic potentials of nonsteroidal anti-inflammatory agents (NSAIAs);1,91,92,140 when NSAIAs are administered short-term, the incidence of adverse effects is about 10-50% of that associated with chronic administration.1,91 Adverse reactions to ketorolac tromethamine usually are mild,1,23,47,50,53,55,56,58,70 dose related,1,142 and reportedly occur in about 39% of patients.91 Ketorolac tromethamine usually is well tolerated.24,47,49,50,51,53,54,68,73,74,76,80,91,99,102 The most common adverse effects associated with short-term IM or oral therapy with the drug are nervous system and GI effects.2,47,60,70,91,140 Results of premarketing studies indicated that short-term IM ketorolac tromethamine therapy was associated with a lower incidence of adverse effects compared with short-term IM morphine therapy.47,70,91 During clinical trials in patients receiving short-term, postoperative, intranasal therapy with ketorolac tromethamine, the most common adverse effects were mild and transient nasal discomfort or irritation, and the most common adverse effects resulting in early discontinuance of therapy were nasal discomfort or nasal pain (rhinalgia).208

The manufacturer conducted a postmarketing, nonrandomized, observational study to examine the relative risks and benefits of ketorolac tromethamine and parenteral opiate agonists in a hospital setting.137,142,143,154 In this study, no attempt was made to assign the drug or dosage employed, and while patients included in the opiate group could not receive NSAIAs concomitantly, there was no limitation on concomitant opiate use by those receiving ketorolac.142 Interim analysis of data involving 6721 patients in the ketorolac group and 3943 patients in the opiate group revealed an association between mortality rate and age, increasing with age in both groups; the mortality rate was 0.9 and 1.7% for the respective drug groups.142 In addition, the frequency of GI bleeding, which ranged in severity from occult blood in stools to frank bleeding, also increased with age in both groups but was higher in the ketorolac than opiate group; about half of the reported GI effects involved occult blood in stools only, although death was attributed to GI bleeding in 2 patients (one in each drug group).142 Final analysis of data accumulated on approximately 10,000 patients revealed that the risk of clinically serious GI bleeding depended on the dose of ketorolac tromethamine; this appeared to be particularly important in geriatric patients who received an average daily dose greater than 60 mg.1,154 Serious adverse effects also were associated with long-term ketorolac therapy or therapy in patients with GI bleeding, renal impairment (without appropriate dose modification), or a history of sensitivity reactions to aspirin or other NSAIA-type agents.154 In addition, through December 4, 1992, the manufacturer had accumulated information on 73 spontaneously reported deaths in patients who received ketorolac.137

Cardiovascular Effects

Adverse cardiovascular effects occur in about 4% of patients receiving IM ketorolac tromethamine.91,137 Edema occurred in 1-3% of patients receiving the drug IM91,140 or orally.70 Hypertension has been reported in greater than 1% of patients.1,91 Vasodilation,1,47,53,56,70,91 pallor,1,91 hypotension,91 flushing,1,91 syncope,1,91 or palpitation56,61,70,91 has been reported in 1% or less of patients receiving the drug IM1 or orally.56,70 Bradycardia and hypertension each have been reported in 2% of patients receiving intranasal ketorolac tromethamine.208

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500,502,508 Use of NSAIAs also is associated with an increased risk of heart failure.500,508

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.199,206,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500,502,505,506,508 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500,502,506,508

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505,508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500,508,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508,511

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.202,203,204,206,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.507,508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500,504,508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.198,502,508

GI Effects

Adverse GI effects reportedly occur in about 13% of patients receiving IM ketorolac tromethamine.91 Dyspepsia,1,50,70,91,140 nausea,1,23,47,50,51,53,70,91,134,140 and GI pain1,53,140 are the most common adverse GI effects of ketorolac tromethamine, occurring in about 12-13% of patients receiving the drug.1,91,142 Diarrhea occurs in 3-9% of patients receiving ketorolac tromethamine.1,91,140 Constipation,1,91 flatulence,1,91 feeling of GI fullness,1,91 and vomiting1,23,50,53,70,91,134 occur in less than 3% of patients receiving ketorolac tromethamine.1,91 Melena,1,91 peptic ulcer,1,31,91 rectal bleeding,1,91 stomatitis,1,91 dysgeusia,1,50,70,91 gastritis,1,91 eructation,1,91 anorexia,1,91 increased appetite,1,91 GI bleeding,1,91 GI perforation,1,91,150 dry mouth,1,47,51,91 and excessive thirst1,91 occur in 1% or less of patients receiving the drug.1,91 GI ulceration has been reported rarely in patients receiving ketorolac tromethamine.149,150 Most of these adverse GI effects also have been reported in patients receiving the drug orally55,58,59,70,83 but may occur more frequently than in those receiving the drug IM, since the duration of oral therapy often exceeds that of IM therapy.70,138 Although a causal relationship to ketorolac tromethamine has not been established, acute pancreatitis has occurred during therapy with the drug.1

Usual IM dosages of ketorolac tromethamine reportedly produce fewer adverse GI effects than usual analgesic dosages of aspirin.31,70,91 In healthy individuals, the frequency of GI mucosal lesions observed endoscopically was lower with usual dosages of IM ketorolac tromethamine than with usual analgesic dosages of aspirin;31,70,91,140 higher than usual dosages of ketorolac tromethamine (i.e., IM dosages of 90 mg 4 times daily) were associated with a frequency of GI mucosal lesions similar to that associated with usual analgesic dosages of aspirin.31,70,91 However, the frequency of adverse GI effects may be increased during long-term administration70 and, in chronic toxicity studies in animals, GI toxicity (irritation and/or ulceration) was observed with oral but not parenteral ketorolac administration.91 The incidence of GI ulceration and bleeding in patients receiving long-term oral therapy (10 mg 1-4 times daily for up to 1 year) with the drug occurs at a rate of 1.2-5.4% per year.1,91 In one short-term (5 days' duration) study, endoscopically evident ketorolac tromethamine-induced mucosal injury, including GI ulceration, was dose related31,70 and independent of the route of administration.31

Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.1,124,125,141,198,208 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.198 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.1,198 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.1 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.198

Studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.1,122,124 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.1 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.198 However, short-term therapy is not without risk.198 High dosages of any NSAIA probably are associated with an increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.1,124 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.1 122,124,141

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold increased risk for developing GI bleeding than patients without these risk factors.192,193,208 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.192,193,195 Risk of bleeding also is increased in patients with advanced liver disease and/or coagulopathy.208 Geriatric or debilitated patients appear to tolerate ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.1,122,125,126,127,141

Results of a postmarketing, nonrandomized, observational study involving approximately 10,000 patients receiving ketorolac tromethamine indicated that the incidence of serious GI bleeding after up to 5 days of therapy with the drug is dose related and that serious GI bleeding occurs most commonly in geriatric patients receiving higher than recommended dosages of the drug.1201 In patients with a history of GI perforation, ulceration, or bleeding, serious GI bleeding occurred in 2.1, 4.6, 7.8, or 15.4% of those younger than 65 years of age receiving total daily IV ketorolac tromethamine dosages of 60 mg or less, 61-90 mg, 91-120 mg, or more than 120 mg, respectively, and in 4.7, 3.7, 2.8, or 25% of those 65 years of age or older receiving these respective dosages.1201 In patients without a history of GI perforation, ulceration, or bleeding, serious GI bleeding occurred in 0.4, 0.4, 0.9, or 4.6% of those younger than 65 years of age receiving total daily IV ketorolac tromethamine dosages of 60 mg or less, 61-90 mg, 91-120 mg, or more than 120 mg, respectively, and in 1.2, 2.8, 2.2, or 7.7% of those 65 years of age or older receiving these respective dosages.1201

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.192,194 (See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that concomitant use of a proton-pump inhibitor (e.g., omeprazole) may be used to decrease the incidence of serious GI toxicity associated with NSAIA therapy.192

Nervous System Effects

Adverse nervous system effects reportedly occur in about 23% of patients receiving IM ketorolac tromethamine.91 Headache,1,23,70,91,34 somnolence or drowsiness,1,23,47,50,51,53,61,70,91,134,140 and dizziness1,23,50,53,70,91 have been reported in 17, 3-14, and 3-9%, respectively, of patients receiving ketorolac therapy. Nervousness,1,91 abnormal thinking,1,91 depression,1,91 euphoria,1,91 difficulty in concentration,1,91 insomnia,1,91 CNS stimulation,1,91 seizures,1,91 tremors,1,91 extrapyramidal manifestations,1 abnormal dreams,1,56,70,91 hallucinations,1,56,91 vertigo,1,91 asthenia,1,53,91 and paresthesia1,50,91 have been reported in 1% or less of patients receiving the drug.1 Psychosis also has been reported.1

Nervousness,56,70,83 hyperkinesia,1,56,70 and asthenia/fatigue1,58,70,83,137 have been reported in 1-4% of patients receiving oral ketorolac tromethamine. Euphoria,56,61,83 stupor,1 and malaise56 have been reported rarely in patients receiving the drug orally.

Local and Dermatologic Effects

IM administration of ketorolac tromethamine has produced pain at the injection site in about 2-4% of patients.1,23,26,49,50,53,70,91,140 Ecchymosis,23,47,91 bruising,24 hematoma or other signs of wound bleeding,1,47,91 and tingling47 at the injection site have been reported rarely. Adverse local effects may be minimized by applying pressure over the injection site for 15-30 seconds after administration.91 There has been no evidence (e.g., alterations in serum creatine kinase [CK, creatine phosphokinase, CPK] concentrations) of substantial adverse muscular tissue effects following single or multiple IM injections of ketorolac tromethamine.91

Intranasal administration of ketorolac tromethamine has resulted in nasal discomfort or rhinalgia in 13-15% of patients, increased lacrimation or throat irritation in 4-5%, and rhinitis in 2%.208

Pruritus occurred in 3-9% of patients receiving ketorolac tromethamine therapy,1,70,91 and sweating1,47,50,53,70,91,140 has been reported in 1-3% of patients receiving IM ketorolac tromethamine.1,91 Rash1,91 (may be maculopapular), urticaria,1,91 toxic epidermal necrolysis (Lyell's syndrome),1,91 and exfoliative dermatitis1,91 have been reported in 1% or less of patients receiving the drug IM.1,70 These effects also have been reported in patients receiving ketorolac tromethamine orally.56,70 Rash also has been reported in 3% of patients receiving intranasal ketorolac tromethamine.208

Sensitivity Reactions

Severe anaphylactoid reactions have been reported in patients receiving ketorolac tromethamine.1,151 Anaphylactoid reactions may occur in patients with known hypersensitivity to aspirin or other NSAIA, including ketorolac tromethamine;1 however, these reactions also have been reported in patients without a history of hypersensitivity or known previous exposure to these drugs.1,151 Patients should be questioned carefully before ketorolac tromethamine therapy is initiated about development of allergic reactions (e.g., asthma, nasal polyps, urticaria, hypotension) associated with administration of NSAIAs; if such manifestations occur during therapy, the drug should be discontinued.1 In premarketing studies in a limited number of patients previously exposed to ketorolac tromethamine but with no history of hypersensitivity to it, there was no evidence that the drug possessed an unusual propensity for causing hypersensitivity reactions.1,91 Anaphylaxis, bronchospasm, and laryngeal and/or lingual edema have been reported in 1% or less of patients receiving the drug.1,47,91,142,146,148 Angioedema and anaphylactoid reaction also have been reported.1,169

Renal, Electrolyte, and Genitourinary Effects

Chronic administration of oral ketorolac tromethamine occasionally has caused impairment of renal function, resulting in hematuria,1 proteinuria,1 and transiently increased BUN91 and serum creatinine concentrations.91 Increased BUN and serum creatinine concentrations have occurred in about 3 and 2% of patients, respectively, receiving the drug orally for 1 year.91 Oliguria or decreased urine output has been reported in 2-3% of patients receiving short-term therapy with intranasal ketorolac tromethamine.208 Oliguria, urinary frequency, urinary retention, hemolytic-uremic syndrome, acute renal failure, flank pain (with or without hematuria and/or azotemia), hyponatremia, and hyperkalemia have occurred in about 1% or less of patients receiving short-term oral or parenteral ketorolac tromethamine therapy.1,91,147,152,166,167,168,170,171 Glomerular nephritis, interstitial nephritis, renal papillary necrosis, and nephrotic syndrome have been reported in patients receiving ketorolac tromethamine; patients at greatest risk of adverse renal effects include those with impaired renal function and geriatric patients.1,142 Although a causal relationship to ketorolac tromethamine has not been established, polyuria has occurred during therapy with the drug.1 As with other NSAIAs, renal papillary necrosis and other evidence of renal toxicity have occurred following prolonged administration of the drug in animals.1

Hepatic Effects

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs;1 meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving oral ketorolac tromethamine in controlled clinical studies.1,91 Increased ALT and/or AST concentrations also have been reported in 2% of patients receiving short-term therapy with intranasal ketorolac tromethamine in controlled clinical studies.208 In addition, liver function abnormalities have been reported in less than 1% of patients receiving short-term, IM therapy with the drug.1 Such abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.1 Hepatitis, liver failure, and cholestatic jaundice have been reported in 1% or less of patients receiving ketorolac tromethamine.1

Hematologic Effects

Purpura has been reported in less than 3% of patients receiving IM ketorolac tromethamine.1,91 Ketorolac tromethamine may inhibit platelet adhesion and aggregation1,2,23,24,34,65,70,91 and prolong bleeding time (generally by approximately 3 minutes from baseline values).1,2,23,24,34,140 However, the drug has a transient effect on platelet function, and aggregation usually returns to normal within 24-48 hours after discontinuing ketorolac tromethamine.1,23,34,91 The drug usually does not affect prothrombin time,1,2,23,70 partial thromboplastin time,1,2,23,70 or kaolin-cephalin coagulation time.24,70 Platelet count may23,70 or may not1,34,70 be affected by ketorolac tromethamine; thrombocytopenia (which was not considered clinically important) has been reported rarely in patients receiving the drug IM.23 Patients who may be affected adversely by a prolongation of bleeding time should be observed carefully during ketorolac tromethamine therapy.1,23,24,34,91 (See Hematologic Precautions under Cautions.)

Bleeding at the operative site (rarely requiring blood transfusions) has been reported in 1% or less of patients receiving parenteral ketorolac tromethamine therapy.1,91,142 In controlled clinical trials in patients undergoing major (e.g., orthopedic, abdominal) surgery, serious bleeding or hematoma at the operative site was reported in 1.5% of patients receiving intranasal ketorolac tromethamine.208 Bleeding has occurred following tonsillectomy in pediatric patients receiving ketorolac tromethamine.1,174,196,197 In one retrospective analysis of patients undergoing tonsillectomy with or without adenoidectomy, the risk of bleeding was 10.1 or 2.2% in patients receiving ketorolac or an opiate agonist, respectively, for pain management.1 In pediatric patients 12 years of age or younger, postoperative hemorrhage occurred in 6.5% of those given ketorolac and in 3.3% of those who did not receive the drug.1 In a prospective study in children 3-9 years of age undergoing tonsillectomy with or without adenoidectomy, the overall incidence of bleeding in children receiving ketorolac (16.3%) was similar to the incidence in children receiving morphine (17%).1 However, the incidence of bleeding during the first 24 hours after surgery was higher in those receiving ketorolac (14.3%) than in those receiving morphine (4.2%).1

Thrombocytopenia, epistaxis, and anemia have been reported in 1% or less of patients receiving the drug.1,91 Although a causal relationship to ketorolac tromethamine has not been established, leukopenia and eosinophilia have occurred during therapy with the drug.1

Ocular and Otic Effects

Visual disturbances (e.g., blurred vision) have occurred in 1% or less of patients receiving IM ketorolac tromethamine therapy1 and also have been reported in patients receiving the drug orally.55,83 Tinnitus and hearing loss have been reported in 1% or less of patients receiving the drug.1,50,70

Other Adverse Effects

Dyspnea,1,70 infection,1 pulmonary edema,1,91 and myalgia91 have been reported in 1% or less of patients receiving ketorolac tromethamine IM1,91,140 or orally.70 Chills occurred in at least one patient receiving the drug IM.53 Other adverse effects reported rarely in patients receiving oral ketorolac tromethamine include weight gain,70,91 generalized pain,70 and fever.58,60,91 Although a causal relationship to ketorolac tromethamine has not been established, aseptic meningitis, rhinitis, and cough have occurred during therapy with the drug.1,50,70

Precautions and Contraindications

Ketorolac tromethamine, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort; more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.1,91,122,137,154,198,500,508 The total duration of ketorolac therapy (including parenteral, oral, and intranasal formulations) in adults is not to exceed 5 days because of an increased frequency and severity of adverse effects associated with more prolonged therapy;1,142,154,208 patients should be switched to alternative analgesic agents as soon as clinically possible.1,154

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.198

Cardiovascular Precautions

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.198,202,203,204,206,500,502,508 (See Cardiovascular Effects under Cautions.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.198,500 508 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.198,500,508 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.198,500,508 Ketorolac tromethamine should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if ketorolac tromethamine is used in such patients, the patient should be monitored for cardiac ischemia.508

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.198,199,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.198 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.198 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.198,508,509 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.198

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that ketorolac tromethamine should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if ketorolac tromethamine is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)

GI Precautions

Serious GI toxicity (e.g., bleeding, ulceration, perforation), with or without warning symptoms, can occur at any time during ketorolac tromethamine therapy.1,154 Studies to date have not identified any subset of patients who are not at risk of NSAIA-associated bleeding or peptic ulceration.1,154 Geriatric (i.e., 65 years of age or older) or debilitated patients appear to be more susceptible to such GI bleeding and ulceration and most spontaneous reports of fatal GI events during ketorolac therapy were in these populations.1,154

Use of NSAIAs should be avoided in patients at higher risk (see GI Effects under Cautions) unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, alternate therapy other than an NSAIA should be considered.208 NSAIAs should be used with great caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease), since these diseases may be exacerbated by NSAIAs.208 Postmarketing experience with parenterally administered ketorolac suggests that there may be a greater risk of GI ulcerations, bleeding, and perforation in geriatric patients.1,154 (See Geriatric Precautions under Cautions.) The incidence and severity of adverse GI effects increase with increasing dose and duration of ketorolac tromethamine therapy.1,154 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest duration of therapy should be employed,198 and use of more than one NSAIA at a time should be avoided.208 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

In a hospital-based, nonrandomized, observational postmarketing study comparing patients receiving parenteral ketorolac therapy with patients receiving parenteral opiate therapy, higher rates of clinically serious GI bleeding were observed in patients younger than 65 years of age who received an average total daily parenteral ketorolac tromethamine dose of greater than 90 mg.1,154 In this same study, patients with a history of peptic ulcer disease also appeared to be at increased risk of developing serious GI complications.1,154 The manufacturer states that clinicians should inform their patients of the potential risks of ketorolac tromethamine therapy prior to initiating treatment.1,154

Renal Precautions

Patients receiving ketorolac tromethamine are at risk of developing adverse renal effects, including interstitial nephritis and acute renal failure.1,154 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1,15,84,128,129,130,131,132,147,154,168,198 Patients at greatest risk of this reaction include those with impaired renal function,1,91,147,154 heart failure,1,91,147,154 or hepatic dysfunction;1,91,154 those with extracellular fluid depletion (e.g., patients receiving diuretics, dehydrated patients);1,91,154 those taking an ACE inhibitor198 or angiotensin II receptor antagonist concomitantly201 ; and geriatric patients.1,91,154,171 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1,91,154,166 The manufacturer recommends that hypovolemia be corrected prior to initiating therapy with ketorolac.1,154 Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.84

The manufacturer states that ketorolac tromethamine should be used with caution in patients with renal impairment or a history of kidney disease, since ketorolac is a potent inhibitor of prostaglandin synthesis and the drug and its metabolites are excreted principally by the kidneys.1,91,92,154,1201 Such patients should be monitored closely during ketorolac therapy.1,154 Because patients with underlying renal insufficiency are at risk of developing acute renal failure, the risks and benefits of ketorolac therapy must be considered before instituting therapy with the drug in these patients.1,154 In patients with moderately elevated serum creatinine, the manufacturer recommends that the usual daily dose of parenteral ketorolac tromethamine be halved, and not exceed 60 mg daily in these patients.1 (See Dosage in Renal and Hepatic Impairment under Dosage and Administration.)

Hepatic Precautions

Elevations in serum ALT concentrations may be the most sensitive indicator of NSAIA-induced liver dysfunction.1 Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result (especially those with a history of hepatic impairment) while receiving ketorolac tromethamine should be evaluated for evidence of the development of a more severe hepatic reaction;1,91 the manufacturer states that therapy with the drug should be discontinued in such patients.1 The manufacturer states that ketorolac tromethamine should be used with caution in patients with a history of hepatic impairment or with a history of liver disease.1,91,92,154

Hematologic Precautions

Ketorolac tromethamine should be used very cautiously and with careful monitoring in patients who may be adversely affected by prolongation of bleeding time (e.g., patients receiving anticoagulant therapy, patients with hemophilia, von Willebrand's disease, or platelet deficiency) and only when the potential benefits justify the possible risks to the patient,1,91,145 since the drug may inhibit platelet function and hemorrhage is possible.1,2,23,24,34,65,91,92 (See Anticoagulants and Thrombolytic Agents under Drug Interactions.) In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular hematoma formation from administration of IM ketorolac tromethamine.1,154 In addition, since hematomas and other signs of wound bleeding have been reported in patients receiving ketorolac tromethamine perioperatively, the manufacturer states that postoperative administration of ketorolac tromethamine should be undertaken with caution in any patient in whom hemostasis is critical.1

Precautions Related to Sensitivity or Dermatologic Reactions

Anaphylactoid reactions have been reported in patients receiving NSAIAs.198 Patients receiving ketorolac should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.198

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving ketorolac.1,198 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.198 Ketorolac should be discontinued at the first appearance of rash or any other sign of hypersensitivity.198

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1201 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1201 Symptoms may resemble those of an acute viral infection.1201 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1201 If such signs or symptoms develop, ketorolac should be discontinued and the patient evaluated immediately.1201

Other Precautions

In adults who weigh less than 50 kg, the dosage of ketorolac tromethamine should be reduced.1,154 (See Dosage under Dosage and Administration.)

The possibility that the antipyretic and anti-inflammatory effects of ketorolac tromethamine may mask the usual signs and symptoms of infection or other diseases should be considered,138 although some evidence suggests that the likelihood of such an effect may be small.137

Ketorolac is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency.1201 Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions.1201 If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.1201

Use of corticosteroids during NSAIA treatment may increase the risk of GI ulceration and the drugs should be used concomitantly with caution.

Ketorolac tromethamine therapy is contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, or a history of peptic ulcer disease or GI bleeding;1,154 in patients with advanced renal impairment or patients at risk of renal failure because of volume depletion;1,154 in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, or incomplete hemostasis, and in patients at a high risk of bleeding;1,154 in the setting of CABG surgery;1201 and in patients receiving concomitant probenecid or pentoxifylline therapy.1201 The manufacturers of oral and parenteral formulations of ketorolac also state that the drug is contraindicated in patients receiving concomitant aspirin or NSAIA therapy, because of the cumulative risk of serious NSAIA-related adverse effects.207,1201 Use of ketorolac tromethamine as a prophylactic analgesic before any major surgery also is contraindicated.1,154,1201 Because of the alcohol content of the parenteral formulations of the drug, epidural or intrathecal administration of ketorolac is contraindicated.1,154

The manufacturers state that ketorolac is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation.198,208,1201 In addition, NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.85,86,87,88,89,90,146,148,198 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization.86,87,88,89,90 Because patients with asthma may have aspirin-sensitivity asthma, NSAIAs should be used with caution in patients with asthma.198 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.198 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

Pediatric Precautions

Safety and efficacy of ketorolac (oral, parenteral, or intranasal) have not been established in pediatric patients younger than 17 years of age.207,208,1201 The manufacturer states that ketorolac tromethamine nasal spray should not be used in pediatric patients younger than 2 years of age.208

Meta-analysis of data from 13 randomized controlled trials that compared postoperative analgesic efficacy of ketorolac (at any dosage and any route of administration) with that of placebo or another active treatment following any type of surgery in pediatric patients up to 18 years of age indicated that available data were inadequate to determine efficacy or assess safety in this population.211 The studies provided insufficient data regarding postoperative pain intensity or the proportion of patients obtaining at least 50% pain relief and provided only limited data regarding use of rescue medications or opiate analgesics.211

Ketorolac tromethamine appears to increase the risk of bleeding following tonsillectomy.1

Geriatric Precautions

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.208 Many of the spontaneous reports of fatal GI effects in patients receiving NSAIAs involve geriatric individuals.1201 Because ketorolac tromethamine may be cleared more slowly in geriatric individuals (i.e., 65 years of age or older) and because this population may be more susceptible to the adverse effects of NSAIA-type drugs, ketorolac therapy must be instituted with extreme caution, with careful clinical monitoring, and at reduced dosages in these patients.154,171,1201 The incidence and severity of GI complications increase with increasing dose and duration of ketorolac therapy.1,154 If the anticipated benefits of ketorolac therapy outweigh the potential risks, ketorolac should be initiated at the lower end of the dosing ran the total daily parenteral dose of the drug should not exceed 60 mg, and the total daily intranasal dose should not exceed 63 mg.154,208,1201 (See Dosage under Dosage and Administration.) The dose and frequency of administration should be adjusted based on response to initial therapy.208 Ketorolac and its metabolites are substantially excreted by the kidneys, and the risk of adverse effects may be greater in patients with impaired renal function; because geriatric patients are more likely to have decreased renal function, it may be useful to monitor renal function.208

Mutagenicity and Carcinogenicity

No evidence of ketorolac tromethamine-induced mutagenesis was seen in in vitro studies with Salmonella typhimurium , Saccharomyces cerevisiae , or Escherichia coli .1,91,92 There also was no evidence of mutagenicity when ketorolac tromethamine was tested for chromosome breaks in vivo in the micronucleus assay in mice.1 Ketorolac was not mutagenic in the Ames microbial mutagen test or in the forward mutation assay; there was no increase in DNA repair when ketorolac tromethamine was tested in an unscheduled DNA synthesis.1 Ketorolac tromethamine increased chromosomal aberrations in Chinese hamster ovarian cells when they were exposed to the drug at concentrations of 1.59 mg/mL (about 1000 times the average human plasma ketorolac concentrations).1

No evidence of carcinogenic potential was seen in an 18-month study in mice receiving oral ketorolac tromethamine dosages up to 2 mg/kg daily (approximately equivalent to the maximum recommended human dosage of IM ketorolac tromethamine).1,91 There also was no evidence of carcinogenic potential in a 24-month study in rats receiving oral ketorolac tromethamine dosages up to 5 mg/kg daily (approximately 2.5 times the maximum recommended human dosage of IM ketorolac tromethamine).1,91,92

Pregnancy, Fertility, and Lactation

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200,1201 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1200,1201 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1200,1201 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1200,1201

Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1200,1201 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1201 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1201 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200,1201 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1201 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1201

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis, such as ketorolac, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1201 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1201

Reproduction studies in rabbits and rats receiving oral ketorolac tromethamine dosages of 3.6 and 10 mg/kg daily, respectively (about 1.8 and 5 times the maximum recommended human parenteral dosage, respectively), during the period of organogenesis have not revealed evidence of harm to the fetus;1,91,92 however, oral dosages exceeding the maximum recommended human parenteral dosage in rats produced delayed parturition and dystocia, probably secondary to inhibition of prostaglandin synthesis.1,91

Use of ketorolac during labor and delivery is contraindicated, since its inhibitory effect on prostaglandin synthesis may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.1201 In animal studies, NSAIAs, including ketorolac, delayed parturition and increased the incidence of stillbirths.208

Fertility

Use of NSAIAs, including ketorolac, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.208 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.208 Therefore, withdrawal of ketorolac tromethamine should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.208,1201

Reproduction studies in male and female rats using ketorolac tromethamine dosages of 9 or 16 mg/kg daily (about 0.9 or 1.6 times, respectively, the human exposure) have not revealed evidence of impaired fertility.91,92,1201

Lactation

Ketorolac may be distributed into milk in small amounts.208 (See Distribution under Pharmacokinetics.) The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ketorolac and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.208

Caution should be exercised when ketorolac is used in nursing women; although available information has not revealed any specific adverse events in nursing infants, women who are breast-feeding should be advised to contact their infant's clinician if they observe any adverse events.208

Protein-bound Drugs

Because ketorolac tromethamine is highly protein bound,1,2,37,38,70 it could be displaced from binding sites by, or it could displace from binding sites, some other protein-bound drugs.91 However, the clinical importance of such potential drug interactions has not been established for ketorolac.138 In vitro studies indicate that salicylates may displace ketorolac from protein-binding sites.1,91 (See Nonsteroidal Anti-Inflammatory Agents under Drug Interactions.) In addition, in vitro studies indicate that ketorolac may displace warfarin slightly from protein-binding sites;1,91 however, it appears that the NSAIA does not displace digoxin from its protein-binding sites.1,91,140 (See Digoxin under Drug Interactions.) Therapeutic plasma concentrations of digoxin, warfarin, ibuprofen, naproxen, acetaminophen, phenytoin, tolbutamide, or piroxicam do not appear to alter the protein binding of ketorolac.1,91

Antihypertensive Agents

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent.198,205,207,208 Blood pressure should be monitored to ensure that target blood pressure is achieved.208

Concomitant use of ketorolac with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function, including possible acute renal failure; such patients should be monitored for signs of worsening renal function.208 Patients receiving concomitant therapy with ketorolac and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.208

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic.198 Concomitant use of NSAIAs and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.198

While in vitro studies indicate that protein binding of warfarin may be decreased slightly from 99.5 to 99.3% by ketorolac,91,92 a ketorolac dosage of 10 mg daily for 6 days did not substantially alter the pharmacokinetics or pharmacodynamics of a single dose of warfarin in one study in healthy adults.1 No drug interaction was observed in healthy adults following concomitant administration of heparin (5000 units) and ketorolac tromethamine.1,24,70,91,92,137 However, because ketorolac tromethamine can inhibit platelet function,1,2,23,24,34 the drug should be used with extreme caution and prothrombin time should be monitored carefully in patients who may be adversely affected by prolongation of bleeding time (e.g., patients receiving anticoagulant therapy, patients with hemophilia, von Willebrand's disease, or platelet deficiency).1,91,145,154 Patients receiving therapeutic doses of anticoagulants (e.g., heparin, warfarin) have an increased risk of bleeding complications if ketorolac is administered concomitantly; therefore, the manufacturer recommends that such concomitant therapy be undertaken with extreme caution.1,154 The concurrent use of ketorolac tromethamine and prophylactic low-dose heparin (2500-5000 units every 12 hours), warfarin, or dextrans has not been studied extensively, but also associated with an increased risk of bleeding.1,154 Until more data are available, the manufacturer recommends that such concomitant therapy be undertaken only very cautiously, and only when the potential benefits justify the possible risks to the patient.1,91,145,154 Patients receiving ketorolac concomitantly with drugs that alter hemostasis should be monitored for signs of bleeding.208

Anticonvulsants

Seizures have been reported rarely in patients receiving concomitant ketorolac and anticonvulsant therapy (e.g., phenytoin, carbamazepine).1

Cyclosporine

Concomitant use of ketorolac and cyclosporine may increase cyclosporine-associated nephrotoxicity.208 Patients should be monitored for signs of worsening renal function.208

Digoxin

Concomitant use of ketorolac and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.208 Serum digoxin concentrations should be monitored.208

Diuretics

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs, including ketorolac tromethamine.1 (See Renal Precautions under Cautions.) In addition, NSAIAs (including ketorolac tromethamine) can reduce the natriuretic effects of furosemide or thiazide diuretics.1,104,198 This effect may be related to inhibition of renal prostaglandin synthesis.1,104,198 Patients receiving concomitant ketorolac and diuretic therapy should be monitored for signs of worsening renal function and for adequacy of diuretic and antihypertensive effects.208

Lithium

NSAIAs appear to decrease renal clearance of lithium,1,113 which may lead to an increase in serum113 or plasma1,114,115 lithium concentrations. Limited reports suggest that concomitant administration of ketorolac tromethamine and lithium results in increased lithium concentrations, with associated symptoms of lithium toxicity (e.g., nausea, vomiting, neurologic effects).1,157,158 NSAIAs reportedly increase mean trough lithium concentrations by 15% and decrease lithium clearance by approximately 20%; these effects have been attributed to inhibition of renal prostaglandin synthesis by NSAIAs.208 Although such concomitant therapy is not recommended, if patients must receive concomitant ketorolac and lithium therapy, plasma lithium concentrations should be monitored closely,158 and the patient should be observed for signs and symptoms of lithium toxicity.198

Methotrexate

While the effect of ketorolac tromethamine on clearance of methotrexate has not been evaluated to date,1,91,92 severe, sometimes fatal, toxicity has occurred following administration of an NSAIA concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis.1,105,106,107,108,109,110 The toxicity was associated with elevated and prolonged blood concentrations of methotrexate.1,105,106,107,108,109,110,111 The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination.1,105,106,107,108,109,110,111 Further studies are needed to evaluate the interaction between NSAIAs and methotrexate.105,106,107,108,109,112 Caution is advised if methotrexate and an NSAIA are administered concomitantly.198 Patients should be monitored for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).208

Nonsteroidal Anti-inflammatory Agents

In vitro studies indicate that therapeutic anti-inflammatory concentrations (e.g., 300 mcg/mL) of salicylates may displace ketorolac from protein binding sites, possibly resulting in elevated plasma concentrations of unbound ketorolac.1,91 Protein binding of ketorolac may be decreased from 99.2% to 97.5%, which would represent a potential two-fold increase in plasma concentrations of unbound drug.91,92 When NSAIAs were administered with aspirin, protein binding of the NSAIA was reduced but clearance of the free (unbound) NSAIA was not altered.208 The clinical importance of this interaction is unknown.208

In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.208 However, concomitant use of aspirin and an NSAIA increases the risk for bleeding and serious GI events.198,208 Because of the potential for increased adverse effects, concomitant use of ketorolac and analgesic dosages of aspirin generally is not recommended.208 Manufacturers of oral and parenteral formulations of ketorolac state that the drug is contraindicated in patients receiving aspirin or other NSAIAs because of the cumulative risk of serious adverse effects.207,1201

Patients receiving ketorolac should be advised not to take low-dose aspirin without consulting their clinician.198,208 Ketorolac is not a substitute for low-dose aspirin therapy for prophylaxis of cardiovascular events, and patients receiving antiplatelet agents such as aspirin concomitantly with ketorolac should be monitored closely for bleeding.208 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.199,502,508

Pemetrexed

Concomitant use of ketorolac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.208 Administration of NSAIAs with short elimination half-lives (e. g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.208 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.208 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant ketorolac and pemetrexed therapy.208

Pentoxifylline

When ketorolac is used concomitantly with pentoxifylline, the risk of bleeding is increased; such concomitant use is contraindicated.207,208,1201

Probenecid

Concomitant administration of ketorolac tromethamine and probenecid has reportedly decreased clearance and increased plasma concentration, total AUC (by approximately threefold), and half-life (by approximately twofold) of ketorolac.1 Therefore, the manufacturer states that ketorolac is contraindicated in patients receiving probenecid.1,154

Psychotherapeutic Agents

Hallucinations have been reported in patients receiving therapy with ketorolac and psychoactive drugs (e.g., fluoxetine, thiothixene, alprazolam).1 Patients receiving such concomitant therapy should be monitored for hallucinations.208

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.208 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.208 Patients receiving concomitant therapy with ketorolac and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.208

Skeletal Muscle Relaxants

Results of postmarketing studies indicate that ketorolac tromethamine may potentiate the effects of nondepolarizing skeletal muscle relaxants, resulting in apnea; however, the drug interaction potential of the drugs has not been specifically studied.1 Patients receiving concomitant therapy with ketorolac and nondepolarizing skeletal muscle relaxants should be monitored for apnea.208

Other Drugs

Ketorolac tromethamine has been administered concomitantly with morphine or meperidine for the management of postoperative pain without apparent adverse interaction.1,91,92 No drug interactions were reported following concomitant administration of ketorolac with some anti-infective agents (e.g., cephalosporins, penicillins, aminoglycosides), antiemetic agents, laxatives, sedatives, anxiolytic agents, corticosteroids, bronchodilators, or hormones.91

In individuals with symptomatic allergic rhinitis, the rate and extent of absorption of intranasally administered ketorolac tromethamine (single 31.5-mg dose) were not substantially altered by oxymetazoline hydrochloride nasal spray (single dose administered 30 minutes before ketorolac administration) or by fluticasone propionate nasal spray (200 mcg daily for 7 days).208

Evidence from animal or human drug interaction studies suggest that ketorolac is unlikely to interact with the metabolism of itself or other drugs via the hepatic microsomal enzyme system (cytochrome P-450 system).1

Acute Toxicity

Limited information is available on the acute toxicity of ketorolac tromethamine.1,21,91 The acute lethal dose of ketorolac tromethamine in humans is not known.1,91 The oral LD₅₀ of the drug is 200 mg/kg in mice.21

Daily parenteral ketorolac tromethamine dosages of 360 mg (3 times the maximum daily recommended dose) for 5 days resulted in abdominal pain and peptic ulcers, which healed after drug discontinuance.1 Metabolic acidosis following intentional overdosage of ketorolac (amount of drug not specified) also has been reported.1 Dialysis does not appear to be effective in removing the drug from circulation.1 In rats, mice, and monkeys, single oral ketorolac tromethamine doses exceeding 100 mg/kg produced diarrhea, pallor, labored breathing, rales, vomiting, and decreased activity.1,91

Chronic Toxicity

Tolerance, psychological dependence, or physical dependence does not appear to occur in patients receiving chronic (for 6 months) oral ketorolac tromethamine.70,91,103 There also was no evidence of manifestations of withdrawal following abrupt discontinuance of IM ketorolac tromethamine.91 The drug does not appear to affect opiate receptors and does not appear to exhibit opiate agonist or antagonist activity.1,91 The most frequent adverse effects observed during chronic toxicity studies in animals were GI irritation and/or ulceration, which at high dosages resulted occasionally in peritonitis, anemia, and death.91 Renal toxicity also was evident after prolonged therapy at relatively high dosages in animals.91

Pharmacology

Ketorolac tromethamine has pharmacologic actions similar to those of other prototypical NSAIAs.1,2,21,32,33,91 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,2,21,32,33,70,91,140 The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.1,2,21,32,91 Ketorolac tromethamine inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase;2,21,32,70,91,140 at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Ketorolac, like other prototypical NSAIAs, inhibits both COX-1 and COX-2. Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.91

Analgesic Effect

The analgesic effect of ketorolac tromethamine appears to result from inhibition of prostaglandin synthesis.1,70,91 While the precise mechanism of the analgesic effect of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.186,187,188,189,190,191 Prostaglandins appear to sensitize pain receptors to mechanical stimulation and to other chemical mediators (e.g., bradykinin, histamine).12,14,18,91 Since many NSAIAs, including ketorolac tromethamine,21 do not directly alter the pain threshold or prevent pain caused by exogenous or previously synthesized prostaglandins, the drugs may produce analgesia by inhibiting the synthesis of prostaglandins peripherally and possibly centrally.12,14,18,91 Animal studies suggest that the analgesic activity of ketorolac tromethamine results principally from a peripheral action.1,21,32,51,70,91 In addition, the anti-inflammatory effect of NSAIAs may contribute to their analgesic effect.12,18 Ketorolac tromethamine does not appear to affect opiate receptors;1,70,91,100,103 however, in one animal study, naloxone decreased the analgesic activity of ketorolac tromethamine.79 There is no evidence that therapy with ketorolac tromethamine results in physical dependence on the drug.1,2,56,91,100

On a weight basis, the analgesic potency of oral ketorolac tromethamine was about 3-6, 25-50, 180-350, or 180-350 times that of indomethacin, naproxen, aspirin, or phenylbutazone, respectively, as determined by antagonism of phenylbenzoquinone-induced writhing in mice.21,32,33,70 On a weight basis, as determined by the adjuvant-inflamed paw test in rats, the analgesic potency of oral ketorolac tromethamine was about 500-800 times that of aspirin.21,32 The analgesic potency of oral ketorolac tromethamine was similar to that of indomethacin and about 11-25, 30-90, or 100-200 times that of naproxen, phenylbutazone, or aspirin, respectively, as determined by the yeast-inflamed paw test in rats.21,32

Anti-inflammatory Effect

The anti-inflammatory effect of ketorolac tromethamine and other NSAIAs may result in part from inhibition of prostaglandin synthesis and release during inflammation.11,12,13,14,15,17 While the precise mechanism of the anti-inflammatory effect of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.186,187,188,189,190,191 It appears that ketorolac tromethamine does not suppress phagocytic activity of mononuclear macrophages.22 Ketorolac tromethamine does not possess glucocorticoid or mineralocorticoid activity.21

On a weight basis, the anti-inflammatory potency of oral ketorolac tromethamine has been shown to be 2-3 times that of indomethacin21 or naproxen21,70 and about 36 times that of phenylbutazone,21,32,33,70 as determined by inhibition of carrageenan-induced paw edema in rats.21,32 However, when determined by inhibition of cotton pellet-induced granuloma in rats, the anti-inflammatory potency of ketorolac tromethamine was comparable to that of indomethacin.21,70 In adjuvant-induced arthritis in rats, the anti-inflammatory activity of oral ketorolac tromethamine was approximately twice that of naproxen.21,70 However, there is limited evidence from studies in patients with inflammatory diseases (e.g., rheumatoid arthritis) and in animals that the anti-inflammatory potency of ketorolac is less than the drug's analgesic potency.70,137

Antipyretic Effect

Ketorolac tromethamine lowers body temperature in animals with antigen-induced fever.21,32,91 Although the mechanism of antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.12,20 In rats, the antipyretic activity of a ketorolac tromethamine dose of 0.1-2.7 mg/kg was similar to that of an aspirin dose of 5-45 mg/kg.21,70,137 However, results of clinical studies on the antipyretic activity of ketorolac tromethamine in humans have been equivocal, and further studies are needed.137

Renal Effects

Ketorolac tromethamine has been reported to adversely affect renal function.1,154 (See Renal, Electrolyte and Genitourinary Effects under Cautions.) Although the exact mechanism of adverse renal effects of NSAIAs has not been determined, the effects may be related to inhibition of renal prostaglandin synthesis.10,15,16,17

GI Effects

Ketorolac tromethamine can cause gastric mucosal damage, which may result in ulceration and/or bleeding.1,21,31,32,141,154 (See GI Effects under Cautions.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.186,187,188,189,190,191,192 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.190,192

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.190 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.190

Hematologic Effects

Ketorolac tromethamine can inhibit collagen- and arachidonic acid-induced platelet aggregation and may prolong bleeding time.1,2,23,24,34,70,91,98,140 Information on the effect of the drug on ADP-induced platelet aggregation has been equivocal.23,39,70,98 It appears that ketorolac tromethamine does not affect thromboxane A₂-induced platelet aggregation, prothrombin time, or partial thromboplastin time;1,2,23,91 however, serum thromboxane B₂ concentrations are decreased by the drug.24,70 In vitro, ketorolac tromethamine is more potent than aspirin in inhibiting collagen-induced platelet aggregation.23

Following IM administration of 30 mg of ketorolac tromethamine 4 times daily in healthy adults, bleeding time was prolonged from 4.9 minutes to 7.8 minutes;2,23,70,91 prolongation of bleeding time was more pronounced in men than in women.2,23 In controlled clinical studies, clinically important postoperative bleeding occurred in 0.4 or 0.2% of patients receiving ketorolac tromethamine or opiate analgesics, respectively.1,91,92 In healthy individuals, oral administration of single 2.5- to 200-mg doses of ketorolac tromethamine resulted in 75-100% inhibition of ADP-, collagen-, or arachidonic acid-induced platelet aggregation 3 hours after administration of the drug.34 Unlike the irreversible action of aspirin on platelets and the resultant prolonged effect on platelet aggregation,1,30 ketorolac tromethamine had a transient effect on platelet function, and aggregation returned to normal within 24-48 hours after discontinuance of the drug in individuals receiving oral doses up to 200 mg.1,34,91,92 Like other prototypical NSAIAs,12,15 these effects of ketorolac tromethamine appear to be associated with inhibition of synthesis of prostaglandins produced by COX-1.24,30,190 In healthy adults, ketorolac tromethamine does not produce excessive perioperative bleeding23 and it appears that prolongation of bleeding time is of little clinical importance in most patients.24,137,138 However, caution is necessary in some patients. (See Hematologic Precautions under Cautions.)

CNS Effects

In animals, high doses (up to 300 mg/kg) of ketorolac tromethamine did not appear to cause appreciable CNS effects (e.g., CNS depression, EEG disturbances).32 In mice, ketorolac tromethamine doses of 100 mg/kg did not potentiate barbiturate-induced sleep or protect against drug- or electroshock-induced seizures.32 Usual doses of ketorolac tromethamine did not appear to cause psychomotor effects in healthy individuals.66,67,91

Respiratory Effects

Unlike opiate agonists,26,35,136 ketorolac tromethamine does not appear to cause respiratory depression.25,26,35,70,91,136,140 In a limited number of patients undergoing surgery, postoperative increases in carbon dioxide tension (PCO₂) were less in patients receiving IM ketorolac tromethamine concomitantly with IM morphine than in patients receiving IM morphine with placebo,49,70 although the dose of morphine was higher in patients receiving morphine with placebo.49,70 In healthy adults, including some undergoing minor surgery, ketorolac tromethamine did not depress the ventilatory response to carbon dioxide.25,26,91,136 In patients with chronic obstructive pulmonary disease (COPD), ketorolac tromethamine did not produce substantial decreases in minute ventilation or inspiratory flow.91

Cardiovascular Effects

Usual doses of ketorolac tromethamine do not appear to cause appreciable cardiovascular effects.32,135,140 In healthy individuals, therapeutic doses of the drug did not affect mean arterial blood pressure,25,70,91 heart rate,25,91 stroke volume,70,91 left ventricular performance,70,91 or left ventricular stroke index.70,91 It appears that administration of parenteral ketorolac tromethamine does not alter the hemodynamics of anesthetized patients.1,91,135

Ocular Effects

Following topical application to the eye, ketorolac tromethamine may reduce some manifestations of ocular inflammation induced by ocular trauma (e.g., ocular surgery)32,82 or external agents27,28,70 and also may inhibit corneal neovascularization.32,78,94 The exact mechanism of the ocular effects of the drug has not been clearly established, but these actions appear to be associated principally with the inhibition of ocular prostaglandin synthesis.32,137,138 Topically applied ketorolac tromethamine does not appear to affect intraocular pressure (IOP)32 nor to worsen bacterial,27,70 fungal,28,70 or viral29,70 ocular infections.

Other Effects

In a limited number of patients with diabetes mellitus receiving insulin or oral sulfonylurea antidiabetic agents, ketorolac tromethamine did not appear to affect glucose metabolism.91 Ketorolac tromethamine may exhibit weak anticholinergic and α-adrenergic blocking activity.70

Pharmacokinetics

The pharmacokinetics of ketorolac after IM, IV, or oral administration are best described by a linear, two-compartment model1,91 with first-order absorption and elimination, and pharmacokinetics of the drug after IV administration are best described by a two- or three-compartment model.37

Absorption

Ketorolac tromethamine is rapidly and completely or almost completely absorbed following IM1,2,36,37,38,140,173 or oral1,2,36,37,38,70,95,173 administration, respectively. Bioavailability has been reported to range from 80-100% following oral administration.1,2,36,37,38,70,95,173 Bioavailability following intranasal administration is approximately 60% of that achieved with IM injection.208 At physiologic pH, ketorolac tromethamine is present in dissociated form as ketorolac (anion) and tromethamine (cation).37,38,70,137 The rate of absorption appears to be slower following IM administration than following oral administration of the drug in fasting, healthy adults;1,36,137,138 however, the extent of absorption is similar following parenteral or oral routes of administration.1,36 Food decreases the rate, but not the extent, of absorption of orally administered ketorolac tromethamine.1,2,70,83 The rate of absorption from the GI tract also may be decreased in patients with hepatic43,70 or renal44,70 impairment and in geriatric individuals.43,70 The presence of allergic rhinitis does not substantially alter the pharmacokinetics of intranasally administered ketorolac tromethamine.208

Following IV administration of 15- or 30-mg doses of ketorolac tromethamine injection in healthy adults, time to peak plasma concentration was about 1 or 3 minutes, respectively.1 Peak plasma concentration following single-dose IV administration of 15 or 30 mg of ketorolac in healthy adults was approximately 2.5 or 4.7 mcg/mL, respectively.1 Following IM administration of the drug in adults, plasma concentrations of the drug increase proportionally with increasing doses.1,36,70,91 Average peak plasma ketorolac concentrations of 0.7-1.4, 2.2-3, 4-4.6 or 6.9 mcg/mL occur within 30-60 minutes following IM administration of a single 10-, 30-, 60-, or 90-mg dose of ketorolac tromethamine, respectively, in healthy adults.1,2,36,37,42,43,44,70,80,91,140 Following IM administration of a single 30-, 60-, or 90-mg dose of ketorolac tromethamine in healthy adults, peak plasma p -hydroxyketorolac (the principal metabolite of ketorolac) concentrations of about 30, 63, or 102 ng/mL, respectively, occur at about 2 hours.36 Following oral administration of a single 10- or 30-mg dose of ketorolac tromethamine in healthy adults, average peak plasma ketorolac concentrations of 0.7-1.1 or 2.7 mcg/mL, respectively, occur at about 1 hour (range: 20-60 minutes).1,2,36,37,42,43,44,46,70,80 Peak plasma p -hydroxyketorolac concentrations of about 37 ng/mL occur in about 1 hour following oral administration of a single 30-mg dose of the drug in healthy adults.36 Following intranasal administration of a 31.5-mg dose, peak ketorolac concentrations of approximately 1.8 mcg/mL occur at about 45 minutes.208 The area under the plasma concentration-time curves (AUCs) of ketorolac and p -hydroxyketorolac increase linearly with single IM ketorolac tromethamine doses of 30-90 mg.36,38 AUCs of ketorolac also increase proportionally with oral ketorolac tromethamine doses of 0.8-3.2 mg/kg,36 and may be increased in adults with renal impairment compared with those in healthy adults.44

In healthy adults,137 steady-state plasma concentrations of ketorolac generally are reached within 24 hours following multiple dosing and average approximately 0.6-0.8 (range: 0.2-1.7) or 1.3-1.5 (range: 0.3-3.5) mcg/mL with IM ketorolac tromethamine dosages of 15 or 30 mg, respectively, 4 times daily.1,91,140 In multiple-dose IV studies, peak plasma steady-state ketorolac concentration following administration of 15- or 30-mg doses 4 times daily in healthy adults was approximately 3.1 or 6.9 mcg/mL, respectively.1 Mean steady-state plasma concentration following IV ketorolac doses of 15 or 30 mg 4 times daily in healthy adults was approximately 1.1 or 2.2 mcg/mL, respectively.1 Mean steady-state plasma concentration following oral administration of 10 mg 4 times daily in adults was approximately 0.6 mcg/mL.1 Steady-state plasma concentrations of ketorolac also generally are reached within 24 hours following multiple dosing with oral ketorolac tromethamine dosages of 12.5 mg 3 times daily; appreciable accumulation of ketorolac does not appear to occur.1,46,173 However, accumulation of ketorolac in special populations (e.g., geriatric, renal failure, or hepatic disease patients) has not been studied.1

Following IM administration of ketorolac tromethamine in adults, the onset of analgesic action usually is evident within 10 minutes, and peak analgesia occurs within 75-150 minutes;1,47,50,51,53 analgesia may be maintained for up to 6-8 hours.47,50,51,53,137,138 Following oral administration of the drug in adults, onset of analgesic action usually is evident within about 30-60 minutes, peak analgesia occurs within 1.5-4 hours, and analgesia usually is maintained up to 6-8 hours.55,56,57,58,59,60,61,137,138 Although the relationship between plasma ketorolac concentrations and therapeutic effect has not been precisely determined,137,138 an estimated therapeutic range of 0.3-5 mcg/mL has been suggested.1,91 In adults undergoing dental surgery, pain intensity was reduced by 50% at plasma concentrations of 0.1-0.3 mcg/mL, and adverse effects generally became frequent at concentrations exceeding 5 mcg/mL.1,91

Distribution

Distribution of ketorolac into human body tissues and fluids has not been fully characterized.1,2,38,70,91 Following oral administration in mice, ketorolac is distributed into the kidneys, liver, lungs, heart, muscle, gonads, and spleen, with an average tissue/plasma concentration ratio of about 1.5 for the kidney and less than 1 for the other tissues.38,91,173 However, following oral, IM, or IV administration of ketorolac tromethamine in humans, ketorolac does not appear to be distributed widely.1,2,37,70,140 The apparent volume of distribution of ketorolac during the terminal elimination phase in healthy adults is approximately 0.15-0.3 L/kg and the volume of distribution at steady state (V_ss) is about 0.11-0.33 L/kg following IV, IM, or oral administration.1,2,37,38,46,70,97,173 Following IV administration of a single dose of the drug in children 3-18 years of age, the apparent volume of distribution averaged 0.25-0.26 L/kg.1,197 Ketorolac appears to cross the blood-brain barrier poorly;1,91 CSF concentrations are reported to be about 0.2% of concurrent plasma concentrations.1,91 Following topical application of a ketorolac tromethamine gel to the knee, the drug is distributed into synovial fluid, achieving synovial fluid concentrations approximately 50% of those attained in plasma.137 Ketorolac is more than 99% bound to plasma proteins;1,2,37,38,70 the degree of protein binding appears to be independent of plasma concentration of the drug38,91 and constant over the therapeutic range of the drug.1

Ketorolac crosses the placenta.2,41,65,91,173 In pregnant women receiving single 10-mg IM doses of ketorolac tromethamine during labor, cord blood concentrations averaged about 11.6% (range: 4-25%) of maternal plasma concentrations.2,41,70,91,173 Ketorolac is distributed into milk, but in relatively small amounts.1,40,70,91,92 Following oral administration of a single 10-mg dose of ketorolac tromethamine in nursing women, peak milk ketorolac concentrations of 7.3 ng/mL occurred within about 2 hours,1 and the milk-to-plasma ratio was about 0.04.1,2 Following oral administration of 10-mg of ketorolac tromethamine 4 times daily for 2 days in nursing women, peak milk ketorolac concentrations 2 hours after dosing on the first or second day were 5.2-7.9 ng/mL and the milk-to-plasma ratio ranged from 0.015-0.037.1,40,70,91,92,173

Following intranasal administration, most of the ketorolac dose is deposited in the nasal cavity and pharynx; less than 20% of the dose is deposited in the esophagus and stomach, and little or no drug (less than 0.5%) is deposited in the lungs.208

Elimination

Ketorolac tromethamine dissociates into ketorolac (anion) and tromethamine (cation) at physiologic pH.37,38,70 Following single oral, IM, or IV doses of ketorolac tromethamine in healthy adults, plasma concentrations of ketorolac appear to decline in a biphasic manner with a terminal elimination half-life of about 4-6 hours (range: 2.4-9.2 hours).1,2,36,37,38,70,80,91,97,140,173 A half-life of approximately 5 hours has been reported following intranasal administration.208 In a limited number of pediatric patients receiving the drug IV, an elimination half-life of 3.8-6.1 hours has been reported.1,173,197 In geriatric individuals, the elimination half-life was reported to increase to an average of about 5-7 hours (range: 4.3-8.6 hours).1,2,42,70,80,91,173 The elimination half-life of ketorolac also is prolonged in patients with renal impairment to about 9-10 hours (range: 3.2-19 hours) following oral or IM administration of the drug;1,2,44,91,173 in patients undergoing dialysis, elimination half-life of ketorolac tromethamine was about 13.6 hours (range: 8-39.1 hours).1 There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in geriatric individuals and in patients with renal impairment.1 It appears that hepatic impairment (e.g., liver cirrhosis) does not affect substantially the elimination half-life of ketorolac.1,2,43,173 In patients with liver cirrhosis, elimination half-life of ketorolac was about 5.4 hours (range: 2.2-6.9 hours) and 4.5 hours (range: 1.6-7.6 hours) following IM and oral administration, respectively.1,43,91,173

The exact metabolic fate of ketorolac is not clearly established, but the drug undergoes hydroxylation in the liver1,91 to form p -hydroxyketorolac.36,38,70,91,173 This hydroxy metabolite exhibits limited pharmacologic activity, having less than 20 or 1% of the anti-inflammatory or analgesic potency, respectively, of the parent drug.36,38,173 Ketorolac also undergoes conjugation with glucuronic acid.1,37,38,173 The drug also is metabolized to unidentified polar metabolites, which appear to be pharmacologically inactive probably because of their high polarity and rapid elimination.91

Following oral, IM, or IV administration, ketorolac and its metabolites are excreted mainly in urine; only small amounts of the drug and its metabolites are excreted in feces,1,38,70,173 probably via biliary elimination.38,137 Following a single oral or IV dose of ketorolac tromethamine in healthy adults, about 91% of the dose is excreted in urine within 2 days1,37,140,173 and about 6% in feces1,38,173 within 3 days; most urinary excretion (about 75% of the dose) occurs within about 7 hours.137 In healthy adults, about 56-60% of a single oral or IV dose is excreted in urine as ketorolac, 20-26% as ketorolac glucuronide, 11-12% as p -hydroxyketorolac, and 6-7% as unidentified polar metabolites.36,37,38,70,97,173

Following IM, IV, or oral administration of the drug in healthy adults, total plasma clearance of ketorolac averages approximately 0.42-0.55 (range: 0.21-0.83) mL/minute per kg.1,37,38,42,44,46,70,91,97 Following single IV doses of ketorolac tromethamine in children 3-18 years of age, plasma clearance of the drug reportedly averaged 0.7-1.13 mL/minute per kg.1,197 Total plasma clearance of ketorolac is decreased in patients with reduced renal function.1,44,91 Following IM or oral administration of ketorolac tromethamine in patients with serum creatinine concentrations of 1.9-5 mg/dL, total apparent plasma ketorolac clearance was reduced to about 0.27 (range: 0.1-0.87) mL/minute per kg.1,44,70 Total plasma clearance reportedly also is decreased in geriatric individuals.1,42,70,80 In geriatric individuals, total apparent plasma clearance of ketorolac averaged 0.32-0.4 (range: 0.22-0.57) mL/minute per kg.1,42,80 It appears that hepatic impairment does not affect total clearance of ketorolac.1,91 In a group of patients with liver cirrhosis, total apparent plasma clearance averaged about 0.5 (range: 0.22-1.1) mL/minute per kg.1,43,91

The effect of hemodialysis and/or peritoneal dialysis on elimination of ketorolac is not known but probably is minimal secondary to the drug's high protein binding.137,138 Limited data indicate that following IM administration of the drug in patients undergoing dialysis total apparent plasma clearance of ketorolac averaged 0.27 (range: 0.05-0.6) mL/minute per kg.1

Chemistry and Stability

Chemistry

Ketorolac, a pyrrolizine carboxylic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,21,32,33,70,91,92,93,96,140 The drug is structurally and pharmacologically related to tolmetin, zomepirac, and indomethacin,2,33,47,70,83 but unlike these pyrrole acetic acid derivatives, ketorolac is a cyclic propionic acid derivative.21,33

Ketorolac is commercially available as the tromethamine salt.1,2,91,92,93 The tromethamine moiety enhances the aqueous solubility of ketorolac.2,32,47,83 Ketorolac tromethamine is commercially available as a racemic mixture.1,5,137,138 The analgesic and anti-inflammatory activity of the drug results principally from the levorotatory ( l ) isomer,1,5 which has approximately twice the pharmacologic activity of the racemic mixture.5

Ketorolac tromethamine occurs as an off-white crystalline powder91 and has solubilities of 3 mg/mL in alcohol and more than 500 mg/mL in water at 23°C.137,139 The pK_a of the drug in water is 3.54.1,2,3,33,91,93

Ketorolac tromethamine injection is a sterile solution of the drug in alcohol and sterile water for injection.1,91,93,137 The commercially available injection occurs as a clear, slightly yellow solution;1 hydrochloric acid and/or sodium hydroxide may be added during manufacture1,93 to adjust the pH to 6.9-7.9.137 About 6.68 or 4.35 mg of sodium chloride is added to each mL of the injection containing 15 or 30 mg of ketorolac tromethamine per mL, respectively, to provide an isotonic solution.1,137

Ketorolac tromethamine nasal spray is commercially available as a preservative-free solution that is administered by spray pump; each 100-µL metered spray delivers 15.75 mg of ketorolac tromethamine, and each bottle contains sufficient solution to deliver 8 sprays.208

Stability

Ketorolac tromethamine injection and oral tablets should be stored at 15-30°C and protected from light.1,4,91,93,153 The tablets also should be stored in well-closed containers and protected from excessive humidity.1,153 Prolonged exposure of the injection to light may produce discoloration of the solution and also may promote precipitation91,92 of the 1-keto derivative (constituting more than 80% of the light-induced degradation products) and, to a lesser extent, the decarboxy and 1-hydroxy derivatives.137 In commercially available ketorolac tromethamine injections, air has been replaced with nitrogen; the injections have an expiration date of 24 months following the date of manufacture.91,92

Ketorolac tromethamine nasal spray should be stored at 2-8°C prior to opening and protected from light and freezing; during use, bottles of the nasal spray should be stored at 15-20°C out of direct sunlight.208 The bottle should be discarded within 24 hours after priming the pump.208

When stored at 15-30°C, ketorolac tromethamine solutions containing 0.6 mg/mL are chemically and physically compatible for at least 48 hours in the following IV solutions: 0.9% sodium chloride, 5% dextrose, 5% dextrose and 0.9% sodium chloride, Ringer's, lactated Ringer's, or Plasma-Lyte^® A.69

When admixed in the same syringe to produce the concentrations listed, ketorolac tromethamine (15 mg/mL) is incompatible with solutions of drugs such as opiate agonists (e.g., meperidine hydrochloride [50 mg/mL], morphine sulfate [7.5 mg/mL]), promethazine hydrochloride (25 mg/mL), or hydroxyzine hydrochloride (25 mg/mL) that result in a relatively low pH following admixture since precipitation of the NSAIA can occur.1,91,92,137 Therefore, ketorolac tromethamine should not be administered in the same syringe with any such drug solutions.1,91,92 Specialized references should be consulted for additional compatibility information.212

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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