Professional Drug Information > Ketorolac Tromethamine

Ketorolac (Systemic)

VA CLASSIFICATION
Primary: CN103

Commonly used brand name(s): Toradol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Analgesic—

Indications

Note: Ketorolac, like other nonsteroidal anti-inflammatory drugs (NSAIDs), has antipyretic and anti-inflammatory, as well as analgesic actions ^{23}. However, indications for specific NSAIDs may vary because of lack of specific testing and/or clinical-use data as well as the toxicity of the individual agent.


Accepted

Pain (treatment)—Ketorolac is indicated for the short-term management of moderately severe acute pain that would otherwise require treatment with an opioid analgesic ^{37}. It is most commonly used to relieve postoperative pain ^{{08} {10} {18} {20} {37}}. The oral dosage form is indicated only for continuation of therapy following initial parenteral administration. Because the risk of gastrointestinal bleeding and other severe adverse effects increases with the duration of treatment, ketorolac should not be administered by any route or combination of routes for longer than 5 days ^{37}.
—Before ketorolac is used perioperatively, its platelet aggregation–inhibiting activity, which increases the risk of bleeding, must be considered ^{37}. Postoperative hematomas and other signs of wound bleeding have been reported in ketorolac-treated patients ^{37}. Therefore, ketorolac should not be given prior to major surgery to prevent postoperative pain; nor should it be administered intraoperatively when control of bleeding is critical ^{37}. Also, ketorolac lacks the sedative and anti-anxiety activity usually desired in a preoperative medication ^{37}.

[Pain, postoperative, in pediatric patients (treatment)]¹—Intravenous ketorolac is indicated for short term use in the treatment of postoperative pain in pediatric patients.^{{44}{45}{46}{47}{48}{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}{65}}

Unaccepted
Although ketorolac may be used for short-term (up to 5 days) ^{40} treatment of moderately severe acute arthritic pain in patients who are not receiving chronic treatment with other NSAIDs, it is not recommended for the long-term treatment of chronic rheumatic disease ^{29}.

Ketorolac is not recommended for treatment of mild pain or for long-term treatment of chronic pain ^{37}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    376.41 ^{02}

pKa—
    3.5 ^{37}

Mechanism of action/Effect:

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) chemically related to indomethacin and tolmetin ^{20}. Currently available NSAIDs inhibit the activity of the enzyme cyclo-oxygenase, leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid ^{21}. The resultant reduction in prostaglandin synthesis and activity may be at least partially responsible for many of the adverse, as well as the therapeutic, effects of these medications ^{21}. Analgesia is probably produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity ^{21}. However, inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation may also contribute to the analgesic effect ^{21}.


Other actions/effects:

Ketorolac has anti-inflammatory and antipyretic actions ^{23} that, together with its analgesic effects, may mask the onset and/or progression of an infection ^{{21} {23}}.

Ketorolac inhibits platelet aggregation ^{{09} {13} {23}}. This effect is reversible (unlike aspirin-induced platelet inhibition, which persists for the life of the exposed platelets). Recovery of platelet function usually occurs within 24 to 48 hours following discontinuation of ketorolac ^{{23} {37}}.

Like other NSAIDs, ketorolac may cause gastrointestinal ulceration and bleeding ^{23}. These effects probably result from ketorolac-induced reduction of the synthesis and activity of prostaglandins that exert a protective effect on the gastrointestinal mucosa ^{21}; they may occur after parenteral as well as after oral administration ^{{23} {30}}. However, when administered orally, this acidic medication probably also exerts a direct irritant or erosive effect on the mucosa ^{24}.

Like other NSAIDs, ketorolac may cause renal toxicity ^{23} (i.e., sodium and fluid retention, decreased renal perfusion, and decreased renal function), probably by inhibiting the synthesis and activity of renal prostaglandins, which are directly involved in the maintenance of renal hemodynamics and sodium and fluid balance. Renal prostaglandins are especially important in maintaining renal function in the presence of generalized vasoconstriction or volume depletion ^{{21} {23}}.

Absorption:

Intramuscular—Rapid ^{12} and complete ^{{12} {23}}.

Oral—Rapid ^{23} (more rapid than after intramuscular administration in some individuals) and complete ^{23}. The rate, but not the extent, of absorption is decreased when the medication is taken with a high-fat meal ^{{23} {37}}. Absorption is not altered by concurrent administration with an antacid ^{{23} {37}}.

Distribution:

The volume of distribution (Vol _D) of racemic ketorolac in patients with normal renal function is 0.15 ^{23} to 0.33 L per kg of body weight. In patients with renal function impairment, the Vol _D of the active S-enantiomer of ketorolac is twice as large as in individuals with normal renal function, and the Vol _D of the inactive R-enantiomer is approximately 20% larger ^{37}.

In breast milk—Maximum concentrations of 7.3 nanograms per mL (0.019 micromoles/L) 2 hours after the first dose and 7.9 nanograms per mL (0.021 micromoles/L) 2 hours after the fifth dose were measured in the breast milk of women receiving 10 mg of ketorolac, orally, 4 times a day ^{07}. However, in 40% of the subjects tested, the concentration in breast milk did not reach the lowest detection limit of 5 nanograms per mL (0.013 micromoles/L) ^{07}.

Protein binding:

Very high (> 99%) ^{23}.

Biotransformation:

Primarily hepatic ^{37}. Less than 50% of a dose is metabolized ^{37}. The major metabolites are a glucuronide conjugate ^{{01} {04} {12} {17}}, which may also be formed in the kidney ^{17}, and p-hydroxy ketorolac ^{{12} {17} {23}}. Neither metabolite has significant analgesic activity ^{{04} {17} {23}}.

Half-life:

Terminal—


Individuals with normal renal function:

About 5.3 hours in healthy young adults (ranges, 3.5 to 9.2 hours after 30 mg intramuscularly ^{37}, 4 to 7.9 hours after 30 mg intravenously, ^{37} and 2.4 to 9.0 hours after 10 mg orally ^{37}). Mean values are higher in healthy geriatric subjects, but remain within the same ranges reported for younger adults. Hepatic function impairment does not significantly prolong the half-life ^{37}.



Patients with renal function impairment:

About 10.3 to 10.8 hours in patients with a serum creatinine of 1.9 to 5 mg per 100 mL (168 to 442 micromoles/L) (ranges, 5.9 to 19.2 hours after 30 mg intramuscularly and 3.4 to 18.9 hours after 10 mg orally). ^{37} Values are even higher in patients receiving renal dialysis (13.6 [range, 8 to 39.1] hours after 30 mg intramuscularly) ^{37}.


Note: The above values apply to racemic ketorolac. In patients with normal renal function, terminal half-life values for the active S-enantiomer and the inactive R-enantiomer are approximately 2.5 hours and 5 hours, respectively ^{37}.


Onset of action:

Dose-dependent; generally within 30 minutes to 1 hour ^{37}.

Time to peak plasma concentration


Intramuscular:

Single dose of up to 60 mg: 30 to 60 minutes ^{37}.



Intravenous:

Single 15-mg dose: 1.1 ± 0.7 minutes ^{37}.

Single 30-mg dose: 2.9 ± 1.8 minutes ^{37}.



Oral:

Single 10-mg dose: 44 ± 34 minutes ^{37}.


Time to steady-state plasma concentration

Intramuscular or oral—About 24 hours, when the medication is administered at 6-hour intervals ^{23}.

Steady-state plasma concentration


With administration 4 times a day at 6-hour intervals:



Intramuscular:

15 mg: Average, 0.94 ± 0.29 mcg/mL (2.5 ± 0.77 micromoles/L) ^{37}.

30 mg: Average, 1.88 ± 0.59 mcg/mL (5 ± 1.57 micromoles/L) ^{37}.



Intravenous:

15 mg: Average, 1.09 ± 0.3 mcg/mL (2.89 ± 0.8 micromoles/L) ^{37}.

30 mg: Average, 2.17 ±0.59 mcg/mL (5.77 ± 1.57 micromoles/L) ^{37}.



Oral:

10 mg: Average, 0.59 ± 0.2 mcg/mL (1.57 ± 0.53 micromoles/L) ^{37}.


Note: Determination of minimum (trough) concentrations for each of the above routes of administration has shown that ketorolac concentrations do not decrease to subtherapeutic levels between doses ^{37}.


Peak plasma concentration

Following administration of a single dose ^{37}

Route *	Dose (mg)	Concentration
		mcg/mL	micromoles/L
IM	15	1.14±0.32	3.03±0.85
	30	2.42±0.68	6.44±1.81
	60	4.5±1.27	11.97±3.38
IV	15	2.47±0.51	6.57±1.36
	30	4.65±0.96	12.37±2.55
PO	10	0.87±0.22	2.31±0.58

^* IM = intramuscular; IV = intravenous; PO = oral.


Time to peak effect

Intramuscular or intravenous—1 to 2 hours ^{37}.

Oral—2 to 3 hours ^{{23} {37}}.

Duration of action:

Intramuscular or intravenous—4 to 6 hours ^{37}.

Elimination:
    91% ^{37} renal; approximately 6% biliary/fecal ^{{12} {17} {23} {37}}. The active S-enantiomer is cleared approximately twice as rapidly as the inactive R-enantiomer ^{37}.


Average total clearance rates following administration of a single dose —


Healthy young adults—
        Intramuscular, 30 mg—0.023 (range, 0.01 to 0.046) liters per hour per kg of body weight (L/hr/kg) ^{37}.
        Intravenous, 30 mg—0.03 (range, 0.017 to 0.051) L/hr/kg ^{37}.
        Oral, 10 mg—0.025 (range, 0.013 to 0.05) L/hr/kg ^{37}.



Elderly adults—
        Intramuscular, 30 mg—0.019 (range, 0.013 to 0.034) L/hr/kg ^{37}.
        Oral, 10 mg—0.024 (range, 0.018 to 0.034) L/hr/kg ^{37}.



Patients with hepatic function impairment—
        Intramuscular, 30 mg—0.029 (range, 0.13 to 0.066) L/hr/kg ^{37}.
        Oral, 10 mg—0.033 (range, 0.019 to 0.051) L/hr/kg ^{37}.



Patients with renal function impairment—


Serum creatinine 1.9 to 5 mg/100 mL (168 to 442 micromoles/L) —
        Intramuscular, 30 mg: 0.015 (range, 0.005 to 0.043) L/hr/kg ^{37}.
        Oral, 10 mg: 0.016 (range, 0.007 to 0.052) L/hr/kg ^{37}.



Renal dialysis patients—
        Intramuscular, 30 mg: 0.016 (range, 0.003 to 0.036) L/hr/kg ^{37}.





In dialysis—
        Hemodialysis does not remove significant quantities of ketorolac from the body ^{37}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may be sensitive to ketorolac also ^{23}. Severe asthmatic ^{25} and anaphylactoid reactions have occurred in such patients ^{37}.

Tumorigenicity

No evidence of tumorigenicity was found in an 18-month study in mice receiving up to 2 mg per kg of body weight (mg/kg) per day or a 24-month study in rats receiving up to 5 mg/kg per day orally. These doses are considered, on the basis of area under the concentration–time curve (AUC) comparisons, to be equivalent to 0.9 and 0.5 times, respectively, the human exposure resulting from intramuscular or intravenous administration of 30 mg 4 times a day ^{37}.

Mutagenicity

No evidence of mutagenicity was found in the Ames test, unscheduled DNA synthesis and repair, and forward mutation assays ^{37}. Also, ketorolac did not cause chromosome breakage in the in vivo mouse micronucleus assay ^{37}. However, in a concentration of 1590 mcg per mL (mcg/mL)(approximately 1000 times average human plasma concentrations), ketorolac increased the occurrence of chromosomal aberrations in Chinese hamster ovarian cells ^{37}.

Pregnancy/Reproduction
Fertility—
No impairment of fertility was observed in male rats given 9 mg/kg per day or female rats given 16 mg/kg per day, orally (53.1 and 50 mg per square meter of body surface area [mg/m ²] per day) ^{37}. These doses are equivalent to 0.9 and 1.6 times, respectively, the human exposure resulting from intramuscular or intravenous administration of 30 mg 4 times a day, based on AUC comparisons ^{37}.

Pregnancy—

First trimester

Adequate and well-controlled studies have not been done in pregnant women ^{37}.

No teratogenicity occurred in offspring of rabbits receiving oral doses of up to 3.6 mg/kg per day (42.35 mg/m ² per day; equivalent to 0.37 times the human exposure resulting from intramuscular or intravenous administration of 30 mg 4 times a day, based on AUC comparisons) ^{37} or rats receiving orally up to 10 mg/kg per day (59 mg/m ² per day; equivalent to the human exposure, based on AUC comparisons) ^{37}.



Second and third trimesters

Although studies in pregnant women have not been done with ketorolac, chronic use of any NSAID during the second half of pregnancy is not recommended because of possible adverse effects in the fetus, such as premature closure of the ductus arteriosus, which may lead to persistent pulmonary hypertension in the newborn ^{21}. Such effects have been documented in animal studies with other NSAIDs ^{21}.

Chronic administration of 1.5 mg/kg per day (8.8 mg/m ² per day) of ketorolac to rats after Day 17 of gestation caused dystocia and higher pup mortality ^{37}. This dose is equivalent to 0.14 times the human exposure resulting from intramuscular or intravenous administration of 30 mg 4 times a day, based on AUC comparisons ^{37}. Higher doses (9 mg/kg or more per day, administered to rats from Day 15 of gestation) significantly increased the length of gestation, in addition to increasing the incidence of maternal deaths associated with dystocia and decreasing birth weights and survival rates in the offspring ^{23}.

FDA Pregnancy Category C ^{37}.



Labor and delivery—

When administered during labor, ketorolac crosses the placenta ^{{11} {14}} and inhibits platelet aggregation in the neonate ^{11}. Ketorolac may cause adverse effects on uterine contractility and on the fetal ductus arteriosus, resulting in an increased risk of uterine bleeding and fetal circulatory disturbances, respectively ^{37}. Therefore, ketorolac should not be used during labor and delivery ^{37}.

Breast-feeding

Because of potential adverse effects in the nursing infant, use of ketorolac by nursing mothers is not recommended ^{37}. Ketorolac is distributed into breast milk in small quantities ^{07}. Maximum concentrations of 7.3 nanograms per mL (nanograms/mL) (0.019 micromoles/L) 2 hours after the first dose and 7.9 nanograms/mL (0.021 micromoles/L) 2 hours after the fifth dose were measured in the breast milk of women receiving 10 mg of ketorolac, orally, 4 times a day ^{07}, although the concentration in breast milk failed to reach the lowest detection limit of 5 nanograms/mL (0.013 micromoles/L) in 40% of the subjects tested. ^{07} Milk-to-plasma concentration ratios of 0.037 and 0.025 have been calculated after administration of a single dose and at steady-state, respectively ^{37}.

Pediatrics

No information is available on the relationship of age to the effects of ketorolac in pediatric patients. Safety and efficacy in patients younger than 16 years of age have not been established ^{37}.


Geriatrics


Studies have shown that clearance of ketorolac is reduced in healthy individuals 65 years of age or older, leading to significant prolongation of the elimination half-life ^{{03} {37}}. Also, geriatric patients are more likely to have age-related renal function impairment, which may further reduce ketorolac clearance ^{{03} {16}} and increase the risk of NSAID-induced renal ^{{21} {23}} or hepatic ^{21} toxicity. The risk of gastrointestinal ulceration, bleeding, and perforation is higher in elderly patients receiving ketorolac than in younger adults ^{37}. Also, ketorolac-induced gastrointestinal ulceration and/or bleeding is more likely to cause serious consequences, including fatalities, in geriatric patients ^{31}. It is recommended that ketorolac be used with caution ^{21}, in the lower of the recommended dosage regimens ^{37}, and with careful monitoring of the patient ^{21}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
All of the interactions listed below have not been documented with ketorolac. However, they have been reported with other NSAIDs and should be considered potential precautions to the use of ketorolac also.
In addition to the interactions listed below, the possibility should be considered that additive or multiple effects leading to impaired blood clotting and/or increased risk of bleeding may occur if any NSAID is used concurrently with any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.

Acetaminophen ^{21}    (prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects; it is recommended that patients be under close medical supervision while receiving such combined therapy)


Alcohol or
Corticosteroids, glucocorticoid or
Corticotropin (chronic therapeutic use) or
Potassium supplements    (concurrent use with an NSAID may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage ^{21})


» Anticoagulants, coumarin- or indanedione-derivative or ^{{21} {37}}
» Heparin or ^{{21} {37}}
» Thrombolytic agents, such as: ^{21}
Alteplase
Anistreplase
Streptokinase
Urokinase    (ketorolac has not been shown to alter the pharmacokinetic or pharmacodynamic properties of warfarin or heparin; however, inhibition of platelet aggregation by ketorolac, and the potential occurrence of ketorolac-induced gastrointestinal ulceration or bleeding, may be hazardous to patients receiving anticoagulant or thrombolytic therapy; caution and careful monitoring of the patient are recommended, as there is evidence that administration of ketorolac to patients receiving an anticoagulant, possibly including low [prophylactic] doses of heparin [2500 to 5000 Units every 12 hours], increases the risk of bleeding and intramuscular hematoma formation ^{37})


Antihypertensives or
Diuretics    (increased monitoring of the response to any antihypertensive agent may be advisable when ketorolac is used concurrently because several other NSAIDs have been shown to reduce or reverse the effects of many antihypertensives, possibly by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention ^{21})

    (NSAIDs may decrease the diuretic and natriuretic, as well as the antihypertensive, effects of diuretics, probably by inhibiting renal prostaglandin synthesis ^{21}; ketorolac inhibited the diuretic effect of furosemide, decreasing sodium and urine output by about 20%, in a study in normovolemic healthy subjects ^{23})

    (concurrent use of an NSAID and a diuretic may also increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis ^{23})

    (concurrent use of ketorolac with an angiotensin-converting enzyme [ACE] inhibitor may also increase the risk of renal function impairment, especially in hypovolemic patients ^{{23} {37}})


» Aspirin or other salicylates or
» Other NSAIDs    (concurrent use of aspirin or other NSAIDs with ketorolac is not recommended because of the potential for additive toxicity ^{23})

    (concurrent use of ketorolac with antirheumatic doses of salicylates other than aspirin should be undertaken with caution and in reduced doses because therapeutic plasma concentrations of salicylate [30 mg per 100 mL (2.17 mmol per L)] decrease the protein binding of ketorolac sufficiently to potentially double the plasma concentration of free [unbound] ketorolac ^{37})


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin or
» Valproic acid    (these medications may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with an NSAID may increase the risk of bleeding because of additive interferences with blood clotting and/or the potential occurrence of gastrointestinal ulceration or hemorrhage during NSAID therapy ^{21})


Gold compounds    (although other NSAIDs are commonly used concurrently with gold compounds in the treatment of arthritis, the possibility should be considered that concurrent use of a gold compound with any NSAID, including ketorolac, may increase the risk of adverse renal effects ^{21})


» Lithium    (although the effect of ketorolac on lithium plasma concentration has not been studied, increases in lithium concentration have been reported during concomitant administration of ketorolac ^{37}; increased monitoring of lithium plasma concentrations is recommended during and following concurrent use so that lithium dosage can be adjusted if necessary ^{21})


» Methotrexate    (the effect of ketorolac on methotrexate concentrations and/or toxicity has not been studied ^{23}; however, administration of moderate- or high-dose methotrexate infusions to patients receiving other NSAIDs has resulted in severe, sometimes fatal, methotrexate toxicity, possibly because NSAIDs may reduce renal function, thereby decreasing methotrexate excretion; it is recommended that ketorolac not be administered for 24 hours prior to, and for at least 12 hours [or until the methotrexate plasma concentration has decreased to a nontoxic level] following, a high-dose methotrexate infusion ^{21})

    (severe, sometimes fatal, methotrexate toxicity has also been reported with the relatively low to moderate doses of methotrexate used in the treatment of rheumatoid arthritis or psoriasis when an NSAID was given concurrently; it is recommended that concurrent use of ketorolac with low to moderate doses of methotrexate also be undertaken with caution, with methotrexate dosage being adjusted as determined by monitoring plasma methotrexate concentration and/or adequacy of the patient's renal function ^{21})


Nephrotoxic medications, other (see Appendix II )    (concurrent use with an NSAID may increase the risk and/or severity of adverse renal effects)


Platelet aggregation inhibitors, other (see Appendix II )    (concurrent use of any of these medications with an NSAID, including ketorolac, may increase the risk of bleeding because of additive inhibition of platelet aggregation as well as the potential occurrence of gastrointestinal ulceration or hemorrhage during NSAID therapy ^{21})


» Probenecid    (concurrent use with ketorolac is not recommended because probenecid decreases elimination of ketorolac, resulting in significantly increased ketorolac plasma concentrations [the area under the concentration–time curve (AUC) being increased about threefold, from 5.4 to 17.8 mcg per hour per mL] and half-life [which is more than doubled, to about 15 hours] ^{{27} {37}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Bleeding time    (may be prolonged because ketorolac inhibits platelet aggregation; ^{09} effects may persist for 24 to 48 hours after discontinuation of therapy ^{37})


Blood urea nitrogen (BUN) or ^{23}
Creatinine, serum ^{23} or
Potassium, serum ^{26}    (may be increased)


Liver function tests, especially serum transaminase activity    (although borderline elevations in test values may occur in up to 15% of patients receiving ketorolac, significant elevations [3 times the upper limit] of serum transaminases have occurred in fewer than 1%; ketorolac therapy should be discontinued if significant abnormalities occur ^{{37} {43}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cerebrovascular bleeding, suspected or confirmed or
» Hemophilia or other bleeding problems including coagulation or platelet function disorders    (increased risk of bleeding because ketorolac inhibits platelet aggregation and may also cause gastrointestinal ulceration or hemorrhage ^{37})


» Gastrointestinal bleeding, active, recent, or history of or
» Gastrointestinal perforation, recent or
» Peptic ulceration, ulcerative colitis, or other ulcerative gastrointestinal disease, active or history of    (increased risk of gastrointestinal ulceration, perforation, and/or hemorrhage ^{37})


» Nasal polyps associated with bronchospasm, aspirin-induced, or angioedema, anaphylaxis, or other severe allergic reaction induced by aspirin, ketorolac, or other NSAIDs, history of    (high risk of severe allergic reactions because of cross-sensitivity ^{37})


» Renal function impairment, severe    (increased risk of renal failure ^{37})


Risk-benefit should be considered when the following medical problems exist
» Allergic reaction, mild, such as allergic rhinitis, urticaria, or skin rash, induced by aspirin, ketorolac, or other NSAIDs, history of    (possibility of cross-sensitivity ^{37})


Asthma    (may be exacerbated ^{25})


Cholestasis or
Hepatitis, active    (although other forms of hepatic function impairment apparently do not alter the clearance of ketorolac ^{{03} {23}}, studies to assess the possible effect of cholestasis or active hepatitis on the pharmacokinetics of the medication have not been done ^{{01} {23}})


Conditions predisposing to gastrointestinal toxicity, such as:
Alcoholism, active or
» Inflammatory bowel disease ^{41}
Tobacco use, or recent history of    (caution and close supervision are recommended for patients in whom there is a significant risk of gastrointestinal toxicity ^{{21} {23}}; misoprostol or sucralfate should be considered as prophylaxis for those at high risk ^{21})


Conditions predisposing to and/or exacerbated by fluid retention, such as:
Compromised cardiac function or
Congestive heart disease or
Edema, pre-existing or
Hypertension    (ketorolac may cause fluid retention and edema ^{{23} {37}})


Congestive heart failure or ^{37}
Diabetes mellitus or ^{21}
Edema, pre-existing or ^{21}
Hepatic function impairment or ^{37}
» Hypovolemia or ^{37}
Sepsis ^{{21} {23}}    (increased risk of renal failure; caution and monitoring of urine output, serum urea, and serum creatinine are advised ^{23}; hypovolemia should be corrected before ketorolac therapy is initiated ^{37})

    (hepatotoxicity, as indicated by significant abnormalities in liver function tests, is more likely to occur in patients with pre-existing hepatic function impairment ^{37})


» Renal function impairment, mild to moderate    (ketorolac and its metabolites are excreted primarily via the kidney, which may also be a site of ketorolac metabolism ^{17}; a substantial reduction in ketorolac clearance, leading to significant prolongation of its half-life, has been demonstrated in patients with renal function impairment; a reduction in dosage is recommended for patients with moderate elevations of serum creatinine ^{37})

    (caution and careful monitoring of the patient are also recommended because of possible patient predisposition toward development of NSAID-induced adverse renal effects, including acute renal failure ^{37})


Systemic lupus erythematosus (SLE)    (increased risk of renal function impairment ^{21})




Side/Adverse Effects

Note: The risk of adverse effects increases with the duration of treatment as well as with the total daily dose of ketorolac ^{37}. In a long-term study in patients with chronic pain, oral administration of 10 mg 4 times a day of ketorolac caused more gastrointestinal toxicity than 650 mg 4 times a day of aspirin; the frequency of occurrence of gastrointestinal ulceration or bleeding was 0.69% after 3 months and 1.59% after 6 months in patients receiving ketorolac and 0% after 3 months and 0.73% after 6 months in patients receiving aspirin ^{01}. An unusually large number of cases of upper gastrointestinal bleeding (20% of which were fatal) has been reported with ketorolac, mostly in elderly patients ^{{31} {34}}.
Studies have shown that there is also a substantial risk of gastrointestinal bleeding during short-term parenteral administration of ketorolac (a maximum of 20 doses, administered over 5 days), especially in patients older than 65 years of age and/or patients with a history of gastrointestinal perforation, ulcer, or bleeding (PUB). The following percentages of patients experienced clinically significant gastrointestinal bleeding in these studies: ^{37}

Patient		Total dose/day (mg)
Age (yr)	PUB History	£60	>60– 90	>90– 120	>120
<65	No Yes	0.4% 2.1%	0.4% 4.6%	0.9% 7.8%	4.6% 15.4%
³65	No Yes	1.2% 4.7%	2.8% 3.7%	2.2% 2.8%	7.7% 25%

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (4%)
    
Edema ^{37} ( swelling of face, fingers, lower legs, ankles, and/or feet; unusual weight gain)

Incidence less frequent (1 to 3%)
    
Hypertension ^{37} ( high blood pressure)
    
purpura ^{37} (small, red spots on skin ; bruising)
    
skin rash ^{37} — rarely including maculopapular rash, or itching
    
stomatitis ^{37} ( sores, ulcers, or white spots on lips or in mouth)

Incidence rare (< 1%)
    
Anaphylaxis or anaphylactoid reaction ^{37} (changes in facial skin color; skin rash, hives, and/or itching; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing )
    
anemia ^{37} (unusual tiredness or weakness )
    
aseptic meningitis ^{37} (fever; severe headache; drowsiness; confusion; stiff neck and/or back; general feeling of illness; nausea)
    
asthma, bronchospasm, or dyspnea ^{37} (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
    
bleeding from wound, postoperatively ^{37}
    
bloody stools ^{37}
    
blurred vision or other vision change ^{37}
    
cholestatic jaundice ^{37} (dark urine; fever ; itching; light-colored stools; pain, tenderness, and/or swelling in upper abdominal area; skin rash; swollen glands; yellow eyes or skin)
    
convulsions ^{37}
    
edema of tongue ^{37}
    
eosinophilia ^{37}
    
exfoliative dermatitis ^{37} (fever with or without chills; red, thickened, or scaly skin; swollen and/or painful glands; unusual bruising )
    
fainting ^{37}
    
fever ^{37}
    
flank pain, with or without hematuria and/or azotemia ^{37} (pain in lower back and/or side; bloody or cloudy urine)
    
gastrointestinal, usually peptic, ulceration, possibly with perforation and/or bleeding ^{37} (abdominal pain, cramping, or burning, severe; bloody or black, tarry stools; vomiting of blood or material that looks like coffee grounds ; nausea, heartburn, and/or indigestion, severe and continuing)
    
hallucinations ^{37}
    
hearing loss ^{37}
    
hemolytic uremic syndrome ^{37}
    
hepatitis ^{37} ( loss of appetite; nausea; vomiting; yellow eyes or skin; swelling in upper abdominal area)
    
hives ^{37}
    
hyperactivity ^{37} (restlessness, severe)
    
hypotension ^{37} (low blood pressure)
    
increase in frequency of urination ^{37}
    
increased urine volume ^{37}
    
laryngeal edema ^{37} (shortness of breath or troubled breathing)
    
leukopenia ^{37} (rarely, fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination )—usually asymptomatic
    
mental depression ^{37}
    
nephritis ^{37} (bloody or cloudy urine; increased blood pressure; sudden decrease in amount of urine; swelling of face, fingers, feet, and/or lower legs; rapid weight gain)
    
nosebleeds ^{37}
    
oliguria ^{37} (decrease in amount of urine)
    
pancreatitis, acute ^{37} (abdominal pain; fever with or without chills; swelling and/or tenderness in upper abdominal or stomach area)
    
psychosis ^{37} (mood changes; unusual behavior)
    
pulmonary edema ^{37} ( difficult, fast, noisy breathing, sometimes with wheezing; blue lips and fingernails; pale skin; increased sweating)
    
rectal bleeding ^{37}
    
renal failure, acute ^{37} (increased blood pressure; shortness of breath, troubled breathing, tightness in chest, and/or wheezing ; sudden decrease in amount of urine ; swelling of face, fingers, feet, and/or lower legs; continuing thirst; unusual tiredness or weakness; weight gain)
    
rhinitis ^{37} ( runny nose)
    
Stevens-Johnson syndrome ^{37} ( bleeding or crusting sores on lips; chest pain; fever with or without chills ; muscle cramps or pain; skin rash; sores, ulcers, or white spots in mouth; sore throat)
    
thrombocytopenia ^{37} ( rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
    
tinnitus ^{37} (ringing or buzzing in ears )
    
toxic epidermal necrolysis [Lyell's syndrome] ^{37} (redness, tenderness, itching, burning, or peeling of skin ; sore throat; fever with or without chills)
Note: Hemolytic uremic syndrome is characterized by hemolytic anemia, renal failure, thrombocytopenia, and purpura. These adverse effects may also occur independently of hemolytic uremic syndrome and are listed separately above.





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 3%)
    
Abdominal pain ^{{23} {37}} —[13%]
    
bruising at injection site ^{{23} {37}}
    
diarrhea ^{{23} {37}} —[7%]
    
dizziness ^{{23} {37}} —[7%]
    
drowsiness ^{{23} {37}} —[6%]
    
headache ^{{23} {37}} —[17%]
    
indigestion ^{{23} {37}} —[12%]
    
nausea ^{{23} {37}} —[12%]

Incidence less frequent (1 to 3%)
    
Bloated feeling or gas ^{{23} {37}}
    
burning or pain at injection site ^{{23} {37}}
    
constipation ^{{23} {37}}
    
feeling of fullness in gastrointestinal tract ^{{23} {37}}
    
increased sweating ^{{23} {37}}
    
vomiting ^{{23} {37}}





Overdose
For specific information on the agents used in the management of ketorolac overdose, see:

   • Antacids (Oral-Local) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Histamine H ₂-receptor Antagonists (Systemic) monograph;
   • Misoprostol (Systemic) monograph;
   • Omeprazole (Systemic) monograph; and/or
   • Sucralfate (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Factors that are associated with an increased risk of ketorolac toxicity (in addition to total daily dosage and duration of treatment) include hypovolemia; renal insufficiency; a patient history of gastrointestinal perforation, ulceration, or bleeding; and patient age of 65 years or older ^{37}.

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Abdominal pain

gastrointestinal ulceration and bleeding

metabolic acidosis ^{37}

Treatment of overdose
To decrease absorption—

Administering activated charcoal (if the medication was ingested orally) ^{38}. The initial dose of charcoal may be followed by a cathartic, such as magnesium citrate, if the charcoal is not pre-mixed with sorbitol ^{39}. Gastric lavage may also be performed ^{38}.

Induction of emesis may also be helpful.

To enhance elimination—Hemodialysis does not remove significant quantities of ketorolac from the body ^{37}.

Specific treatment—

For treatment of abdominal pain: Administering an antacid. See the product label or Antacids (Oral-Local) for specific dosing guidelines.

For treatment of gastrointestinal ulceration or bleeding: Discontinuing ketorolac therapy immediately. Depending on the site and severity of the ulcer, administering antacids, histamine H ₂-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine), misoprostol, omeprazole, and/or sucralfate. See the package inserts or Antacids (Oral-Local) , Histamine H ₂-receptor Antagonists (Systemic) , Misoprostol (Systemic) , Omeprazole (Systemic) , or Sucralfate (Oral-Local) for specific dosing guidelines for these products. ^{42}

Supportive care—Supportive measures, such as establishing intravenous lines, hydration, administration of plasma volume expanders, and support of ventilatory function, should be instituted as needed ^{38}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ketorolac (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ketorolac, aspirin, or any other nonsteroidal anti-inflammatory drug (NSAID)

Pregnancy—Crosses the placenta; use during second half of pregnancy may cause adverse effects on fetal or neonatal blood flow





Breast-feeding—Not recommended because of potential adverse effects in the infant; ketorolac is distributed into breast milk





Use in the elderly—Higher risk of gastrointestinal and/or renal toxicity, possibly because of reduced clearance in addition to increased sensitivity
Other medications, especially anticoagulants, aspirin or other salicylates, other NSAIDs, those cephalosporins that may adversely affect blood clotting, lithium, methotrexate, plicamycin, probenecid, and valproic acid
Other medical problems, especially bleeding (active, history of, or predisposition to), peptic ulcer or other ulcerative or inflammatory gastrointestinal tract disease (active or history of), and renal function impairment

Proper use of this medication
Proper administration:

For oral dosage form
Taking with food (a meal or snack) to reduce gastrointestinal irritation, or with an antacid

Taking with a full glass of water, then remaining in an upright position for at least 15 to 30 minutes, to reduce risk of esophageal irritation

For injection
Proper injection technique (if self-medicating at home)
» Not using more medication than prescribed or using for longer than 5 days

Not saving unused medication for the future, and not sharing it with others

» Proper dosing
Missed dose (scheduled dosing): Using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Not using acetaminophen concurrently for more than a few days, and not using aspirin, other salicylates, or other NSAIDs concurrently, unless combination therapy prescribed and monitored by physician or dentist

» Caution if dizziness or drowsiness occurs; not driving, using machines, or doing anything else that requires alertness


Side/adverse effects
Signs of potential side effects, especially edema; hypertension; purpura; skin rash or itching; stomatitis; anaphylaxis or anaphylactoid reaction; aseptic meningitis; asthma, bronchospasm, or dyspnea; anemia; aseptic meningitis; bloody stools; blurred vision or other vision change; cholestatic jaundice; convulsions; edema of tongue; exfoliative dermatitis; fainting; fever; flank pain; gastrointestinal ulceration or bleeding; hallucinations; hearing loss; hemolytic uremic syndrome; hepatitis; hives; hyperactivity; hypotension; increase in frequency or volume of urination; laryngeal edema; leukopenia; mental depression; nephritis; nosebleeds; oliguria; pancreatitis, acute; psychosis; pulmonary edema; rectal bleeding; renal failure; rhinitis; Stevens-Johnson syndrome; thrombocytopenia; tinnitus; or toxic epidermal necrolysis


General Dosing Information
Ketorolac may be administered on a scheduled or on an as-needed basis, depending on the type and severity of pain ^{37}.

Ketorolac may be administered intramuscularly, intravenously, or orally ^{37}. An intravenous dose should be given over at least 15 seconds ^{37}. An intramuscular injection should be given slowly, deep into the muscle. Ketorolac injection contains alcohol and should not be administered intrathecally or epidurally ^{37}.

Because of the risk of anaphylaxis or other severe allergic reactions, equipment and medications to treat these complications should be available for immediate use when the first dose of ketorolac is administered ^{37}.

Hypovolemia increases the risk of adverse renal effects and should be corrected before ketorolac therapy is instituted ^{37}.

Ketorolac therapy should be initiated with parenteral administration, after which additional doses may be given parenterally or orally ^{37}. However, the duration of treatment by any route or combination of routes is not to exceed 5 days ^{37}. The patient should be transferred to another analgesic as quickly as possible ^{37}.

Concurrent use of ketorolac with an opioid analgesic provides additive analgesia ^{15} and may permit lower doses of both medications to be utilized ^{15}. Breakthrough pain that occurs during ketorolac treatment may be treated with an opioid analgesic (unless contraindicated); increasing the dose or the frequency of administration of ketorolac is not recommended ^{37}.

For treatment of adverse effects
For abdominal pain—Administering an antacid. See the product label or Antacids (Oral-Local) for specific dosing guidelines for these products.

For gastrointestinal ulceration or bleeding—Discontinuing ketorolac therapy immediately. Depending on the site and severity of the ulcer, administering antacids, histamine H ₂-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine), misoprostol, omeprazole, and/or sucralfate. See the package inserts or Antacids (Oral-Local) , Histamine H ₂-receptor Antagonists (Systemic) , Misoprostol (Systemic) , Omeprazole (Systemic) , or Sucralfate (Oral-Local) monographs for specific dosing guidelines for these products. ^{42}

For severe hypersensitivity reactions (e.g., anaphylaxis or anaphylactoid reaction or laryngeal edema)—Depending on the nature and severity of the symptoms, administering epinephrine and corticosteroids, and, in some cases, antihistamines. See the package inserts or Antihistamines (Systemic) , Corticosteroids—Glucocorticoid Effects (Systemic), or Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monographs for specific dosing guidelines for individual agents.

For renal failure—Dialysis may be needed ^{21}. However, dialysis is not likely to assist in removing ketorolac from the body after an overdose; decreased clearance and prolongation of half-life have been reported in patients receiving dialysis ^{37}.


Oral Dosage Forms

KETOROLAC TROMETHAMINE TABLETS USP

Usual adult dose
Analgesic:
Oral, as a continuation of initial parenteral therapy



Patients 16 to 64 years of age who weigh at least 50 kg and have normal renal function
20 mg initially, followed by 10 mg up to four times a day at four- to six-hour intervals as needed ^{37}.

Patients weighing less than 50 kg; and/or
Patients with renal function impairment
10 mg up to four times a day, at four- to six-hour intervals as needed ^{37}.


Note: The recommended doses and frequency of administration should not be increased if pain relief is inadequate or breakthrough pain occurs between doses ^{37}. Supplemental doses of opioid analgesic may be used, if not contraindicated, to provide additional analgesia ^{37}.


Usual adult prescribing limits
Oral, 40 mg per day ^{{23} {37}}. The duration of treatment (parenteral followed by oral administration) is not to exceed five days ^{37}.

Usual pediatric dose
Patients up to 16 years of age— Safety and efficacy have not been established ^{37}.

Usual geriatric dose
Analgesic
Oral, as a continuation of initial parenteral therapy: 10 mg up to four times a day at four- to six-hour intervals as needed ^{37}.

Note: The recommended doses and frequency of administration should not be increased if pain relief is inadequate or breakthrough pain occurs between doses ^{37}. Supplemental doses of opioid analgesic may be used, if not contraindicated, to provide additional analgesia ^{37}.



Usual geriatric prescribing limits
Oral, 40 mg per day ^{37}. The duration of treatment (parenteral followed by oral administration) is not to exceed five days ^{37}.

Strength(s) usually available
U.S.—


10 mg (Rx) [Toradol (lactose)]

Canada—


10 mg (Rx) [Toradol (lactose)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer ^{23}. Protect from light ^{37} and excessive humidity.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


KETOROLAC TROMETHAMINE INJECTION USP

Usual adult dose
Analgesic: Patients 16 to 64 years of age who weigh at least 50 kg and have normal renal function
Intramuscular, a single dose of 60 mg followed, if necessary, by oral ketorolac (see Ketorolac Tromethamine Tablets USP ) or by other analgesic therapy, or

Intramuscular, 30 mg every six hours, up to a maximum of twenty doses given over five days, or

Intravenous, 30 mg as a single dose or as multiple doses administered every six hours, up to a maximum of twenty doses given over five days ^{37}.

Patients weighing less than 50 kg; and/or
Patients with renal function impairment
Intramuscular, a single dose of 30 mg followed, if necessary, by oral ketorolac (see Ketorolac Tromethamine Tablets USP ) or by other analgesic therapy, or

Intramuscular, 15 mg every six hours, up to a maximum of twenty doses given over five days, or

Intravenous, 15 mg as a single dose or as multiple doses administered every six hours, up to a maximum of twenty doses given over five days ^{37}.


Note: The recommended doses and frequency of administration should not be increased if pain relief is inadequate or breakthrough pain occurs between doses ^{37}. Supplemental doses of opioid analgesic may be used, if not contraindicated, to provide additional analgesia ^{37}.


Usual adult prescribing limits ^{37}
Patients 16 to 64 years of age who weigh at least 50 kg and have normal renal function
Intramuscular or intravenous, 120 mg per day. The duration of therapy is not to exceed five days.

Patients weighing less than 50 kg; and/or
Patients with renal function impairment
Intramuscular or intravenous, 60 mg per day. The duration of therapy is not to exceed five days.


Usual pediatric dose
Patients up to 16 years of age—Safety and efficacy have not been established ^{37}.
[Post operative pain management, short term use]¹
Intravenous, 1 mg per kg of body weight alone or as an adjunct.^{{44}{45}{46}{47}{48}{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}{65}}


Usual geriatric dose
Analgesic ^{37}
Intramuscular, a single dose of 30 mg, followed, if necessary, by oral ketorolac (see Ketorolac Tromethamine Tablets USP ) or by other analgesic therapy, or

Intramuscular, 15 mg every six hours, up to a maximum of twenty doses administered over five days, or

Intravenous, 15 mg as a single dose or as multiple doses administered every six hours, up to a maximum of twenty doses administered over five days.

Note: The recommended doses and frequency of administration should not be increased if pain relief is inadequate or breakthrough pain occurs between doses ^{37}. Supplemental doses of opioid analgesic may be used, if not contraindicated, to provide additional analgesia ^{37}.



Usual geriatric prescribing limits
Intramuscular or intravenous, 60 mg per day ^{37}. The duration of therapy is not to exceed five days ^{37}.

Strength(s) usually available
U.S.—


1.5% (15 mg per mL) (Rx) [Toradol (alcohol 10%)]


3% (30 mg per mL; 60 mg per 2 mL) (Rx) [Toradol (alcohol 10%)]

Canada—


1% (10 mg per mL) (Rx) [Toradol (alcohol 10%)]


1.5% (15 mg per mL) (Rx) [Toradol (alcohol 10%)]


3% (30 mg per mL; 60 mg per 2 mL) (Rx) [Toradol (alcohol 10%)]

Note: The product containing 60 mg in 2 mL is not recommended for intravenous administration ^{37}.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light ^{37}.

Incompatibilities:
Ketorolac and morphine should not be mixed in the same syringe ^{37}.

Revised: 08/17/2000

References

1. Rubin P, Yee JP, Ruoff G. Comparison of long-term safety of ketorolac tromethamine and aspirin in the treatment of chronic pain. Pharmacotherapy 1990; 10(6) (Pt 2): 106-10.
   

2. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The US Pharmacopeial Convention Inc 1997. p. 404.
   
   
   

3. Jallad NS, Pages LJ, Mroszczak EJ, et al. Pharmacokinetics of oral and intramuscular ketorolac tromethamine (KT) in healthy geriatric, renally and hepatically impaired subjects [abstract]. J Clin Pharmacol 1989 Sep; 29: 855.
   

4. Jung D, Mroszczak EJ, Wu A, et al. Pharmacokinetics of ketorolac and p-hydroxyketorolac following oral and intramuscular administration of ketorolac tromethamine. Pharm Res 1989: 62-5.
   

5. MacDonald FC, Gough KJ, Nicoll RAG, et al. Psychomotor effects of ketorolac in comparison with buprenorphine and diclofenac. Br J Clin Pharmacol 1989; 27: 453-9.
   

6. Staquet JH. A double-blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain. J Clin Pharmacol 1989 Nov; 29: 1031-6.
   

7. Wischnik A, Manth SM, Lloyd J, et al. The excretion of ketorolac tromethamine into breast milk after multiple oral dosing. Eur J Clin Pharmacol 1989; 36: 521-4.
   

8. Arsac M, Frileux C. Comparative analgesic efficacy and tolerability of ketorolac tromethamine and glafenine in patients with postoperative pain. Curr Med Res Opin 1988; 11: 214-20.
   

9. Conrad KA, Fagan TC, Mackie MJ, et al. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988 May; 43: 542-6.
   

10. Estenne B, Julien M, Charleux H, et al. Comparison of ketorolac, pentazocine, and placebo in treating postoperative pain. Curr Ther Res Clin Exp 1988 Jun; 43: 1173-82.
    

11. Greer IA, Johnson J, Tulloch I, et al. Effect of maternal ketorolac administration on platelet function in the newborn. Eur J Obstet Gynecol Reprod Biol 1988 Dec; 29: 257-60.
    

12. Jung D, Mroszczak E, Bynum L. Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration. Eur J Clin Pharmacol 1988; 35: 423-5.
    

13. Spowart K, Greer IA, McLaren M, et al. Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thromb Haemost 1988; 60: 382-6.
    

14. Walker JJ, Johnstone J, Lloyd J, et al. The transfer of ketorolac tromethamine from maternal to fetal blood. Eur J Clin Pharmacol 1988; 34: 509-11.
    

15. Gillies GWA, Kenny GNJC, Bullingham RES, et al. The morphine sparing effect of ketorolac tromethamine. Anaesthesia 1987; 42: 727-31.
    

16. Martinez JJ, Garg DC, Pages LJ, et al. Single dose pharmacokinetics of ketorolac in healthy young and renal impaired subjects [abstract]. J Clin Pharmacol 1987 Sep; 27: 722.
    

17. Mroszczak EJ, Lee FW, Combs D, et al. Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos 1987; 15: 618-26.
    

18. O'Hara DA, Fragen RJ, Kinzer M, et al. Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther 1987 May; 41: 556-61.
    

19. Bloomfield SS, Mitchell J, Cissell GB, et al. Ketorolac versus aspirin for postpartum uterine pain. Pharmacotherapy 1986; 6: 247-52.
    

20. Yee JP, Koshiver JE, Allbon C, et al. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986; 6: 253-61.
    

21. Panel consensus
    

22. HOLD
    

23. Ketorolac product monograph (Syntex—Canada), New 3/91, Rec 7/91.
    

24. Dukes MNG, editor. Meyler's side effects of drugs: an encyclopedia of adverse reactions and interactions. 10th ed. Amsterdam: Elsevier; 1984. p. 151-71.
    

25. Sitz KV, Engler RJM, Carpenter GB. Ketorolac tromethamine (Toradol) induced asthma: a case report. Ann Allergy 1992; 68: 115.
    

26. Rotenberg FA, Giannini VS. Hyperkalemia associated with ketorolac. Ann Pharmacother 1992; 26: 778-9.
    

27. Mroszczak EJ, Combs DL, Goldblum R, et al. The effect of probenecid (P) on ketorolac (K) pharmacokinetics after oral dosing of ketorolac tromethamine (KT) [abstract]. Clin Pharmacol Ther 1992; 51: 154.
    

28. Panel comments, Anesthesiology Panel Meeting, 10/17/92.
    

29. Panel consensus on draft of 11/13/92.
    

30. Comment on draft of 11/13/92.
    

31. Drug Brief, Canadian Pharmaceutical Association, 12/14/92.
    

32. Panel consensus on ballot of 3/93.
    

33. Panel consensus on ballot of 2/93.
    

34. Health Protection Branch of Canada. “Dear Doctor” letter, 11/27/92.
    

35. Panel consensus on ballot of 2/93.
    

36. Comment on ballot of 2/93.
    

37. Ketorolac package insert (Syntex—US), Rev 8/97, Rec 2/99.
    

38. Reviewers' responses to Anti-inflammatory Analgesics, Nonsteroidal (Systemic) monograph revision 1988.
    

39. Clinical Toxicology/Substance Abuse Panel Meeting, 4/17/94, revised per Panelist comment, draft 3/27/95.
    

40. Panelist comment on draft of 3/27/95.
    

41. Reviewers' responses to monograph draft 3/27/95.
    

42. Reviewers' responses to monograph draft 3/27/95.
    

43. Panel comments on draft of 3/27/95.
    

44. Panel consensus January 2000 (Ketorolac for the treatment/prophylaxis of pain in pediatric patients).
    

45. Gunter JB, Varughese AM, Harrington JF et al. Recovery and complication after tonsillectomy in children: a comparison of ketorolac and morphine. Anesth Analg 1995; 81(6): 1136-41.
    

46. Agrawal A, Gerson CR, Seligman I, et al. Postoperative hemorrhage after tonsillectomy; use of ketorolac tromethamine. Otolaryngol Head Neck Surg 1999; 120(3): 335-9.
    

47. Romsing J, Ostergaard D, Walther-Larsen S, et al. Analgesic efficacy and safety of preoperative versus postoperative ketorolac in pediatric tonsillectomy. Acta Anaesthesiol Scan 1998; 42(7): 770-5.
    

48. Mather SJ, Peutrell JM. Postoperative morphine requirements, nausea, and vomiting following anesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques. Pediatr Anesth 1995; 5:185-8.
    

49. Splinter WM, Rhine EJ, Roberts DW, et al. Preoperative ketorolac increases bleeding after tonsillectomy in children. Can J Anaesth 1996; 43(6): 560-3.
    

50. Sutters KA, Levine JD, Dibble S. Analgesic efficacy and safety of single-dose intramuscular ketorolac for postoperative pain management in children following tonsillectomy. Pain 1995; 61(1): 145-53.
    

51. Watcha MF, Ramirez-Ruiz M, White PF, et al. Perioperative effects of oral ketorolac and acetaminophen in children undergoing bilateral myringotomy. Can J Anaesth 1992; 39(7): 649-54.
    

52. Bean-Lijewski JD, Stinson JC. Acetaminophen or ketorolac for post myringotomy pain in children? A prospective double-blinded comparison. Paediatr Amaesta 1997; 7: 131-7.
    

53. Mendel HG, Guarnieri KM, Sundt LM, et al. The effects of ketorolac and fentanyl on postoperative vomiting and analgesic requirements in children undergoing strabismus surgery. Anesth Analg 1995; 80: 1129-33.
    

54. Munro HM, Riegger LQ, Reynolds PI. Comparison of the analgesic and emetic properties of ketorolac and morphine for pediatric outpatient strabismus surgery. Br J Anaesth 1994; 72: 624-8.
    

55. Graham SG, Wandless JG. The effects of ketorolac as an adjuvant to local anaesthetic infiltration for analgesia in pediatric umbilical hernia surgery. Paediatr Anaesth 1995; 5: 161-3.
    

56. Maunuksela EL, Kokki H, Bullingham RE. Comparison of intravenous ketorolac with morphine for postoperative pain in children. Clin Pharmacol Ther 1992; 52(4): 436-43.
    

57. Watcha MF, Jones MB, Lagueruela RG, et al. Comparison of ketorolac and morphine as adjuvants during pediatric surgery. Anesthesiology 1992; 76: 368-72.
    

58. Bean-Lijewski JD, Hunt RD. Effect of ketorolac on bleeding time and postoperative pain in children: a double-blind, placebo-controlled comparison with meperidine. J Clin Anesth 1996; 8: 25-30.
    

59. Vetter TR, Heiner EJ. Intravenous ketorolac as an adjuvant to pediatric patient-controlled analgesia with morphine. J Clin Anesth 1994; 6: 110-3.
    

60. Pierce MC, Fuchs S. Evaluation of ketorolac in children with forearm fractures. Acad Emerg Med 1997; 4(1): 22-6.
    

61. Foster PN, Williams JG. Bradycardia following intravenous ketorolac in children. Eur J Anaesthesiol 1997; 14(3): 307-9.
    

62. Gonzalez-Martin G, Maggio L, Gonzalez-Sotomayor J, Zuniga S. Pharmacokinetics of ketorolac in children after abdominal surgery. Int J Clin Pharmacol Ther 1997; 35(4): 160-3.
    

63. Olkkola KT, Maunuksela EL. The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children. Br J Clin Pharmac 1991; 31: 182-4.
    

64. Houck CS, Wilder RF, McDermott JS. Safety of intravenous ketorolac therapy in children and cost savings with a unit dosing system. J Pediatr 1996; 129(2): 292-6.
    

65. Rusy LM, Houck CS, Sullivan HJ, et al. A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy; analgesic and bleeding. Anesth Analg 1995 80(2): 226-9.
    

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