Ketorolac Tromethamine

TORADOL (ketorolac tromethamine) ORAL10 mg tablets are round, white, film-coate d, red printed tablets. There is a large T printed on both sides of the tablet, with TORADOL (ketorolac tromethamine) on one side, and ROCHE on the other, available in bottles of 100 tablets (NDC 0004-0273-01).

Storage

Store bottles at 15°to 30°C (59°to 86°F).

Distributed by: Roche Laboratories Inc.340 Kingsland Street, Nutley, New Jersey 07110 - 1199. FDA revision date: 11/13/2007

Your pharmacist can provide more information about ketorolac.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Adverse reaction rates increase with higher doses of TORADOL (ketorolac tromethamine) . Practitioners should be alert for the severe complications of treatment with TORADOL (ketorolac tromethamine) , such as GI ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (see BOXED WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). These NSAID-related complications can be serious in certain patients for whom TORADOL (ketorolac tromethamine) is indicated, especially when the drug is used inappropriately.

In patients taking TORADOL (ketorolac tromethamine) or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:

Additional adverse experiences reported occasionally ( < 1% in patients taking TORADOL (ketorolac tromethamine) or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infections, sepsis

Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope

Dermatologic: alopecia, photosensitivity, urticaria

Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise

Reproductive, female: infertility

Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention

Other rarely observed reactions (reported from postmarketing experience in patients taking TORADOL (ketorolac tromethamine) or other NSAIDs) are:

Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see WARNINGS), myalgia

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion - see BOXED WARNING, WARNINGS, and PRECAUTIONS)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome

Postmarketing Surveillance Study

A large postmarketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamineIV/IM, demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamineIV/IM (see Table 3A).

Table 3 Incidence of Clinically Serious GI Bleeding as Related to Age, Total Daily Dose, and History of GI Perforation, Ulcer, Bleeding (PUB) After up to 5 Days of Treatment With Ketorolac TromethamineIV/IMA.

Read the entire FDA prescribing information for Toradol (Ketorolac Tromethamine)

Prototypical NSAIA;1 2 3 21 32 33 70 91 92 93 96 140 pyrrolizine carboxylic acid derivative;2 3 21 32 33 70 91 92 93 96 140 structurally related to tolmetin and indomethacin.2 33 47 70 83

General

• Current principles of pain management indicate that analgesics, including ketorolac, 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

• Consider potential benefits and risks of ketorolac therapy as well as alternative therapies before initiating therapy with the drug.198

Administration

Administer IV, IM, or orally in adults; administer IV or IM in children 2–16 years of age.1

Initiate therapy in adults with parenteral (IV or IM) ketorolac; oral formulation is used as continuation therapy, as required.1 154 Administer IV or IM as a single dose or every 6 hours; administer orally every 4–6 hours.1

In children 2–16 years of age, administer as a single IV or IM dose.1

Switch patients to alternate analgesic therapy as soon as clinically possible.1 154

Oral Administration

Manufacturer makes no specific recommendations regarding administration with meals; high-fat meal may decrease rate but not extent of absorption and reduce peak plasma concentrations.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer over ≥15 seconds.1

IM Administration

Administer IM slowly and deeply into the muscle.1

For drug compatibility information, see Compatibility under Stability.

Dosage

Available as ketorolac tromethamine; dosage expressed in terms of the salt.1

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.198 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.198

For breakthrough pain, supplement with low doses of opiate analgesics (unless contraindicated) as needed rather than higher or more frequent doses of ketorolac.1 142

Pediatric Patients

Children 2–16 years of age: One dose of 0.5 mg/kg (maximum 15 mg).1

Children 2–16 years of age: One dose of 1 mg/kg (maximum 30 mg).1

Adults

When switching from parenteral to oral therapy, the first oral dose is 20 mg, followed by 10 mg every 4–6 hours (maximum 40 mg in a 24-hour period).1

Weight <50 kg: When switching from parenteral to oral therapy, 10 mg every 4–6 hours (maximum 40 mg in a 24-hour period).1

30 mg.1

Weight <50 kg: 15 mg.1

60 mg.1

Weight <50 kg: 30 mg.1

30 mg every 6 hours.1

Weight <50 kg: 15 mg every 6 hours.1

Prescribing Limits

Pediatric Patients

Only a single parenteral dose is recommended.1

15 mg.1

30 mg.1

Adults

Total combined duration of parenteral and oral therapy should not exceed 5 days.1 137 142 143 154

All adults: Maximum 40 mg in a 24-hour period.1

Maximum 120 mg in a 24-hour period.1

Weight <50 kg: Maximum 60 mg in a 24-hour period.1

Special Populations

Hepatic Impairment

Need for dosage adjustment not fully established;1 70 evidence in patients with cirrhosis suggests that dosage adjustment may not be necessary.137

Renal Impairment

Safety not established in patients with Scr >5 mg/dL and/or those undergoing dialysis.1

When switching from parenteral to oral therapy, 10 mg every 4–6 hours (maximum 40 mg in a 24-hour period).1

15 mg.1

30 mg.1

15 mg every 6 hours.1 Maximum 60 mg in a 24-hour period.1

Geriatric Patients

Dosage recommendations are the same as those for patients with moderately increased Scr or for those weighing <50 kg.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ketorolac Tromethamine Injection, USP is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for Ketorolac Tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the structural formula is presented in Figure 1 

FIGURE 1

C15H13NO3 • C4H11NO3
Ketorolac Tromethamine is a racemic mixture of [-]S and [+]R Ketorolac Tromethamine. Ketorolac Tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac Tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of Ketorolac Tromethamine is 376.40.

Ketorolac Tromethamine Injection , USP is available for intravenous (IV) or intramuscular (IM) administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in sterile solution; 60 mg in 2 mL (3%) of Ketorolac Tromethamine in sterile solution is available for IM administration only. The solutions contain 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg and 8.70  mg respectively, of sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear to slightly yellow in color.

Pharmacodynamics

Ketorolac Tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. The biological activity of Ketorolac Tromethamine is associated with the S-form.
Ketorolac Tromethamine possesses no sedative or anxiolytic properties.

The peak analgesic effect of Ketorolac Tromethamine occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of Ketorolac Tromethamine. The greatest difference between large and small doses of Ketorolac Tromethamine by either route is in the duration of analgesia.

Pharmacokinetics

Ketorolac Tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.

Comparison of IV, IM and Oral Pharmacokinetics: The pharmacokinetics of Ketorolac Tromethamine, following IV, IM and oral doses of Ketorolac Tromethamine are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL and IM forms of Ketorolac Tromethamine was equal to that following an IV bolus.

Linear Kinetics
In adults, following administration of single ORAL, IM or IV doses of Ketorolac Tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of Ketorolac Tromethamine in adults, following single or multiple IM, IV or recommended oral doses of Ketorolac Tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Distribution
The mean apparent volume (Vβ) of Ketorolac Tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The Ketorolac Tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations.

Ketorolac Tromethamine is excreted in human milk (see PRECAUTIONS - Nursing mothers).

Metabolism
Ketorolac Tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.

Excretion
The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces.A single-dose study with 10 mg Ketorolac Tromethamine (n=9) demonstrated that the S-enantiomer is cleared approximately two times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in Table 2 (see CLINICAL PHARMACOLOGY - Kinetics in Special Populations).

The half-life of the Ketorolac Tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.

Accumulation
Ketorolac Tromethamine administered as an IV bolus, every 6 hours for 5 days to healthy subjects (n = 13), showed no significant difference in Cmax on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD ± 0.13) on Day 1 and 0.55 mcg/mL (SD ± 0.23) on Day 6. Steady state was approached after the fourth dose.
Accumulation of Ketorolac Tromethamine has not been studied in special populations (geriatric, pediatric, renal failure or hepatic disease patients).

Kinetics in Special Populations

Geriatric Patients
Based on single-dose data only, the half-life of the Ketorolac Tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS - Geriatric use).

Pediatric Patients
Limited information is available regarding the pharmacokinetics of dosing of Ketorolac Tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1). There are no pharmacokinetic data available for administration of Ketorolac Tromethamine by the IM route in pediatric patients.

Renal Insufficiency
Based on single-dose data only, the mean half-life of Ketorolac Tromethamine in renally impaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total Ketorolac Tromethamine clearance in the elderly and populations with renal impairment (r = 0.5).

In patients with renal disease, the AUC∞of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of Ketorolac Tromethamine implies an increase in unbound fraction.

The AUC∞-ratio of the Ketorolac Tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see WARNINGS - Renal Effects).

Hepatic Insufficiency: There was no significant difference in estimates of half-life, AUC∞and Cmax in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS - Hepatic Effects and Table 2).
Race: Pharmacokinetic differences due to race have not been identified.

1Estimated from 30 mg single IM doses of Ketorolac Tromethamine
2Estimated from 10 mg single oral doses of Ketorolac Tromethamine

3Liters/hours/kilogram

IV-Administration: In normal adult subjects (n=37), the total clearance of 30 mg IV-administered Ketorolac Tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4.0 to 7.9) hours. (See Kinetics in Special Populations for use of IV dosing of Ketorolac Tromethamine in pediatric patients.)

CLINICAL STUDIES 

Adult Patients
In a postoperative study, where all patients received morphine by a PCA device, patients treated with Ketorolac Tromethamine IV as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg q3h), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving Ketorolac Tromethamine IV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

General

Ketorolac Tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Ketorolac Tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Ketorolac Tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Ketorolac Tromethamine. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ketorolac Tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Ketorolac Tromethamine should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Ketorolac Tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Ketorolac Tromethamine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Ketorolac Tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. 

Pre-existing Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Ketorolac Tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Information for Patients

Ketorolac Tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome.

Physicians, when prescribing Ketorolac Tromethamine, should inform their patients or their guardians of the potential risks of Ketorolac Tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to give oral Ketorolac Tromethamine to other family members and to discard any unused drug. Remember that the total combined duration of use of oral Ketorolac Tromethamine and IV or IM dosing of Ketorolac Tromethamine is not to exceed 5 days in adults. Ketorolac Tromethamine is not indicated for use in pediatric patients.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see WARNINGS].

2. Ketorolac Tromethamine, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, andPerforation).

3. Ketorolac Tromethamine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

4. Heart Failure And Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS].
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 
7. In late pregnancy, as with other NSAIDs, Ketorolac Tromethamine should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.) or if abnormal liver tests persist or worsen, Ketorolac Tromethamine should be discontinued.

Drug Interactions

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that Ketorolac Tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Warfarin, Digoxin, Salicylate, and Heparin
The in vitro binding of warfarin to plasma proteins is only slightly reduced by Ketorolac Tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter Ketorolac Tromethamine protein binding. In a study involving 12 adult volunteers, oral Ketorolac Tromethamine was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, Ketorolac Tromethamine dosed IV or IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between Ketorolac Tromethamine and warfarin or heparin, the administration of Ketorolac Tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGS and PRECAUTIONS - Hematological Effects).

The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.

Aspirin
When Ketorolac Tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free Ketorolac Tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Ketorolac Tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects.

Diuretics
Clinical studies, as well as postmarketing observations, have shown that Ketorolac Tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be  observed closely for signs of renal failure (see WARNINGS - Renal Effects), as well as to assure diuretic efficacy.

Probenecid
Concomitant administration of oral Ketorolac Tromethamine and probenecidresulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of Ketorolac Tromethamine and probenecid is contraindicated.

Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

ACE Inhibitors/Angiotensin II Receptor Antagonists
Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients.

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. This interaction should be givenconsideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists.

Antiepileptic Drugs
Sporadic cases of seizures have been reported during concomitant use of Ketorolac Tromethamine and antiepileptic drugs(phenytoin, carbamazepine).

Psychoactive Drugs
Hallucinations have been reported when Ketorolac Tromethamine was used in patients taking psychoactive drugs(fluoxetine, thiothixene, alprazolam).

Pentoxifylline
When Ketorolac Tromethamine is administered concurrently with pentoxifylline, there is an increased tendency to bleeding.

Nondepolarizing Muscle Relaxants
In postmarketing experience there have been reports of a possible interaction between Ketorolac Tromethamine IV/IM and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of Ketorolac Tromethamine with muscle relaxants has not been formally studied.

Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

An 18-month study in mice with oral doses of Ketorolac Tromethamine tablets at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. 
Ketorolac Tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac Tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, Ketorolac Tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.

Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of Ketorolac Tromethamine, respectively.

Pregnancy

Teratogenic Effects
Pregnancy Category C

Reproduction studies have been performed during organogenesis using daily oral doses of Ketorolac Tromethamine tablets at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. However, animal reproduction studies are not always predictive of human response.

Nonteratogenic Effects:

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Oral doses of Ketorolac Tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation day 17, caused dystocia and higher pup mortality in rats.

There are no adequate and well-controlled studies of Ketorolac Tromethamine  in pregnant women. Ketorolac Tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The use of Ketorolac Tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).

Effects on Fertility

The use of Ketorolac Tromethamine, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of Ketorolac Tromethamine should be considered.

Nursing Mothers

Limited data from one published study that included 10 breastfeeding women 2-6 days postpartum showed low levels of ketorolac in breast milk and were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg of Ketorolac Tromethamine, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1,000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight-adjusted dose.
Exercise caution when ketorolac is administered to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infants healthcare provider if they note any adverse events.

Pediatric Use

Ketorolac Tromethamine is not indicated for use in pediatric patients. The safety and effectiveness of Ketorolac Tromethamine in pediatric patients below the age of 17 have not been established.

Geriatric Use

(≥65 Years of Age)
Because Ketorolac Tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related adverse effects of NSAIDs (see WARNINGS - Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation), extreme caution and reduced dosages (see DOSAGE AND ADMINISTRATION) and careful clinical monitoring must be used when treating the elderly with Ketorolac Tromethamine.

Symptoms and Signs 
Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Treatment
Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients se en within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis or hemoperfusion may not be useful due to high protein binding.
Single overdoses of Ketorolac Tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction which have resolved after discontinuation of dosing.