Ketorolac

Generic Name: Ketorolac tromethamine

Dosage Form: tablet, film coated
Ketorolac TROMETHAMINE TABLETS USP, 10 mg

0314

Rx only

WARNING

Ketorolac tromethamine tablets, a non-steroidal anti-inflammatory drug (NSAID), are indicated for the short-term (up to 5 days in adults), management of moderately severe acute pain that requires analgesia at the opioid level and only as continuation treatment following IV or IM dosing of Ketorolac tromethamine, if necessary. The total combined duration of use of Ketorolac tromethamine tablets and Ketorolac tromethamine should not exceed 5 days.

Ketorolac tromethamine tablets are not indicated for use in pediatric patients and they are NOT indicated for minor or chronic painful conditions. Increasing the dose of Ketorolac tromethamine tablets beyond a daily maximum of 40 mg in adults will not provide better efficacy but will increase the risk of developing serious adverse events.

GASTROINTESTINAL RISK

• Ketorolac tromethamine, including Ketorolac tromethamine tablets can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, Ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

CARDIOVASCULAR RISK

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS and CLINICAL STUDIES).


• Ketorolac tromethamine is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

RENAL RISK

• Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS).

RISK OF BLEEDING

• Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).

Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery.

RISK DURING LABOR AND DELIVERY

• The use of Ketorolac tromethamine in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions. The use of Ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.

CONCOMITANT USE WITH NSAIDs

• Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.

SPECIAL POPULATIONS

• Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see WARNINGS).

Ketorolac Description

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of non-steroidal 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. The structural formula is:

C19H24N2O6          M.W. 376.41

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.

Ketorolac tromethamine tablets are round, white, unscored, film-coated tablets. Each tablet, for oral administration, contains 10 mg Ketorolac tromethamine, the active ingredient. In addition, each tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.

Ketorolac - Clinical Pharmacology

Pharmacodynamics

Ketorolac tromethamine is a non-steroidal 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 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 and IM doses of Ketorolac tromethamine and oral doses of Ketorolac tromethamine, are compared in TABLE 1. In adults, the extent of bioavailability following administration of the ORAL form of Ketorolac tromethamine and IM form of Ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics

In adults, following administration of single ORAL doses of Ketorolac tromethamine or 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 or IV doses of Ketorolac tromethamine 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.

Absorption

Ketorolac tromethamine is 100% absorbed after oral administration (see TABLE 1). Oral administration of Ketorolac tromethamine after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of Ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of absorption.

Distribution

The mean apparent volume (Vß) 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 (≥ 65 Years of Age)).

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 Effect and TABLE 2).

Race

Pharmacokinetic differences due to race have not been identified.

TABLE 1: Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine

* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers † Derived from IM pharmacokinetic studies in 54 normal volunteers ‡ Derived from IV pharmacokinetic studies in 24 normal volunteers § Time-to-peak plasma concentration ¶ Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data # Peak plasma concentration Þ Not applicable because 60 mg is only recommended as a single dose ß Trough plasma concentration à Average plasma concentration è Volume of distribution
Pharmacokinetic Parameters (units)	Oral*	Intramuscular†			Intravenous Bolus‡
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
Tmax§ (min)	44 ± 34	33 ± 21¶	44 ± 29	33 ± 21¶	1.1 ± 0.7¶	2.9 ± 1.8
Cmax# (mcg/mL) [single-dose]	0.87 ± 0.22	1.14 ± 0.32¶	2.42 ± 0.68	4.55 ± 1.27¶	2.47 ± 0.51¶	4.65 ± 0.96
Cmax (mcg/mL) [steady state qid]	1.05 ± 0.26¶	1.56 ± 0.44¶	3.11 ± 0.87¶	N/AÞ	3.09 ± 1.17¶	6.85 ± 2.61
Cminß (mcg/mL) [steady state qid]	0.29 ± 0.07¶	0.47 ± 0.13¶	0.93 ± 0.26¶	N/A	0.61 ± 0.21¶	1.04 ± 0.35
Cavgà (mcg/mL) [steady state qid]	0.59 ± 0.20¶	0.94 ± 0.29¶	1.88 ± 0.59¶	N/A	1.09 ± 0.30¶	2.17 ± 0.59
Vβè (L/kg)	0.175 ± 0.039					0.210 ± 0.044
% Dose metabolized ≤ 50			% Dose excreted in feces = 6
% Dose excreted in urine = 91			% Plasma protein binding = 99

TABLE 2: The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-Life of Ketorolac Tromethamine (IM* and ORAL†) in Adult Populations

* Estimated from 30 mg single IM doses of Ketorolac tromethamine † Estimated from 10 mg single oral doses of Ketorolac tromethamine ‡ Liters/hour/kilogram
	Total Clearance [in L/h/kg]‡		Terminal Half-life [in hours]
Type of Subjects	IM	ORAL	IM	ORAL
	Mean (range)	Mean (range)	Mean (range)	Mean (range)
Normal Subjects IM (n = 54) mean age = 32, range = 18 to 60 Oral (n = 77) mean age = 32, range = 20 to 60	0.023	0.025	5.3	5.3
	(0.010 to 0.046)	(0.013 to 0.050)	(3.5 to 9.2)	(2.4 to 9.0)
Healthy Elderly Subjects IM (n = 13), Oral (n = 12) mean age = 72, range = 65 to 78	0.019	0.024	7.0	6.1
	(0.013 to 0.034)	(0.018 to 0.034)	(4.7 to 8.6)	(4.3 to 7.6)
Patients with Hepatic Dysfunction IM and Oral (n = 7) mean age = 51, range = 43 to 64	0.029	0.033	5.4	4.5
	(0.013 to 0.066)	(0.019 to 0.051)	(2.2 to 6.9)	(1.6 to 7.6)
Patients with Renal Impairment IM (n = 25), Oral (n = 9) serum creatinine = 1.9 to 5.0 mg/dL, mean age (IM) = 54, range = 35 to 71 mean age (Oral) = 57, range = 39 to 70	0.015	0.016	10.3	10.8
	(0.005 to 0.043)	(0.007 to 0.052)	(5.9 to 19.2)	(3.4 to 18.9)
Renal Dialysis Patients IM and Oral (n = 9) mean age = 40, range = 27 to 63	0.016	--	13.6	--
	(0.003 to 0.036)		(8.0 to 39.1)

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 tromethamineIV 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 tromethamineIV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

Pediatric Patients

There are no data available to support the use of Ketorolac tromethamine tablets in pediatric patients.

Indications and Usage for Ketorolac

Carefully consider the potential benefits and risks of Ketorolac tromethamine and other treatment options before deciding to use Ketorolac tromethamine. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Acute Pain in Adult Patients

Ketorolac tromethamine tablets are indicated for the short-term (≤ 5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with IV or IM dosing of Ketorolac tromethamine, and Ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary.

The total combined duration of use of Ketorolac tromethamine tablets and Ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ADVERSEREACTIONS). Patients should be switched to alternative analgesics as soon as possible, but Ketorolac tromethamine tablet therapy is not to exceed 5 days.

Contraindications

(See also Boxed WARNING.)

Ketorolac tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to Ketorolac tromethamine.

Ketorolac tromethamine is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.

Ketorolac tromethamine should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma).

Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.

Ketorolac tromethamine is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Ketorolac tromethamine is contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see WARNINGS for correction of volume depletion).

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.

The use of Ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.

Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).

Ketorolac tromethamine is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.

The concomitant use of Ketorolac tromethamine and probenecid is contraindicated.

The concomitant use of Ketorolac tromethamine and pentoxifylline is contraindicated.

Warnings

(See also Boxed WARNING.)

The total combined duration of use of Ketorolac tromethamine tablets and IV or IM dosing of Ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine tablets are not indicated for use in pediatric patients.

The most serious risks associated with Ketorolac tromethamine are:

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation

Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with Ketorolac tromethamine.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, Ketorolac tromethamine. Do not use Ketorolac tromethamine for more than five days. However, even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of Ketorolac tromethamine until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Hemorrhage

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of Ketorolac tromethamine in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given Ketorolac tromethamine concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of Ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. Patients receiving therapy that affects hemostasis should be monitored closely.

In postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the peri-operative use of IV or IM dosing of Ketorolac tromethamine. Therefore, peri-operative use of Ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see PRECAUTIONS).

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Ketorolac tromethamine and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see CLINICAL PHARMACOLOGY). Therefore, Ketorolac tromethamine should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION) and such patients should be followed closely. With the use of Ketorolac tromethamine, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome.

Impaired Renal Function

Ketorolac tromethamine is contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see CONTRAINDICATIONS). Ketorolac tromethamine should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Because patients with underlying renal insufficiency are at increased risk of developing acute renal decompensation or failure, the risks and benefits should be assessed prior to giving Ketorolac tromethamine to these patients.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to Ketorolac tromethamine. Ketorolac tromethamine should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see Gastrointestinal Effects – RiskofUlceration, Bleeding, and Perforation). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Ketorolac tromethamine, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Ketorolac tromethamine, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with Ketorolac tromethamine. Therefore, Ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.

Skin Reactions

NSAIDs, including Ketorolac tromethamine, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, Ketorolac tromethamine should be avoided because it may cause premature closure of the ductus arteriosus.

Precautions

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 Effect

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.

Hematologic Effect

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.

Preexisting 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 non-steroidal 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 preexisting 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), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to giveKetorolac tromethamine tablets to other family members and to discard any unused drug.

Remember that the total combined duration of use of Ketorolac tromethamine tablets and IV or IM dosing of Ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine tablets are 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. Ketorolac tromethamine, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).


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, and Perforation).


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. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.


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)