TORADOL (ketorolac tromethamine) 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 chemical structure is:

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 376.41. Its molecular formula is C₁₉H₂₄N₂O₆.

TORADOL^ORAL is available as round, white, film-coated, red-printed tablets. Each tablet contains 10 mg ketorolac tromethamine, the active ingredient, with added lactose, magnesium stearate and microcrystalline cellulose. The white film-coating contains hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

The tablets are printed with red ink that includes FD&C Red #40 Aluminum Lake as the colorant. There is a large T printed on both sides of the tablet, as well as the word TORADOL on one side, and the word ROCHE on the other.

Last updated on RxList: 12/17/2007

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

Acute Pain in Adult Patients

TORADOL^ORAL is 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 TORADOL^ORAL is to be used only as continuation treatment, if necessary.

The total combined duration of use of TORADOL^ORAL 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 ADVERSE REACTIONS). Patients should be switched to alternative analgesics as soon as possible, but TORADOL^ORAL therapy is not to exceed 5 days.

Carefully consider the potential benefits and risks of TORADOL and other treatment options before deciding to use TORADOL. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. In adults, the combined duration of use of IV or IM dosing of ketorolac tromethamine and TORADOL^ORAL is not to exceed 5 days. In adults, the use of TORADOL^ORAL is only indicated as continuation therapy to IV or IM dosing of ketorolac tromethamine.

Transition from IV or IM dosing of ketorolac tromethamine (single- or multiple-dose) to multiple-dose TORADOL^ORAL:

Patients age 17 to 64: 20 mg PO once followed by 10 mg q4-6 hours prn not > 40 mg/day

Patients age ≥ 65, renally impaired, and/or weight < 50 kg (110 lbs): 10 mg PO once followed by 10 mg q4-6 hours prn not > 40 mg/day

Note:

Oral formulation should not be given as an initial dose

Use minimum effective dose for the individual patient

Do not shorten dosing interval of 4 to 6 hours

Total duration of treatment in adult patients: the combined duration of use of IV or IM dosing of ketorolac tromethamine and TORADOL^ORAL is not to exceed 5 days.

The following table summarizes TORADOL^ORAL dosing instructions in terms of age group:

Table 4 :Summary of Dosing Instructions

Patient Population	TORADOLORA L(following IV or IM dosing of ketorolac tromethamine)
Age < 17 years	Oral not approved
Adult Age 17 to 64 years	20 mg once, then 10 mg q4-6 hours prn not > 40 mg/day
Adult Age ≥ 65 years, renally impaired, and/or weight < 50 kg	10 mg once, then 10 mg q4-6 hours prn not > 40 mg/day

TORADOL^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 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

Last updated on RxList: 12/17/2007

Adverse reaction rates increase with higher doses of TORADOL. Practitioners should be alert for the severe complications of treatment with TORADOL, 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 is indicated, especially when the drug is used inappropriately.

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

Gastrointestinal (GI) experiences including:
abdominal pain*	constipation/diarrhea	dyspepsia*
flatulence	GI fullness	GI ulcers (gastric/duodenal)
gross bleeding/perforation	Heartburn	nausea*
stomatitis	Vomiting
Other experiences:
abnormal renal function	Anemia	dizziness
drowsiness	Edema	elevated liver enzymes
headaches*	Hypertension	increased bleeding time
injection site pain	Pruritus	purpura
rashes	Tinnitus	sweating
*Incidence greater than 10%

Additional adverse experiences reported occasionally ( < 1% in patients taking TORADOL 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 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 tromethamine^IV/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 tromethamine^IV/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 Tromethamine^IV/IMA.

A. Adult Patients Without History of PUB
Age of Patients	Total Daily Dose of Ketorolac TromethamineIV/IM
	≤ 60 mg	> 60 to 90 mg	> 90 to 120 mg	> 120 mg
< 65 years of age	0.4%	0.4%	0.9%	4.6%
≥ 65 years of age	1.2%	2.8%	2.2%	7.7%
B. Adult Patients With History of PUB
Age of Patients	Total Daily Dose of Ketorolac TromethamineIV/IM
	≤ 60 mg	> 60 to 90 mg	> 90 to 120 mg	> 120 mg
< 65 years of age	2.1%	4.6%	7.8%	15.4%
≥ 65 years of age	4.7%	3.7%	2.8%	25.0%

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that TORADOL 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 μg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 μg/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, TORADOL^ORAL 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 6.4 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 TORADOL and warfarin or heparin, the administration of TORADOL to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGS and PRECAUTIONS: Hematologic Effect).

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 TORADOL is administered with aspirin, its protein binding is reduced, although the clearance of free TORADOL 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 TORADOL 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 TORADOL^ORAL and probenecid resulted 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 μg/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of TORADOL 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/Angiotension II Receptor Antagonists

Concomitant use of ACE inhibitors and/or angiotension 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 angiotension II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotension II receptor antagonists.

Antiepileptic Drugs

Sporadic cases of seizures have been reported during concomitant use of TORADOL and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive Drugs

Hallucinations have been reported when TORADOL 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.

Last updated on RxList: 12/17/2007

(see also BOXED WARNING)

The total combined duration of use of TORADOL^ORAL and IV or IM dosing of ketorolac tromethamine is not to exceed 5 days in adults. TORADOL^ORAL is not indicated for use in pediatric patients.

The most serious risks associated with TORADOL are:

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

TORADOL is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding. Toradol 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 TORADOL.

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, TORADOL. Do not use TORADOL 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 TORADOL 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 TORADOL in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (eg, heparin or dicumarol derivatives) have an increased risk of bleeding complications if given TORADOL concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of TORADOL 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 TORADOL 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.

TORADOL 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, TORADOL 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 TORADOL, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome.

Impaired Renal Function

TORADOL is contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see CONTRAINDICATIONS). TORADOL 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 TORADOL to these patients.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to TORADOL. TORADOL 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 - Risk of Ulceration, Bleeding, and Perforation). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including TORADOL, 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 TORADOL, 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 TORADOL. Therefore, TORADOL should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.

Skin Reactions

NSAIDS, including TORADOL, 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, TORADOL should be avoided because it may cause premature closure of the ductus arteriosus.

General

TORADOL 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 TORADOL in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effect

TORADOL 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 TORADOL. 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 TORADOL. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), TORADOL should be discontinued.

Hematologic Effect

Anemia is sometimes seen in patients receiving NSAIDs, including TORADOL. 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 TORADOL, 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 TORADOL 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 nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, TORADOL 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

TORADOL 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 TORADOL, should inform their patients or their guardians of the potential risks of TORADOL 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 TORADOL^ORAL to other family members and to discard any unused drug.

Remember that the total combined duration of use of TORADOL^ORAL and IV or IM dosing of ketorolac tromethamine is not to exceed 5 days in adults. TORADOL^ORAL 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. TORADOL, 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. TORADOL, 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. TORADOL, 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 (eg, 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 (eg, 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, TORADOL 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 (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, TORADOL should be discontinued.

Carcinogenesis, Mutagenesis and Impairment of Fertility

An 18-month study in mice with oral doses of ketorolac tromethamine 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 μg/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 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 TORADOL in pregnant women. TORADOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The use of TORADOL 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

After a single administration of 10 mg of TORADOL^ORAL to humans, 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 (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.

Pediatric Use

TORADOL^ORAL is not indicated for use in pediatric patients. The safety and effectiveness of TORADOL^ORAL 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, reduced dosages (see DOSAGE AND ADMINISTRATION), and careful clinical monitoring must be used when treating the elderly with TORADOL.

Last updated on RxList: 12/17/2007

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 TORADOL occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of TORADOL. The greatest difference between large and small doses of TORADOL 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 TORADOL, are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL form of TORADOL and the IM form of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics

In adults, following administration of single ORAL doses of TORADOL 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 TORADOL, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Absorption

TORADOL is 100% absorbed after oral administration (see Table 1). Oral administration of TORADOL 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 (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 μg/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 TORADOL (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 μg/mL (SD ± 0.13) on Day 1 and 0.55 μg/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 μg/mL ± 0.77; young, 2.99 μg/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 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

Pharmacokinetic Parameters (units)	Oral*	Intramuscular†			Intravenous Bolus‡
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
Tmax1 (min)	44 ± 34	33 ± 21§	44 ± 29	33 ± 21§	1.1 ± 0.7§	2.9 ± 1.8
Cmax2 (μg/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 (μg/mL) [steady state qid]	1.05 ± 0.26§	1.56 ± 0.44§	3.11 ± 0.87§	N/A||	3.09 ± 1.17§	6.85 ± 2.61
Cmin3 (μg/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
Cavg4 (μg/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
Vβ 5 (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 *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 §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 || Not applicable because 60 mg is only recommended as a single dose 1Time-to-peak plasma concentration 2Peak plasma concentration 3Trough plasma concentration 4Average plasma concentration 5Volume of distribution

Table 2 - The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM¹ and ORAL²) in Adult Populations

Type of Subjects	Total Clearance [in L/h/kg]3		Terminal Half-life [in hours]
	IM	ORAL	IM	ORAL
	Mean (range)	Mean (range)	Mean (range)	Mean (range)
Normal Subjects IM (n=54) mean age=32, range=18-60 Oral (n=77) mean age=32, range=20-60	0.023 (0.010-0.046)	0.025 (0.013-0.050)	5.3 (3.5-9.2)	5.3m (2.4-9.0)
Healthy Elderly Subjects IM (n=13), Oral (n=12) mean age=72, range=65-78	0.019 (0.013-0.034)	0.024 (0.018-0.034)	7.0 (4.7-8.6)	6.1 (4.3-7.6)
Patients with Hepatic Dysfunction IM and Oral (n=7) mean age=51, range=43-64	0.029 (0.013-0.066)	0.033 (0.019-0.051)	5.4 (2.2-6.9)	4.5 (1.6-7.6)
Patients with Renal Impairment IM (n=25), Oral (n=9) serum creatinine=1.9-5.0 mg/dL, mean age (IM)=54, range=35-71 mean age (Oral)=57, range=39-70	0.015 (0.005-0.043)	0.016 (0.007-0.052)	10.3 (5.9-19.2)	10.8 (3.4-18.9)
Renal Dialysis Patients IM and Oral (n=9) mean age=40, range=27-63	0.016 (0.003-0.036)	—	13.6 (8.0-39.1)	—
1Estimated from 30 mg single IM doses of ketorolac tromethamine 2Estimated from 10 mg single oral doses of ketorolac tromethamine 3Liters/hour/kilogram

IV Administration

In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) 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.

Pediatric Patients

There are no data available to support the use of TORADOL^ORAL in pediatric patients.

Last updated on RxList: 12/17/2007

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 TORADOL occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of TORADOL. The greatest difference between large and small doses of TORADOL 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 TORADOL, are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL form of TORADOL and the IM form of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics

In adults, following administration of single ORAL doses of TORADOL 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 TORADOL, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Absorption

TORADOL is 100% absorbed after oral administration (see Table 1). Oral administration of TORADOL 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 (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 μg/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 TORADOL (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 μg/mL (SD ± 0.13) on Day 1 and 0.55 μg/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 μg/mL ± 0.77; young, 2.99 μg/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 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

Pharmacokinetic Parameters (units)	Oral*	Intramuscular†			Intravenous Bolus‡
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
Tmax1 (min)	44 ± 34	33 ± 21§	44 ± 29	33 ± 21§	1.1 ± 0.7§	2.9 ± 1.8
Cmax2 (μg/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 (μg/mL) [steady state qid]	1.05 ± 0.26§	1.56 ± 0.44§	3.11 ± 0.87§	N/A||	3.09 ± 1.17§	6.85 ± 2.61
Cmin3 (μg/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
Cavg4 (μg/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
Vβ 5 (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 *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 §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 || Not applicable because 60 mg is only recommended as a single dose 1Time-to-peak plasma concentration 2Peak plasma concentration 3Trough plasma concentration 4Average plasma concentration 5Volume of distribution

Table 2 - The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM¹ and ORAL²) in Adult Populations

Type of Subjects	Total Clearance [in L/h/kg]3		Terminal Half-life [in hours]
	IM	ORAL	IM	ORAL
	Mean (range)	Mean (range)	Mean (range)	Mean (range)
Normal Subjects IM (n=54) mean age=32, range=18-60 Oral (n=77) mean age=32, range=20-60	0.023 (0.010-0.046)	0.025 (0.013-0.050)	5.3 (3.5-9.2)	5.3m (2.4-9.0)
Healthy Elderly Subjects IM (n=13), Oral (n=12) mean age=72, range=65-78	0.019 (0.013-0.034)	0.024 (0.018-0.034)	7.0 (4.7-8.6)	6.1 (4.3-7.6)
Patients with Hepatic Dysfunction IM and Oral (n=7) mean age=51, range=43-64	0.029 (0.013-0.066)	0.033 (0.019-0.051)	5.4 (2.2-6.9)	4.5 (1.6-7.6)
Patients with Renal Impairment IM (n=25), Oral (n=9) serum creatinine=1.9-5.0 mg/dL, mean age (IM)=54, range=35-71 mean age (Oral)=57, range=39-70	0.015 (0.005-0.043)	0.016 (0.007-0.052)	10.3 (5.9-19.2)	10.8 (3.4-18.9)
Renal Dialysis Patients IM and Oral (n=9) mean age=40, range=27-63	0.016 (0.003-0.036)	—	13.6 (8.0-39.1)	—
1Estimated from 30 mg single IM doses of ketorolac tromethamine 2Estimated from 10 mg single oral doses of ketorolac tromethamine 3Liters/hour/kilogram

IV Administration

In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) 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.

Pediatric Patients

There are no data available to support the use of TORADOL^ORAL in pediatric patients.

Last updated on RxList: 12/17/2007

MEDICATION GUIDE FOR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Nonsteroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma

Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription:

Generic Name	Tradename
Celecoxib	Celebrex
Diclofenac	Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal	Dolobid
Etodolac	Lodine, Lodine XL
Fenoprofen	Nalfon, Nalfon 200
Flurbirofen	Ansaid
Ibuprofen	Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin	Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen	Oruvail
Ketorolac	Toradol
Mefenamic Acid	Ponstel
Meloxicam	Mobic
Nabumetone	Relafen
Naproxen	Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin	Daypro
Piroxicam	Feldene
Sulindac	Clinoril
Tolmetin	Tolectin, Tolectin DS, Tolectin 600

*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Date created: June 15, 2005.Celebrex is a registered trademark of G.D. Searle LLC. Cataflam, Voltaren are registered trademarks of Novartis Corporation. Arthrotec (combined with misoprostol) is a registered trademark of G.D. Searle LLC. Dolobid is a registered trademark of Merck & Co. Inc. Lodine, Lodine XL are registered trademarks of Wyeth. Nalfon, Nalfon 200 are registered trademarks of Pedinol Pharmacal Inc. Ansaid is a registered trademark of Pharmacia & Upjohn Company LLC. Motrin is a registered trademark of Johnson & Johnson. Tab-Profen is a registered trademark of L. Perrigo Company. Vicoprofen (combined with hydrocodone) is a registered trademark of BASF K & F Corporation.
Combunox (combined with oxycodone) is a registered trademark of Forest Laboratories, Inc.Indocin, Indocin SR are registered trademarks of Merck & Co. Inc. Oruvail is a registered trademark of Imperial Bank, As Agent (formerly registered to Aventis Pharma S.A.). Toradol is a registered trademark of Hoffmann-La Roche Inc. Ponstel is a registered trademark of Lasalle National Bank Association.
Mobic is a registered trademark of Boehringer Ingelheim Pharma GMBG & Co. Kg. Relafen is a registered trademark of SmithKline Beecham Corporation. Naprosyn, EC-Naprosyn, Anaprox, Anaprox DS are registered trademarks of Syntex Pharmaceuticals International Ltd. Naprelan is a registered trademark of Elan Corporation PLC. Naprapac (copackaged with lansoprazole) is a registered trademark of Syntex Pharmaceuticals International Ltd. Daypro is a registered trademark of G.D. Searle LLC. Feldene is a registered trademark of Pfizer. Clinoril is a registered trademark of Merck & Co. Inc. Tolectin, Tolectin DS, Tolectin 600 are registered trademarks of Johnson & Johnson Corporation.

Last updated on RxList: 12/17/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

KETOROLAC - ORAL

(kee-TOE-row-lack)

COMMON BRAND NAME(S): Toradol

WARNING: It is important that you use this medication properly to help reduce your risk of side effects. See Uses and How to Use sections.

Ketorolac may infrequently cause serious (rarely fatal) bleeding from the stomach/intestines. Also, drugs related to ketorolac have rarely caused blood clots to form, resulting in serious (possibly fatal) heart attacks and strokes. This medication might also rarely cause similar problems, especially if you have heart disease or have used this drug for a long time. Stop taking ketorolac and seek immediate medical attention if you notice any of these rare but very serious side effects: black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, chest pain, shortness of breath, weakness on one side of the body, sudden vision changes, slurred speech. Talk to your doctor or pharmacist about the benefits and risks of treatment, as well as other possible medication choices.

Do not use this medication if you are in labor, breast-feeding, or have stomach/intestinal problems (e.g., ulcers, bleeding), severe kidney problems, severe loss of body water (dehydration), or bleeding/clotting problems. Do not use ketorolac right before/after heart bypass surgery or before any surgery. Do not use ketorolac with high doses of aspirin or with other nonsteroidal anti-inflammatory drugs (NSAIDs). See Drug Interactions.

Although unlikely, very serious allergic reactions have occurred with ketorolac use. Patients should be closely watched during the first dose for such a reaction. See Side Effects for more information. Do not use ketorolac if you are allergic to it, aspirin, or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib).

Patients who are elderly, weigh less than 110 pounds (50 kilograms), or have mild kidney problems require smaller doses of ketorolac. Consult your doctor for details.

USES: Ketorolac is used for the short-term treatment of moderate to severe pain in adults, usually after surgery. Reducing pain helps you recover more comfortably from surgery and return to your normal daily activity sooner. This medication is known as a nonsteroidal anti-inflammatory drug (NSAID).

Ketorolac should not be used for mild or ongoing painful conditions.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using ketorolac. If you have any questions, consult your doctor or pharmacist.

Treatment with ketorolac tablets should usually be started only after you have already been given the injectable form of ketorolac. The Canadian manufacturer states that the tablets may be used even if you have not received ketorolac injection. If you have been prescribed ketorolac by mouth without first receiving ketorolac injection, promptly consult your doctor or pharmacist before taking this medication. Though it is very unlikely to occur, a severe allergic reaction is possible after taking the first dose. (See Side Effects.)

Take this medication by mouth, usually every 4 or 6 hours with a full glass of water (8 ounces or 240 milliliters) unless your doctor directs you otherwise. Do not lie down for at least 30 minutes after taking this drug. Take it with food, milk, or an antacid to prevent stomach upset.

Dosage is based on your medical condition and response to therapy. To reduce side effect risks (e.g., stomach bleeding), use this medication at the lowest effective dose for the shortest possible time. Do not increase your dose, take it more often than prescribed, or use it for more than 5 days in total (injection and tablets). Do not take more than 40 milligrams per day of ketorolac by mouth. Discuss the risks and benefits with your doctor or pharmacist.

If you are taking this drug on an "as needed" basis (not on a regular schedule), remember that pain medications work best if they are used as the first signs of pain occur. If you wait until the pain has significantly worsened, the medicine may not work as well.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: See also Warning section.

Upset stomach, tiredness, nausea, vomiting, diarrhea, bloating, gas, dizziness, or drowsiness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach pain, difficult/painful swallowing, swelling of the hands/feet, sudden/unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears), mental/mood changes, fast/pounding heartbeat, persistent/severe headache, fainting.

Tell your doctor immediately if any of these rare but very serious side effects occur: change in the amount of urine, easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), unexplained stiff neck, seizures.

This drug may rarely cause serious liver disease. Stop taking ketorolac and tell your doctor immediately if you notice any of the following rare but very serious side effects: yellowing eyes/skin, dark urine, unusual/extreme tiredness, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking ketorolac, tell your doctor or pharmacist if you are allergic to it; or to aspirin or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), severe kidney disease, recent heart bypass surgery (CABG), stomach/intestinal/esophagus problems (e.g., bleeding, ulcers, recurring heartburn), blood disorders (e.g., anemia), bleeding or clotting problems, bleeding inside the brain, severe loss of body water (dehydration).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, poorly controlled diabetes, heart disease (e.g., congestive heart failure, history of heart attack), high blood pressure, stroke, swelling (edema, fluid retention), blood disorders (e.g., anemia), asthma, growths in the nose (nasal polyps).

Ketorolac should not be used before surgery because it can cause bleeding. Tell your doctor or dentist that you are using this medication before having surgery.

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery.

This medicine may cause stomach bleeding. Daily use of alcohol and tobacco may increase your risk for stomach bleeding, especially when combined with this medicine. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

Infrequently, this medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

The elderly may be more sensitive to the side effects of this drug, especially stomach/intestinal bleeding and kidney effects.

This medication should be used only when clearly needed during the first 6 months of pregnancy. It is not recommended for use during the last 3 months of pregnancy due to possible harm to the unborn baby and interference with normal labor/delivery. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Therefore, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: high doses of aspirin and related drugs (salicylates), cidofovir, other NSAIDs (e.g., ibuprofen, naproxen, celecoxib), pentoxifylline, probenecid.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting ketorolac.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-platelet drugs (e.g., cilostazol, clopidogrel), certain anti-seizure drugs (carbamazepine, phenytoin), oral bisphosphonates (e.g., alendronate), "blood thinners" (e.g., enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), cyclosporine, desmopressin, high blood pressure drugs (including ACE inhibitors such as captopril, angiotensin receptor blockers such as losartan, and beta-blockers such as metoprolol), lithium, methotrexate, pemetrexed, certain psychiatric drugs (alprazolam, thiothixene), SSRI antidepressants (e.g., fluoxetine, sertraline), "water pills" (diuretics such as furosemide, amiloride, triamterene).

Check all prescription and nonprescription medicine labels carefully for other pain/fever drugs (NSAIDs such as aspirin, celecoxib, ibuprofen). These drugs are similar to this medication, so taking one of these drugs while also taking this medication may increase your risk of side effects. However, if your doctor has prescribed low doses of aspirin to prevent heart attack or stroke (usually at dosages of 81-325 milligrams a day), you should continue to take the aspirin. Daily use of NSAIDs (e.g., ibuprofen) may decrease aspirin's ability to prevent heart attack/stroke. Consult your doctor or pharmacist for more details and to discuss other possible treatments (e.g., acetaminophen) for your pain/fever.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe stomach pain, vomit that looks like coffee grounds, extreme drowsiness, slow/shallow breathing, loss of consciousness.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in those cases.

MISSED DOSE: If you are prescribed this drug on a regular schedule (not just "as needed") and you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.