PRODUCT DETAILS

Mechanism of Action
TORADOL (ketorolac tromethamine) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity mediated by peripheral effects. The mechanism of action of ketorolac, like that of other NSAIDS, is not completely understood, but is believed to be related to prostaglandin synthetase inhibition.

Pharmacokinetics
The pharmacokinetics are linear following single and multiple dosing. Steady state plasma levels are attained after one day of Q.I.D. dosing.

Following oral administration, peak plasma concentrations of 0.7 to 1.1 ¬g/mL occur at an average of 44 minutes after a single 10 mg dose. The terminal plasma elimination half-life ranges between 2.4 and 9.0 hours in healthy adults, and between 4.3 and 7.6 hours in elderly subjects (mean age 72 yrs). A high fat meal decreases the rate, but not the extent, of absorption of oral ketorolac tromethamine. The use of an antacid has not been demonstrated to affect the pharmacokinetics of ketorolac.

In renally impaired patients there is a reduction in clearance and an increase in the terminal half life of ketorolac tromethamine (see table5 below).
A series of studies were carried out in mice, rats, rabbits, monkeys and humans to characterize the pharmacokinetic profile of the free acid of ketorolac and ketorolac tromethamine. The salt form of the compound was later selected for development due to its more rapid and complete absorption.

Absorption:
Ketorolac tromethamine was rapidly (Tmax ranged from 0.25 to 1.5 hours) and completely absorbed after oral doses in animals (>87%) and humans (>99%).

Distribution:
The volume of distribution of ketorolac was estimated following intravenous dosing and ranged from 0.09 L/kg in mice to 0.38 L/kg in rats; in humans it averaged 0.15 L/kg. Ketorolac was highly protein bound in human (99.2%), monkey (98.3%) and rabbit (98.2%) plasma; moderately bound in rat plasma (92.1%); and poorly bound in mouse plasma (72.0%). Binding was concentration independent in all species studied.The tissue distribution of ketorolac-associated radioactivity was studied in male mice. The highest levels were found in the kidney which was the only organ which exceeded plasma levels at all time points (by about 50%). The lowest levels were present in the brain. However, all tissues eliminated ketorolac-associated radioactivity rapidly with a tissue half-life of <3.6 hours. Distribution studies in pregnant rabbits and rats showed that ketorolac-associated radioactivity distributed into the fetus in low but measurable levels – less than 15% in rabbits and 6% in rats based upon fetal to maternal plasma or blood concentration ratios. Ketorolac-associated radioactivity was also passed into the milk of lactating animals. In rats, radioactivity concentrations in milk exceeded plasma concentrations at all-time points by as much as fourfold. However, in rabbits, milk concentrations were only about 12% of plasma concentrations.

Clearance and Half-life:
The pharmacokinetics of ketorolac in man following single or multiple intramuscular doses are linear. Steady state plasma levels are achieved after dosing every 6 hours for one day. No changes in clearance occurred with chronic dosing. The plasma half-life of ketorolac ranged from 2.1 hours in rabbits to 6.6 hours in rhesus monkeys and 7.7 hours in mice. In humans, the plasma half-life averaged 6.0 hours. Total plasma clearance ranged from 0.44 mL/min/kg
in mice to 2.44 mL/min/kg in rats and averaged 0.35 mL/min/kg in humans.

Metabolism:
Ketorolac is largely metabolized in the liver. The major metabolic path of ketorolac in humans is glucuronic acid conjugation. P-hydroxylation is an additional minor pathway. In vitro and in vivo studies demonstrated that ketorolac does not induce or inhibit its own metabolism or the metabolism other drugs such as aniline, ethylmorphine and hexobarbital, upon multiple dosing. A moderate first pass metabolism (about 20%) was observed in humans, while rabbits exhibited more extensive first pass metabolism (about 50%) following oral doses. The metabolism and excretion patterns of ketorolac and its metabolites were similar following p.o., i.v. and i.m. dosing in the species studied. Ketorolac accounted for most of the radioactivity circulating in the plasma ranging from 79% in rabbits to 99% in mice and averaged 96% in humans. Conjugates of ketorolac were not detected in plasma in appreciable amounts in any species. However, the p-hydroxy metabolite (which is essentially inactive when compared to ketorolac) was detected in the plasma of rats, rabbits and humans. Ketorolac and its metabolites were excreted predominantly in the urine of all species, ranging from 69% in rats to essentially 100% in the cynomolgus monkey and averaged 92% in humans. The most comparable species with respect to man metabolically was the mouse.

Elimination/Excretion:
The primary route of excretion of ketorolac tromethamine and its metabolites (conjugates and the p-hydroxy metabolite) is in the urine (91.4%) with the remainder (6.1%) being excreted in the feces.


Presentation:

Each film coated tablet contains ketorolac tromethamine USP 10 mg.

  Dosage and Administration

Dosage and administration:
Dosing Considerations: Use of TORADOL should be limited to the lowest effective dose for the shortest possible duration of treatment (see INDICATIONS AND CLINICAL USE). In no case is the duration of TORADOL treatment to exceed 7 days.

Recommended Dose and Dosage Adjustment
Adults (>18 years of age): Dosage should be adjusted according to the severity of the pain and the response of the patient.
Oral: The usual oral dose of TORADOL (ketorolac tromethamine) is 10 mg every 4 to 6 hours for pain as required. Doses exceeding 40 mg per day are not recommended. The maximum duration of treatment with the oral formulation is 5 days for post-surgical patients and 7 days for patients with musculoskeletal pain. TORADOL is not indicated for chronic use.

Conversion from Parenteral to Oral Therapy: When TORADOL tablets are used as a follow-on therapy to parenteral ketorolac, the total combined daily dose of ketorolac (oral + parenteral) should not exceed 120 mg in younger adult patients or 60 mg in elderly patients on the day the change of formulation is made. On subsequent days, oral dosing should not exceed the recommended daily maximum of 40 mg. Ketorolac IM should be replaced by an oral analgesic as soon as feasible. The total duration of combined intramuscular and oral treatment should not exceed 5 days.

Renal Impairment: TORADOL is contraindicated in patients with moderate to severe renal impairment (serum creatinine >442 μmol/L). TORADOL should be used with caution in patients with lesser renal impairment (serum creatinine 170 - 442 μmol/L). Such patients should receive a reduced dose o TORADOL, and their renal status should be closely monitored. It is recommended that the daily dose be reduced by half; a total daily dose of 60 mg should not be exceeded. Dialysis does not significantly clear ketorolac from bloodstream. See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS:
Renal and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Renal Insufficiency.

Hepatic Impairment: TORADOL is contraindicated in patients with severe liver impairment or active liver disease. Caution should be observed in giving TORADOL to patient with mild to moderate hepatic insufficiency. See CONTRAINDICATIONS.

  Side Effects

ADVERSE REACTIONS

Adverse Drug Reaction Overview
The most common adverse reactions encountered with non-steroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding is the most severe.
Fatalities have occurred, particularly in the elderly.

Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

TORADOL TABLETS

SHORT-TERM PATIENT STUDIES
The incidence of adverse reactions in 371 patients receiving multiple 10 mg doses of TORADOL (ketorolac tromethamine) for pain resulting from surgery or dental extraction during the postoperative period (less than 2 weeks) is listed below. These reactions may or may not be drug related

Nervous System: abnormal dreams, anxiety, dry mouth, hyperkinesia, paresthesia, increased sweating, euphoria, hallucinations

Digestive System: anorexia, flatulence, vomiting, stomatitis, gastritis, gastrointestinal disorder, sore throat

Body as a Whole: asthenia, pain, back pain

Cardiovascular System: increased cough, rhinitis, dry nose

Musculoskeletal System: myalgia, arthralgia

Skin and Appendages: rash, urticarial

Special Senses: vision, ear pain

Urogenital System: dysuria


LONG-TERM PATIENT STUDY
The adverse reactions listed below were reported to be probably related to study drug in 553 patients receiving long-term oral therapy (approximately 1 year) with TORADOL.

Digestive System: Eructation, stomatitis, vomiting, anorexia, duodenal ulcer, gastritis, gastrointestinal haemorrhage, increased appetite, melena, mouth ulceration, rectal bleeding, sore mouth.

Nervous System: Abnormal dreams, anxiety, depression, dry mouth, insomnia, nervousness, paresthesia

Special Senses: Tinnitus, taste perversion, abnormal vision, blurred vision, deafness, lacrimation disorder

Metabolic/Nutritional Disorder: Weight gain, alkaline phosphatase increase, BUN increased, excessive thirst, generalized edema, hyperuricemia

Skin & Appendages: Pruritus, rash, burning sensation skin

Body as a Whole: Asthenia, pain, back pain, face edema, hernia

Musculo-skeletal System: Arthralgia, myalgia, joint disorder

Cardiovascular System: Chest pain, chest pain substernal, migraine

Respiratory System: Dyspnea, asthma, epistaxis

Urogenital System: Haematuria, increased urinary frequency, oliguria, polyuria

Haematic & Lymphatic: Anemia, purpura

Abnormal Haematologic and Clinical Chemistry Findings
Elevations of blood urea nitrogen (BUN) and creatinine have been reported in clinical trials with ketorolac.

Post-Market Adverse Drug Reactions
Additional reports of adverse events temporally associated with TORADOL during worldwide post-marketing experience are included below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to TORADOL exposure. The following post-marketing adverse experiences have been reported for patients who have received either formulation of TORADOL:

Renal Events: acute renal failure, flank pain with or without haematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome, urinary retention.

Hypersensitivity Reactions: bronchospasm, laryngeal edema, asthma, hypotension, flushing, rash, anaphylaxis, angioedema and anaphylactoid reactions. Such reactions have occurred in patients with no prior history of hypersensitivity.

Gastrointestinal Events: gastrointestinal hemorrhage, peptic ulceration, gastrointestinal perforation, pancreatitis, melena, esophagitis, hematemesis.
Hematologic Events: postoperative wound haemorrhage, rarely requiring blood transfusion (see PRECAUTIONS), thrombocytopenia, epistaxis, leukopenia, hematomata, increased bleeding time.

Central Nervous System: Convulsions, abnormal dreams, hallucinations, hyperkinesia, hearing loss, aseptic meningitis, extrapyramidal symptoms, psychotic reactions.

Hepatic Events: hepatitis, liver failure, cholestatic jaundice.

Cardiovascular: pulmonary edema, hypotension, flushing, bradycardia.

Reproductive female: infertility.

Dermatology: Lyell\'s syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria.

Body as Whole: infection.

Urogenital: interstitial nephritis, nephrotic syndrome, raised serum urea and creatinine.

Types of SubjectsTotal Clearance
(in L/h/kg)2
Terminal HalfLife
(in hours)
ORAl
MEAN(range)
ORAl
MEAN(range)
Normal Subjects
Oral (n=77)
0.025
(0.013-0.050)
5.3
(2.4-9.0)
Healthy Elderly Subjects
Oral (n=12)
(mean age = 72,
range = 65-78)
0.024
(0.018-0.034)
6.1
(4.3-7.6)
Patients with Hepatic
Dysfunction
Oral (n=13)
0.033
(0.019-0.051)
4.5
(1.6-7.6)
Patients with Renal
Impairment
Oral (n=9)
(serum creatinine 1.9-5.0mg/dL)
0.016
(0.007-0.052)
10.8
(3.4-18.9)


Body SystemIncidenceAdverse Reaction
Nervous System4-9%Somnolence, insomnia
2-3%Nervousness, headache, dizziness
Digestive System4-9%Nausea
2-3%Diarrhea, dyspepsia,
gastrointestinal pain,
constipation
Body as a whole2-3%Fever


Body SystemIncidenceAdverse Reaction
Digestive System10-12%Dyspepsia, gastrointestinal pain
4-9%Nausea, constipation
2-3%Diarrhea, flatulence,
gastrointestinal fullness, peptic
ulcers
Nervous System4-9%Headache
Metabolic/Nutritional Disorder2-3%Dizziness, somnolence
2-3%Edema







  Contraindications

Contraindications:
TORADOL is contraindicated in:


  • the peri-operative setting of coronary artery bypass graft surgery (CABG). Although TORADOL has Not been studied in this patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an increased incidence of cardiovascular/thromboembolic events, deep surgical infections and sternal
    wound complications

  • the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition

  • labour and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine haemorrhage

  • women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants

  • severe uncontrolled heart failure

  • known hypersensitivity to TORADOL or to other NSAIDs, including any of the
    components/excipients

  • history of asthma, urticaria, or allergic-type reactions after taking ASA or other
    NSAIDs (i.e. complete or partial syndrome of ASA-intolerance - rhinosinusitis,
    urticaria/angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions have
    occurred in such individuals. Individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. The potential for cross-reactivity between different NSAIDs must be kept in mind (see WARNINGS AND PRECAUTIONS: Hypersensitiv ity Reactions, Anaphylactoid Reactions)

  • active gastric / duodenal / peptic ulcer, active GI bleeding

  • inflammatory bowel disease

  • cerebrovascular bleeding or other bleeding disorders

  • coagulation disorders, post-operative patients with high haemorrhagic risk or
    incomplete haemostasis in patients with suspected or confirmed cerebrovascular
    bleeding.

  • immediately before any major surgery and intraoperatively when haemostasis is critical because of the increased risk of bleeding

  • severe liver impairment or active liver disease

  • moderate to severe renal impairment (serum creatinine >442 μmol/L and/or creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored) (see WARNINGS AND PRECAUTIONS: Renal)

  • known hyperkalemia (see WARNINGS AND PRECAUTIONS: Renal, Fluid and
    Electrolyte Balance)

  • concurrent use with other NSAIDs due to the absence of any evidence demonstrating synergistic benefits and potential for additive side effects

  • concomitant use with probenecid (see DRUG INTERACTIONS)

  • concomitant use with oxpentifylline (see DRUG INTERACTIONS)

  • children and adolescents aged less than 18 years

  Use in Pregnancy and Lactation

Special Populations

Pregnant Women: TORADOL is CONTRAINDICATED for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition (see CONTRAINDICATIONS and TOXICOLOGY). Caution should be exercised in prescribing TORADOL during the first and second trimesters of pregnancy (see TOXICOLOGY).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the
embryo-foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

TORADOL is not recommended in labour and delivery because, through their prostaglandin synthesis inhibitory effect, they may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).

Nursing Women: (see CONTRAINDICATIONS)

Pediatrics: (see CONTRAINDICATIONS)

Geriatrics: Patients older than 65 years (referred to in this document as older or elderly) and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding. For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

Post-marketing experience with TORADOL suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding, and perforation in the elderly and most spontaneous reports of fatal gastrointestinal events are in this population. This is particularly true in elderly patients who receive an average daily dose greater than 60 mg/day of TORADOL. Because ketorolac is cleared somewhat more slowly by the elderly (see PHARMACOKINETICS), extra caution and the lowest effective dose should be used (see DOSAGE ANDADMINISTRATION).

Monitoring and Laboratory Tests: The following testing or monitoring is recommended for various populations of patients taking TORADOL. This is not an exhaustive list.


  • Renal function parameters such as serum creatinine and serum urea (in case of
    coprescription of anti-hypertensives, methotrexate, cyclosporine, adrenergic blockers and in susceptible patients regarding the renal effects of NSAIDS e.g. impaired renal function or dehydration). See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: Renal, and DRUG INTERACTIONS.

  • Blood pressure (in case of anti-hypertensives co-prescription, and in susceptible patients with fluid retention) INR/effects of anticoagulants (Co-prescription of oral anticoagulants). See WARNINGS AND PRECAUTIONS: Hematologic.

  • INR/effects of anticoagulants (Co-prescription of oral anticoagulants). See
    WARNINGS AND PRECAUTIONS: Hematologic.

  • Lithium plasma concentrations (in case of lithium co-prescription)

  Drug Interaction

DRUG INTERACTIONS
Drug-Drug Interactions
Acetylsalicylic acid (ASA) or other NSAIDs: The use of TORADOL in addition to most NSAIDs, including over-the-counter ones (such as ibuprofen) for analgesic and/or anti-inflammatory effects is usually contraindicated because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.

The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions. Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1. In vitro studies indicated that, at therapeutic concentrations of salicylates (300 μg/mL), the binding of ketorolac tromethamine was reduced from approximately 99.2% to 97.5% representing a potential two-fold increase in unbound TORADOL plasma levels.

Antacids: There is no definitive evidence that the concomitant administration of histamine H2receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of TORADOL therapy when and if these adverse reactions appear.

Anti-coagulants: (See WARNINGS AND PRECAUTIONS: Haematologic, Anticoagulants).

Anti-hypertensives: NSAIDs may diminish the anti-hypertensive effects of angiotensin converting enzyme (ACE) inhibitors. Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.

Anti-platelet Agents (including ASA): There is an increased risk of bleeding, via inhibition of platelet function, when anti-platelet agents are combined with NSAIDs, such as TORADOL (see WARNINGS AND PRECAUTIONS: Haematologic, Anti-platelet Effects).

Cyclosporin: (See WARNINGS AND PRECAUTIONS: Renal).

Digoxin: Concomitant administration of an NSAID with digoxin can result in an increase in digoxin concentrations which may result in digitalis toxicity. Increased monitoring and dosage adjustments of digitalis glycosides may be necessary during and following concurrent NSAID therapy. Ketorolac tromethamine does not alter digoxin protein binding.

Diuretics: Clinical studies as well as post-marketing observations have shown that NSAIDs can reduce the effect of diuretics. Ketorolac tromethamine reduces the diuretic response to furosemide by approximately 20% in normovolemic subjects, so particular care should be taken in patients with cardiac decompensation.
Glucocorticoids: Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI adverse events such as ulceration and bleeding. This is especially the case in older (> 65 years of age) individuals.

Lithium: Monitoring of plasma lithium concentrations is advised when stopping or starting a NSAID, as increased lithium concentrations can occur. Some NSAIDs have been reported to inhibit renal lithium clearance, leading to an increase in plasma lithium concentrations and potential lithium toxicity. The effect of ketorolac tromethamine on lithium plasma levels has not been studied. Cases of increased lithium plasma concentrations during therapy with TORADOL have been reported.

Methotrexate: Caution is advised in the concomitant administration of methotrexate and NSAIDs, as this has been reported to reduce the clearance of methotrexate, thus enhancing its toxicity. In case combination treatment with methotrexate and NSAIDs is necessary, blood cell count and the renal function should be monitored. Concomitant administration of NSAIDs with a potentially myelotoxic drug, such as methotrexate, appears to be a predisposing factor to the onset of a cytopenia.

Oxpentifylline: When TORADOL is administered concurrently with oxpentifylline, there is an increased tendency to bleeding. The concomitant use of TORADOL and oxpentifylline is contraindicated.

Probenacid: concomitant administration of ketorolac tromethamine and probenacid results in the decreased clearance and volume of distribution of ketorolac and a significant increase in ketorolac plasma levels (approximately three-fold increase) and terminal half-life (approximately two-fold increase). The concomitant use of TORADOL and probenacid is contraindicated.

Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant administration of NSAIDs and SSRIs may increase the risk of gastrointestinal ulceration and bleeding (see WARNINGS AND PRECAUTIONS: Gastrointestinal).

Drug-Food Interactions
Oral administration of TORADOL tablets after a high-fat meal may result in decreased peak and delayed time-to-peak concentrations of ketorolac by about one hour.


Drug-Herb Interactions
Interactions with herbal products have not been established.


Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions
Potential Effects on Driving and Using Machinery: Some patients may experience drowsiness dizziness vertigo insomnia or depression with the use of Toradol.

  Over Dosage

OVERDOSAGE
Signs and Symptoms: Overdoses of TORADOL have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, gastrointestinal bleeding, and renal dysfunction which have generally resolved after discontinuation of dosing. Metabolic acidosis has been reported following intentional overdosage. Although rare, hypertension, acute renal failure, respiratory depression, coma and death have been reported after significant overdose of NSAIDs.

Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose. In a gastroscopic study of healthy subjects, daily doses of 360 mg given over an 8-hour interval for each of five consecutive days (3 times the highest recommended dose) caused pain and peptic ulcers which resolved after discontinuation of dosing

Treatment
Patients should be managed by symptomatic and supportive care following overdose. There are no specific antidotes. Dialysis does not significantly clear ketorolac from the bloodstream. For management of a suspected drug overdose contact your regional Poison Control Centre.

  Storage

Storage:
Store below 30 ºC.
Pharmaceutical Precaution:
This medicine must not be used after the expiry date (EXP) shown on the pack.

  Commercial Pack

Packs:
Each box contains 2 x 10 tablets in Alu-Alu blister pack.
Medicine: keep out of reach of children.

  Others

Warnings and Precautions

Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease, Cerebrovascular Disease, Congestive Heart Failure (NYHA II-IV) (see WARNINGS AND PRECAUTIONS: Cardiovascular).

TORADOL is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing TORADOL to any patient with ischemic heart disease (including but not limited to acute myocardial infarction, history of myocardial infarction and/or angina), cerebrovascular disease (including but not limited to stroke, cerebrovascular accident, transient ischemic attacks and/or amaurosis fugax) and/or congestive heart failure (NYHA II-IV).

Use of NSAIDs, such as TORADOL, can promote sodium retention in a dose-dependent manner, through a renal mechanism, which can result in increased blood pressure and/or exacerbation of congestive heart failure. (see also WARNINGS AND PRECAUTIONS: Renal, Fluid and Electrolyte Balance)
Randomized clinical trials with TORADOL have not been designed to detect differences in cardiovascular events in a chronic setting. Therefore, caution should be exercised when prescribing TORADOL.

Risk of Gastrointestinal (GI) Adverse Events (see WARNINGS AND
PRECAUTIONS: Gastrointestinal)
Use of NSAIDs, such as TORADOL, is associated with an increased incidence of
gastrointestinal adverse events (such as peptic/duodenal ulceration, perforation, obstruction and gastrointestinal bleeding).

General
The long-term use of TORADOL (ketorolac tromethamine) is not recommended as the incidence of side-effects increases with the duration of treatment (see INDICATIONS and DOSAGE AND ADMINISTRATION).

Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

TORADOL is not recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See DRUG INTERACTIONS: Drug-Drug Interactions, Acetylsalicylic acid (ASA) or other NSAIDs).

Carcinogenicity:
The carcinogenic potential of ketorolac tromethamine was assessed in an 18 month feeding study. Fifty Swiss-Webster albino mice were randomly assigned to receive 0.5, 1.0 or 2.0 mg/kg/day of ketorolac tromethamine in their diet. A control group of 100 animals of each sex received the same diet without ketorolac. The duration of the study was 78 weeks. However, males in the highest dose group received control diet for the last 3 weeks of the study due to the high mortality rate in that group relative to controls. Female survival was not affected. All animals received a complete necropsy. The average body weight of the high dose males was generally lower than that of the controls during the second half of the study. No such effect was evident in males in the lower dose groups or in females. Since the average food intake was similar for all dose groups throughout the study, the difference in body weight was not the result of reduced food intake. Histopathologic examinations revealed no treatment related increase in the incidence of any type of tumor. Enteritis, gastroenteropathy and peritonitis were seen primarily in the high dose group and were considered expected sequelae to high doses of an NSAID. In conclusion, there was no evidence for a carcinogenic effect of ketorolac tromethamine in the mouse. A 24 month feeding study was conducted in rats to assess the carcinogenic potential of ketorolac tromethamine. Fifty Sprague-Dawley rats of either sex were administered in their diet either 0.8, 2.0 or 5.0 mg ketorolac/kg body weight.

A control group of 100 animals received the same diet without the drug. No treatment related changes were noted in clinical condition except for a reddish discoloration of the urine which occurred more frequently in treated males than in controls. The survival times were significantly lower than controls in high dose males and mid and high dose females. The body weights of the high dose group females were approximately 10% lower than the controls during the last 6 months of the study although no differences in food intakes were noted among the various groups. The high dose males had decreased erythroid parameters, elevated platelet count and a higher incidence of blood in the urine specimens. High dose males and females had elevated BUN and increased neutrophil and decreased lymphocyte counts. Mid and high dose females had a lower urinary specific gravity compared to control females. There was no evidence for a carcinogenic effect of ketorolac tromethamine in rats.

Mutagenicity:
In vitro mutagenic studies were performed with ketorolac, ketorolac tromethamine and tromethamine using 5 strains of bacteria and one of yeast. Tests were carried out with and without mammalian microsomal activation. None of the compounds tested were mutagenic in any of these test systems. Ketorolac tromethamine was also negative in the in vivo mouse micronucleus test.

Cardiovascular:
TORADOL is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing TORADOL to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (not an exhaustive list)


  • Hypertension

  • Dyslipidemia / Hyperlipidemia

  • Diabetes Mellitus

  • Congestive Heart Failure (NYHA I)

  • Coronary Artery Disease (Atherosclerosis)

  • Peripheral Arterial Disease

  • Smoking

  • Creatinine Clearance < 60 mL/min or 1 mL/sec


Use of NSAIDs, such as TORADOL, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above.Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing TORADOL should hypertension either develop or worsen with its use.

Use of NSAIDs, such as TORADOL, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism (see WARNINGS AND PRECAUTIONS: Renal, Fluid and Electrolyte Balance).

For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.

Endocrine and Metabolism
Corticosteroids: TORADOL (ketorolac tromethamine) is not a substitute for corticosteroids. It does not treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids (see DRUG INTERACTIONS: Drug-Drug Interactions, Glucocorticoids).

Gastrointestinal
Serious GI toxicity (sometimes fatal), such as peptic/duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as TORADOL. Minor upper GI problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with TORADOL, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this
population.

The incidence of these complications increases with increasing dose. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered (see WARNINGS AND PRECAUTIONS: Special Populations, Geriatrics).

Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using TORADOL and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks. Caution should be taken if prescribing TORADOL to patients with a prior history of peptic/duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors.

Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

  • Anti-coagulants (e.g. warfarin)

  • Anti-platelet agents (e.g. ASA, clopidogrel)

  • Oral corticosteroids (e.g. prednisone)

  • Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline)



Close medical supervision is recommended in patients prone to gastrointestinal tract irritation. In these cases, the physician must weigh the benefits of treatment against the possible hazards. There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of therapy with TORADOL when and if these adverse reactions appear.

Genitourinary
Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), haematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with TORADOL must be stopped immediately to obtain recovery. This should be done before
urological investigations or treatments are carried out.

Haematologic
NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anti-coagulants or suffering from haemophilia or platelet disorders should be carefully observed when TORADOL is administered.

Ketorolac tromethamine inhibits platelet function and may prolong bleeding time (see WARNINGS AND PRECAUTIONS: Anti-platelet Effects). It does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT).

Anti-coagulants:
Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of bleeding. Concurrent therapy of TORADOL with warfarin requires close monitoring of the international normalized ratio (INR). Even with therapeutic INR monitoring, increased bleeding may occur.

Use of TORADOL in patients who are receiving therapy that affects haemostasis should be undertaken with caution, including close monitoring. The concurrent use of TORADOL and prophylactic, low dose heparin (2500-5000 units q12h), warfarin and dextrans may also be associated with an increased risk of bleeding.
Prothrombin time should be carefully monitored in all patients receiving oral anticoagulant therapy concomitantly with ketorolac tromethamine.
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) at plasma concentrations of 5 to10 μg/mL.

Anti-platelet Effects:
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible. The inhibition of platelet function by ketorolac tromethamine is normalized within 24 to 48 hours after the drug is discontinued.

TORADOL and other NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should not be discontinued.

There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA (see DRUG INTERACTIONS: Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or other NSAIDs).

Concomitant administration of TORADOL with low dose ASA increases the risk of GI ulceration and associated complications.

Blood dyscrasias:
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences. Anemia is sometimes seen in patients receiving NSAIDs, including TORADOL. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis.

Patients on long-term treatment with NSAIDs, including TORADOL, should have their haemoglobin or haematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

Hepatic / Biliary / Pancreatic:
As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Meaningful elevations (greater than 3 times normal) of serum transaminases (glutamate pyruvate [SGPT or ALT] and glutamic oxaloacetic [SGOT or AST]), occurred in clinical trials in less than 1% of patients.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with NSAIDs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.),ketorolac tromethamine should be discontinued. TORADOL is contraindicated in patients with severe liver impairment or active liver disease. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation. Caution should be observed if TORADOL is to be used in patients with a history of liver disease. Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac tromethamine clearance (see ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions).

Studies in patients with active hepatitis or cholestasis have not been performed.

Hypersensitivity Reactions
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to TORADOL. In post-marketing experience, rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients receiving TORADOL. TORADOL should not be given to patients with the ASA-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 ASA or other NSAIDs (see CONTRAINDICATIONS).
ASA-Intolerance: TORADOL should NOT be given to patients with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see CONTRAINDICATIONS).

Cross-sensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.

Serious skin reactions: (See WARNINGS AND PRECAUTIONS: Skin)

Immune: (See WARNINGS AND PRECAUTIONS: Infection, Aseptic Meningitis)

Infection:
TORADOL, in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.

Aseptic Meningitis: Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed.

Therefore, in such patients, the health care provider must be vigilant to the development of this complication.

Neurologic
Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as TORADOL. If patients experience such adverse reaction(s), they should exercise caution in carrying out activities that require alertness.

Ophthalmologic
Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms develop, TORADOL should be discontinued and an ophthalmologic examination performed. Ophthalmologic examination should be carried out at periodic intervals in any patient receiving TORADOL for an extended period of time.

Peri-Operative Considerations
(See CONTRAINDICATIONS: Coronary Artery Bypass Graft Surgery, see WARNINGS AND PRECAUTIONS: Haemorrhage)

Psychiatric:
(See WARNINGS AND PRECAUTIONS: Neurologic)

Renal
Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute renal failure, acute interstitial nephritis, renal papillary necrosis, haematuria, low grade proteinuria and occasionally nephrotic syndrome.

Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to reduction in renal blood flow or blood volume. Under these circumstances, renal prostaglandins help maintain renal perfusion and glomerular filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR < 60 mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, sepsis and those who are elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate a NSAID under stable conditions may decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment state. Caution should be used when initiating treatment with NSAIDs, such as TORADOL, in patients with considerable dehydration. Such patients should be rehydrated prior to initiation of therapy. Caution is also recommended in patients with pre-existing kidney disease.

Elevations of blood urea nitrogen (BUN) and creatinine have been reported in clinical trials with ketorolac. TORADOL is CONTRAINDICATED in patients with moderate to severe renal impairment.

Advanced Renal Disease: (See CONTRAINDICATIONS)

Fluid and Electrolyte Balance:
Use of NSAIDs, such as TORADOL, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure, edema, and exacerbation of congestive heart failure. NaCl retention, oliguria, elevations of serum urea nitrogen and creatinine have also been observed in patients treated with TORADOL. Thus, caution should be exercised in prescribing TORADOL in patients with a history of congestive heart failure, compromised cardiac function, cardiac decompensation, hypertension, increased age or other conditions predisposing to fluid retention (see WARNINGS AND PRECAUTIONS: Cardiovascular). Use of NSAIDs, such as TORADOL, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics. Electrolytes should be monitored periodically (see CONTRAINDICATIONS).

Respiratory:
ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Sexual Function/Reproduction/Fertility
The use of TORADOL, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of TORADOL should be considered.

Skin
In rare cases, serious skin reactions, some of them fatal, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Special Populations and Conditions
Geriatrics (>65 years of age): The terminal plasma half-life of ketorolac is prolonged compared to young healthy volunteers to an average of 7 hours (ranging from 4.3 to 8.6 hours). The total plasma clearance may be reduced compared to young healthy volunteers, on average to 0.019 L/h/kg.
Hepatic Insufficiency: Patients with impaired hepatic function do not have any clinically important changes in ketorolac pharmacokinetics, although there is a statistically significant prolongation of Tmax and terminal phase half-life compared to young healthy volunteers.

Renal Insufficiency: Elimination of ketorolac is decreased in patients with renal impairment as reflected by a prolonged plasma half-life and reduced total plasma clearance when compared to young healthy subjects. The rate of elimination is reduced roughly in proportion to the degree of renal impairment except for patients who are severely renally impaired, in whom there is higher plasma clearance of ketorolac than estimated from the degree of renal impairment alone.

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