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TORADOL® TORADOL® IM Roche Ketorolac Tromethamine NSAID Analgesic
 
Action and Clinical

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity mediated by peripheral effects. Ketorolac inhibits the synthesis of prostaglandins through inhibition of the cyclo-oxygenase enzyme system. At analgesic doses it has minimal anti-inflammatory and antipyretic activity.:

Pain relief is comparable following the administration of ketorolac by i.m. or oral routes. The peak analgesic effect occurs at 2 to 3 hours post-dosing with no evidence of a statistically significant difference over the recommended dosage range. The greatest difference between large and small doses of ketorolac administered by either route is in the duration of analgesia.

Pharmacokinetics: Ketorolac is rapidly and completely absorbed when administered by either the oral or the i.m. route. The pharmacokinetics are linear following single and multiple dosing. Steady-state plasma levels are attained after 1 day of q.i.d. dosing.

Following oral administration, peak plasma concentrations of 0.7 to 1.1 µg/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 hours in healthy adults, and between 4.3 and 7.6 hours in elderly subjects (mean age 72 years). A high fat meal decreases the rate, but not the extent, of absorption of oral ketorolac. The use of an antacid has not been demonstrated to affect the pharmacokinetics of ketorolac.

Following i.m. administration, peak plasma concentrations of 2.2 to 3.0 µg/mL occur an average of 50 minutes after a single 30 mg dose. The terminal plasma half-life ranges between 3.5 and 9.2 hours in young adults and between 4.7 and 8.6 hours in elderly subjects (mean age=72 years).

In renally impaired patients there is a reduction in clearance and an increase in the terminal half-life of ketorolac (see Table I).

The primary route of excretion of ketorolac 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.

More than 99% of the ketorolac in plasma is protein bound over a wide concentration range.

The parenteral administration of ketorolac has not been demonstrated to affect the hemodynamics of anesthetized patients.

CPS:TABLE_C52800$$43_t1

Table I - Toradol

Influence of Age, Liver and Kidney Function on the Clearance and Terminal Half-life of Toradol I.M.A and Oral B

Total Clearance (in L/h/kg) C Terminal Half-life (in hours)

Types of Subjects I.M. mean (range) Oral mean (range) I.M. mean (range) Oral mean (range)

Normal Subjects 0.023 0.025 5.3 5.3

I.M. (n=54) Oral (n=77) (0.010-0.046) (0.013-0.050 (3.5-9.2) (2.4-9.0)</

Healthy Elderly Subjects 0.019 0.024 7.0 6.1

I.M. (n=13), Oral (n=12) (mean age=72, range=65-78) (0.013-0.034) (0.018-0.034) (4.7-8.6) (4.3-7.6)</

Patients with Hepatic Dysfunction 0.029 0.033 5.4 4.5

I.M. and Oral (n=7) (0.013-0.066) (0.019-0.051) (2.2-6.9) (1.6-7.6)

Patients with Renal Impairment 0.014 0.016 10.3 10.8

I.M. and Oral (n=9) (serum creatinine 1.9-5.0 mg/dL) (0.007-0.043) (0.007-0.052) (8.1-15.7) (3.4-18.9)

Renal Dialysis Patients 0.016 13.6

I.M. (n=9) (0.003-0.036) (8.0-39.1)</

A Estimated from 30 mg single i.m. doses of ketorolac tromethamine.

B Estimated from 10 mg single oral doses of ketorolac tromethamine.

C Litres/hour/kilogram.

Indications And Clinical Uses :

Oral: For the short-term management (not to exceed 5 days for postsurgical patients or 7 days for patients with musculoskeletal pain) of moderate to moderately severe acute pain, including postsurgical pain (such as general, orthopedic and dental surgery), acute musculoskeletal trauma pain and postpartum uterine cramping pain. (See Warnings and Dosage).

I.M.: For the short-term management (not to exceed 2 days) of moderate to severe acute pain, including pain following major abdominal, orthopedic and gynecological operative procedures. The total duration of combined i.m. and oral treatment should not exceed 5 days.

Contra-Indications:

Patients with active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system. Severe and fatal reactions have occurred in such individuals.:

Known or suspected hypersensitivity to the drug or other NSAIDs. The potential for cross-reactivity between different NSAIDs must be kept in mind. Ketorolac should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, 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 effects.

Significant hepatic impairment or active liver disease.

Patients with moderate to severe renal impairment (serum creatinine >442 µmol/L) or in patients at risk for renal failure due to volume depletion or dehydration. Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored.

The use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

Immediately before any major surgery, and is contraindicated intraoperatively when hemostasis is critical because of the increased risk of bleeding. Ketorolac is also contraindicated in patients with coagulation disorders, postoperative patients with high hemorrhagic risk or incomplete hemostasis, and in patients with suspected or confirmed cerebrovascular bleeding.

In labor 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 hemorrhage.

Neuraxial (epidural or intrathecal) administration of ketorolac i.m. due to its alcohol content.

The concomitant use of ketorolac and probenecid.

The combination of ketorolac and oxpentifylline (see Precautions, Drug Interactions).

Warnings in Clinical States:

The long-term administration of ketorolac is not recommended as the incidence of side effects increases with the duration of treatment (see Indications and Dosage).

The most serious risks associated with NSAIDs including ketorolac are: Gastrointestinal: Gastrointestinal mucosal injury may occur. Serious gastrointestinal toxicity, such as bleeding, peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without warning symptoms, during therapy with NSAIDs including ketorolac.

Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous gastrointestinal tract symptoms. In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2 to 4% of patients treated for 1 year. The risk continues beyond 1 year and possibly increases.

The incidence of these complications increases with increasing dose.

The long-term use of ketorolac is not recommended.

Ketorolac should be given under close medical supervision to patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs ketorolac should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies to date have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.

Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.

Geriatrics: Patients older than 65 years 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 the effects of ulceration and bleeding. Older patients are also at risk of lower esophageal ulceration and bleeding. Postmarketing experience with ketorolac 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 ketorolac. Because ketorolac is cleared somewhat more slowly by the elderly (see , Pharmacokinetics) extra caution and the lowest effective dose should be used (see Dosage).

Hypersensitivity Reactions: The possibility of severe or fatal hypersensitivity reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, angioedema) should be considered, even for patients with no known history of previous exposure or hypersensitivity to ketorolac, ASA or other NSAIDs. Counteractive measures must be available when administering the first dose of ketorolac i.m. As with other NSAIDs, patients should be questioned for history of allergy to NSAIDs or ASA, angioedema, bronchospastic activity or for the syndrome consisting of nasal polyps, ASA allergy and asthma before being prescribed ketorolac. Asthmatic patients with triad asthma (the syndrome of nasal polyps, asthma and hypersensitivity to ASA or other NSAIDs) may be at particular risk for severe hypersensitivity reactions.

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

Aseptic Meningitis: In occasional cases, 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 tissues diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Pregnancy , Labor and Lactation: The administration of ketorolac is not recommended during pregnancy. Ketorolac 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).

The administration of ketorolac is not recommended during lactation. Ketorolac should be used by nursing mothers only if the potential benefit justifies the potential risk to the fetus. After 1 day at 10 mg q.i.d. oral dosing, ketorolac has been detected in the milk of lactating women at a maximum concentration of 7.9 ng/mL

There was no evidence of teratogenicity in rats or rabbits studied at maternally-toxic doses of ketorolac. Prolongation of the gestation period and/or delayed parturition were seen in the rat. Ketorolac crosses the placenta to the extent of approximately 10%.

Children: Safety and efficacy in children have not been established. Therefore, ketorolac is not recommended for use in children under age 16.

Renal Toxicity: The following renal abnormalities have been associated with ketorolac and other drugs that inhibit renal prostaglandin biosynthesis: acute renal failure, nephrotic syndrome, interstitial nephritis, renal papillary necrosis. Elevations of BUN and creatinine have been reported in clinical trials with ketorolac. Ketorolac is contraindicated in patients with moderate to severe renal impairment.

Hypovolemia should be corrected before treatment with ketorolac is initiated. Patients who are volume depleted may be dependent on renal prostaglandin production to maintain renal perfusion and, therefore, glomerular filtration rate. In such patients, the use of drugs which inhibit prostaglandin synthesis has been associated with further decreases in renal blood flow and may precipitate acute renal failure. Predisposing factors include dehydration (e.g., as a result of extreme exercise, vomiting or diarrhea associated with the loss of at least 5 to 10% of total body weight, unreplenished blood loss of approximately 500 mL), sepsis, impaired renal function, heart failure, liver dysfunction, diuretic therapy, and advanced age. Caution is advised if ketorolac is used in such circumstances. Close monitoring of urine output, serum urea and serum creatinine is recommended until renal function recovers. Discontinuation of ketorolac or other nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

Hemorrhage: Postoperative hematomas and other symptoms of wound bleeding have been reported in association with the perioperative use of i.m. ketorolac. Physicians should be aware of the potential risk of bleeding when hemostasis is critical in cases such as, but not limited to, resection of the prostate, tonsillectomy or cosmetic surgery. Ketorolac is contraindicated in patients who have coagulation disorders. If ketorolac is to be administered to patients who are receiving drug therapy that interferes with hemostasis, careful observation is advised.

Use of ketorolac in patients who are receiving therapy that affects hemostasis should be undertaken with caution, including close monitoring. The concurrent use of ketorolac and prophylactic, low dose heparin (2 500 to 5 000 units q12h), warfarin and dextrans may also be associated with an increased risk of bleeding (see Precautions, Drug Interactions).

In patients receiving anticoagulants, the risk of i.m. hematoma formation from ketorolac i.m. injections is increased.

Precautions:

Physicians should be alert to the pharmacologic similarity of ketorolac to other NSAIDs that inhibit cyclo-oxygenase.:

Gastrointestinal: 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 H 2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of ketorolac therapy when and if these adverse reactions appear.

Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (dysuria, urinary frequency), or hematuria. 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, treatment with ketorolac must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hepatic Function: Caution should be observed if ketorolac is to be used in patients with impaired hepatic function, or a history of liver disease. As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 more severe hepatic reaction while on therapy with this drug. Meaningful elevations (greater than 3 times normal) of ALT and AST, occurred in controlled clinical trials in less than 1% of patients. Severe hepatic reactions including jaundice and cases of fatal hepatitis 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, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac should be discontinued. Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac clearance. Studies in patients with active hepatitis or cholestasis have not been performed.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention, edema, hypertension, NaCl retention, oliguria, elevations of serum urea nitrogen and creatinine have been observed in patients treated with ketorolac. Therefore, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be considered. Ketorolac should be used with caution in patients with cardiac decompensation, hypertension or other conditions which cause a predisposition to fluid retention.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with b-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when ketorolac is administered.

Ketorolac inhibits platelet function and may prolong bleeding time. It does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). Unlike the prolonged effects from ASA the inhibition of platelet function by ketorolac is normalized within 24 to 48 hours after the drug is discontinued.

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.

Infection: In common with other NSAIDs, ketorolac may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of ketorolac and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed.

CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of ketorolac. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Concomitant Medications: In patients currently receiving ASA or other NSAIDs, the risk of serious NSAID-related adverse events may be increased. When ketorolac is administered concurrently with oxpentifylline, there is an increased tendency to bleeding (see Contraindications).

Drug Interactions : Protein Binding: Ketorolac is highly bound to human plasma protein (mean 99.2%) and binding is independent of concentration. As ketorolac is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein-bound drugs significantly. Therapeutic concentrations of digoxin, warfarin, acetaminophen, phenytoin, tolbutamide, ibuprofen, naproxen, and piroxicam did not alter ketorolac protein binding.

Anticoagulant Therapy: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding. Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of ketorolac with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary (see Precautions).

Prothrombin time should be carefully monitored in all patients receiving oral anticoagulant therapy concomitantly with ketorolac.

Ketorolac i.m. given with 2 doses of 5 000 U of heparin to 11 healthy volunteers, resulted in a mean template bleeding time of 6.4 min (3.2 to 11.4 min) compared to a mean of 6.0 min (3.4 to 7.5 min) for heparin alone and 5.1 min (3.5 to 8.5 min) for placebo.

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) at plasma concentrations of 5 to 10 µg/mL.

Digoxin: Ketorolac does not alter digoxin protein binding.

Salicylates or Other NSAIDs: The use of ketorolac in addition to any other NSAID, including those over the counter ones (such as ASA and ibuprofen) is contraindicated due to the possibility of additive side effects. In vitro studies indicated that, at therapeutic concentrations of salicylates (300 µg/mL), the binding of ketorolac was reduced from approximately 99.2 to 97.5% representing a potential 2-fold increase in unbound ketorolac plasma levels.

Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Enzyme Induction: There is no evidence, in animal or human studies, that ketorolac induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence, it would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.

Probenecid: Concomitant administration of ketorolac and probenecid results in the decreased clearance and volume of distribution of ketorolac and a significant increase in ketorolac plasma levels (approximately 3-fold increase) and terminal half-life (approximately 2-fold increase). The concomitant use of ketorolac and probenecid is, therefore, contraindicated.

Furosemide: Ketorolac reduces the diuretic response to furosemide by approximately 20% in normovolemic subjects, so particular care should be taken in patients with cardiac decompensation.

Lithium: 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 on lithium plasma levels has not been studied. Cases of increased lithium plasma concentrations during ketorolac therapy have been reported.

Methotrexate: The concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, thus enhancing its toxicity.

ACE Inhibitors: Concomitant use of ACE inhibitors and other NSAIDs may increase the risk of renal impairment, particularly in volume-depleted patients.

Morphine: I.M. ketorolac has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions.

Adverse Reactions:

:The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.

Oral: Short-Term Patient Studies: The incidence of adverse reactions in 371 patients receiving multiple 10 mg doses of ketorolac 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.

Incidence Between 4 and 9%: Nervous System: somnolence, insomnia.

Digestive: nausea.

Incidence Between 2 and 3%: Nervous System: nervousness, headache, dizziness.

Digestive: diarrhea, dyspepsia, gastrointestinal pain, constipation.

Body as a Whole: fever.

Incidence 1% or Less: Nervous System: abnormal dreams, anxiety, dry mouth, hyperkinesia, paresthesia, increased sweating, euphoria, hallucinations.

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

Body as a Whole: asthenia, pain, back pain.

Cardiovascular: vasodilatation, palpitation, migraine, hypertension.

Respiratory: cough increased, rhinitis, dry nose.

Musculoskeletal: myalgia, arthralgia.

Skin and Appendages: rash, urticaria.

Special Senses: blurred vision, ear pain.

Urogenital: 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 ketorolac.

Incidence Between 10 and 12%: Digestive: dyspepsia, gastrointestinal pain.

Incidence Between 4 and 9%: Digestive: nausea, constipation.

Nervous System: headache.

Incidence Between 2 and 3%: Digestive: diarrhea, flatulence, gastrointestinal fullness, peptic ulcers.

Nervous System: dizziness, somnolence.

Metabolic/Nutritional Disorder: edema.

Incidence 1% or Less: Digestive: eructation, stomatitis, vomiting, anorexia, duodenal ulcer, gastritis, gastrointestinal hemorrhage, 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 and Appendages: pruritus, rash, burning sensation skin.

Body as a Whole: asthenia, pain, back pain, face edema, hernia.

Musculoskeletal: arthralgia, myalgia, joint disorder.

Cardiovascular: chest pain, chest pain substernal, migraine.

Respiratory: dyspnea, asthma, epistaxis.

Urogenital: hematuria, increased urinary frequency, oliguria, polyuria.

Hemic and Lymphatic: anemia, purpura.

I.M.: The adverse reactions listed below are reported in ketorolac i.m. clinical efficacy trials. In these trials patients (n=660) received either single 30 mg doses (n=151) or multiple 30 mg doses (n=509) over a time period of 5 days or less for pain resulting from surgery. These reactions may or may not be drug related.

Incidence Between 10 and 13%: Nervous System: somnolence.

Digestive: nausea.

Incidence Between 4 and 9%: Nervous System: headache.

Digestive: vomiting.

Injection Site: injection site pain.

Incidence Between 2 and 3%: Nervous System: sweating, dizziness.

Cardiovascular: vasodilatation.

Incidence 1% or Less: Nervous System: insomnia, increased dry mouth, abnormal dreams, anxiety, depression, paresthesia, nervousness, paranoid reaction, speech disorder, euphoria, libido increased, excessive thirst, inability to concentrate, stimulation.

Digestive: flatulence, anorexia, constipation, diarrhea, dyspepsia, gastrointestinal fullness, gastrointestinal hemorrhage, gastrointestinal pain, melena, sore throat, liver function abnormalities, rectal bleeding, stomatitis.

Cardiovascular: hypertension, chest pain, tachycardia, hemorrhage, palpitation, pulmonary embolus, syncope, ventricular tachycardia, pallor, flushing.

Injection Site: injection site reaction.

Body as a Whole: asthenia, fever, back pain, chills, pain, neck pain.

Special Senses: taste perversion, tinnitus, blurred vision, diplopia, retinal hemorrhage.

Musculoskeletal: myalgia, twitching.

Respiratory: asthma, cough increased, dyspnea, epistaxis, hiccup, rhinitis.

Skin and Appendages: pruritus, rash, s.c. hematoma, skin disorder.

Urogenital: dysuria, urinary retention, oliguria, increased urinary frequency, vaginitis.

Metabolic/Nutritional Disorders: edema, hypokalemia, hypovolemia.

Hemic and Lymphatic: anemia, coagulation disorder, purpura.

Postmarketing Experience: The following postmarketing adverse experiences have been reported for patients who have received either formulation of Toradol: Renal Events: acute renal failure, flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome, urinary retention.

Hypersensitivity Reactions: bronchospasm, laryngeal edema, asthma, hypotension, flushing, rash, anaphylaxis, angiodema 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 hemorrhage, rarely requiring blood transfusion (see Precautions), thrombocytopenia, epistaxis, leukopenia, hematomata, increased bleeding time.

CNS: 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.

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.

Symptoms And Treatment Of Overdose :

OverdoseIn a gastroscopic study of healthy subjects, daily doses of 360 mg given over an 8-hour interval for each of 5 consecutive days (3 times the highest recommended dose) caused pain and peptic ulcers which resolved after discontinuation of dosing.:

Metabolic acidosis has been reported following intentional overdosage. Single doses of ketorolac have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction which have resolved after discontinuation of dosing. Dialysis does not appreciably clear ketorolac from the blood stream.

Dosage And Administration:

Adults: Dosage should be adjusted according to the severity of the pain and the response of the patient.

Oral: The usual oral dose is 10 mg every 4 to 6 hours for pain as required. Doses exceeding 40 mg/day are not recommended. The maximum duration of treatment with oral formulation is 5 days for postsurgical patients and 7 days for patients with musculoskeletal pain.

I.M.: The recommended usual initial dose is 10 to 30 mg, according to pain severity. Subsequent dosing may be 10 to 30 mg every 4 to 6 hours as needed to control pain. The lowest effective dose should be administered.

The administration of ketorolac i.m. should be limited to short-term therapy (not over 2 days). The total daily dose should not exceed 120 mg because the risk of toxicity appears to increase with longer use at recommended doses (see Warnings and Precautions). The administration of continuous multiple daily doses of ketorolac i.m. has not been extensively studied. There has been limited experience with i.m. dosing for more than 3 days since the vast majority of patients have transferred to oral medication or no longer required analgesic therapy after this time.

If supplementary analgesia is required, a concomitant low dose of opiate can be used.

Patients Under 50 kg, Over Age 65 years, or With Less Severe Pain at Baseline: Oral: The lowest effective dose is recommended. Parenteral: The lower end of the dosage range is recommended. The initial dose should be 10 mg. The total daily dose of ketorolac i.m. in the elderly should not exceed 60 mg.

Impaired Renal Function: Ketorolac and its metabolites are eliminated by the kidneys, which in patients with reduced creatinine clearance, will result in diminished plasma clearance of the drug. Ketorolac is contraindicated in patients with moderate to severe renal impairment (serum creatinine >442 µmol/L) (see Contraindications). Ketorolac should be used with caution in patients with lesser renal impairment (serum creatinine 170 to 442 µmol/L). Such patients should receive a reduced dose of ketorolac, 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 blood stream.

Conversion from Parenteral to Oral Therapy: Tablets may be used either as monotherapy or as follow-on therapy to parenteral ketorolac.

When ketorolac 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 i.m. should be replaced by an oral analgesic as soon as feasible.

The total duration of combined i.m. and oral treatment should not exceed 5 days.

Parenteral drug products should be inspected visually for particulate material and discoloration prior to use.

Availability And Storage:

Tablets: Each white, round, film-coated tablet, with one side printed in black ink with KET10 on one side, contains: ketorolac tromethamine 10 mg. Nonmedicinal ingredients: hydroxypropyl-methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Bottles of 100 and 500. Store at room temperature with protection from light.

Parenteral: 10 mg/mL: Each mL of clear, slightly yellow, sterile solution contains: ketorolac tromethamine 10 mg. Nonmedicinal ingredients: alcohol 10% w/v and sodium chloride in sterile water. The pH is adjusted with sodium hydroxide or hydrochloric acid. Ampuls of 1 mL, trays of 5. Store at room temperature with protection from light.

30 mg/mL: Each mL of clear, slightly yellow, sterile solution contains: ketorolac tromethamine 30 mg. Nonmedicinal ingredients: alcohol 10% w/v and sodium chloride in sterile water. The pH is adjusted with sodium hydroxide or hydrochloric acid. Ampuls of 1 mL, trays of 5. Store at room temperature with protection from light.