Orally administered TORADOL (ketorolac tromethamine) is indicated for Â¬the short-term management (not to exceed 5 days for post-surgical patients or 7 days for patients with musculoskeletal pain) of moderate to moderately severe acute pain, including post-surgical pain (such as general, orthopaedic and dental surgery), acute musculoskeletal trauma pain and post-partum uterine cramping pain. (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). The total duration of combined intramuscular and oral treatment should not exceed 5 days. For patients with an increased risk of developing CV and/or GI adverse events, other management strategies that do NOT include the use of NSAIDs should be considered first (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).
Use of TORADOL should be limited to the lowest effective dose for the shortest possible duration of treatment in order to minimize the potential risk for cardiovascular or gastrointestinal adverse events (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). TORADOL, as a NSAID, does not treat clinical disease or prevent its progression. TORADOL, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient continues to take it.
Geriatrics (> 65 years of age): Evidence from clinical studies and post-market experience suggests that use in the geriatric population is associated with differences in safety (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).
Pediatrics (< 18 years of age): Safety and efficacy have not been established in the pediatric population.
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 Î¼mol/L). TORADOL should be used with caution in patients with lesser renal impairment (serum creatinine 170 - 442 Î¼mol/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.
TORADOL is contraindicated in:</br>
<li>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
<li>the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition</li>
<li>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</li>
<li>women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants</li>
<li>severe uncontrolled heart failure</li>
<li>known hypersensitivity to TORADOL or to other NSAIDs, including any of the
<li>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)</li>
<li>active gastric / duodenal / peptic ulcer, active GI bleeding</li>
<li>inflammatory bowel disease</li>
<li>cerebrovascular bleeding or other bleeding disorders</li>
<li>coagulation disorders, post-operative patients with high haemorrhagic risk or
incomplete haemostasis in patients with suspected or confirmed cerebrovascular
<li>immediately before any major surgery and intraoperatively when haemostasis is critical because of the increased risk of bleeding</li>
<li>severe liver impairment or active liver disease</li>
<li>moderate to severe renal impairment (serum creatinine >442 Î¼mol/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)</li>
<li>known hyperkalemia (see WARNINGS AND PRECAUTIONS: Renal, Fluid and
<li>concurrent use with other NSAIDs due to the absence of any evidence demonstrating synergistic benefits and potential for additive side effects</li>
<li>concomitant use with probenecid (see DRUG INTERACTIONS)</li>
<li>concomitant use with oxpentifylline (see DRUG INTERACTIONS)</li>
<li>children and adolescents aged less than 18 years</li>
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.
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
<b>Abnormal Haematologic and Clinical Chemistry Findings</b>
Elevations of blood urea nitrogen (BUN) and creatinine have been reported in clinical trials with ketorolac.
<b>Post-Market Adverse Drug Reactions</b>
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.
<table width=\"535\" style=\"font-size:11px\"><tr align=\"center\"><td><b>Types of Subjects</b></td><td><b>Total Clearance</br> (in L/h/kg)2</b></td><td><b>Terminal HalfLife</br>(in hours)</b></td></tr><tr align=\"center\"><td></td><td>ORAl </br>MEAN(range)</td><td>ORAl </br>MEAN(range)</td></tr><tr align=\"center\"><td>Normal Subjects</br>Oral (n=77)</td><td>0.025</br>(0.013-0.050)</td><td>5.3</br>(2.4-9.0)</td></tr><tr align=\"center\"><td>Healthy Elderly Subjects</br>Oral (n=12)</br>(mean age = 72,</br>range = 65-78)</td><td>0.024</br>(0.018-0.034)</td><td>6.1</br>(4.3-7.6)</td></tr><tr align=\"center\"><td>Patients with Hepatic</br>Dysfunction</br>Oral (n=13)</td><td>0.033</br>(0.019-0.051)</td><td>4.5</br>(1.6-7.6)</td></tr><tr align=\"center\"><td>Patients with Renal</br>Impairment</br>Oral (n=9)</br>(serum creatinine 1.9-5.0mg/dL)</td><td>0.016</br>(0.007-0.052)</td><td>10.8</br>(3.4-18.9)</td></tr></table>
<table width=\"535\" style=\"font-size:11px\"><tr align=\"center\"><th>Body System</th><td><b>Incidence</b></td><td><b>Adverse Reaction</b></td></tr><tr align=\"center\"><th rowspan=\"2\">Nervous System</th><td>4-9%</td><td>Somnolence, insomnia</td></tr><tr align=\"center\"><td>2-3%</td><td>Nervousness, headache, dizziness</td></tr><tr align=\"center\"><th rowspan=\"2\">Digestive System</th><td>4-9%</td><td>Nausea</td></tr><tr align=\"center\"><td>2-3%</td><td>Diarrhea, dyspepsia,</br>gastrointestinal pain,</br>constipation</td></tr><tr align=\"center\"><th>Body as a whole</th><td>2-3%</td><td>Fever</td></tr></table>
<table width=\"535\" style=\"font-size:11px\"><tr align=\"center\"><th>Body System</th><td><b>Incidence</b></td><td><b>Adverse Reaction</b></td></tr><tr align=\"center\"><th rowspan=\"3\">Digestive System</th><td>10-12%</td><td>Dyspepsia, gastrointestinal pain</td></tr><tr align=\"center\"><td>4-9%</td><td>Nausea, constipation</td></tr><tr align=\"center\"><td>2-3%</td><td>Diarrhea, flatulence,</br>gastrointestinal fullness, peptic </br>ulcers</td></tr><tr align=\"center\"><th>Nervous System</th><td>4-9%</td><td>Headache</td></tr><tr align=\"center\"><th rowspan=\"2\">Metabolic/Nutritional Disorder</th><td>2-3%</td><td>Dizziness, somnolence</td></tr><tr align=\"center\"><td>2-3%</td><td>Edema</td></tr></table>
<b>Pregnant Women:</b> 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).
<b>Nursing Women:</b> (see CONTRAINDICATIONS)
<b>Pediatrics:</b> (see CONTRAINDICATIONS)
<b>Geriatrics:</b> 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.
<li>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.</li>
<li>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.</li>
<li>INR/effects of anticoagulants (Co-prescription of oral anticoagulants). See
WARNINGS AND PRECAUTIONS: Hematologic.</li>
<li>Lithium plasma concentrations (in case of lithium co-prescription)</li>
Elderly patients: Patients over the age of 65 years may be at a greater risk of experiencing undesirable effects than younger patients. This age-related risk is common to all NSAIDs. Compared to young adults, the elderly have an increased plasma half-life and reduced plasma clearance of ketorolac tromethamine. With Toradol tablets, a longer dosing interval is advisable (see Dosage and administration).
Gastrointestinal effects: Toradol can cause gastrointestinal irritation, ulcers or bleeding in patients with or without a history of previous symptoms. Elderly and debilitated patients are more prone to develop these reactions. The incidence increases with dose and duration of treatment.
Respiratory effects: Bronchospasm may be precipitated in patients with a history of asthma.
Renal effects: Drugs that inhibit prostaglandin biosynthesis (including NSAIDs) have been reported to cause nephrotoxicity, including but not limited to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. In patients with renal, cardiac or hepatic impairment, caution is required.
As with other drugs that inhibit prostaglandin synthesis, elevations of serum urea, creatinine and potassium have been reported with Toradol and may occur after one dose.
Impaired renal function: Caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients,
administration of an NSAID may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal failure. Patients at greatest risk of this reaction are those who are volume-depleted because of blood loss or severe
dehydration, patients with impaired renal function, heart failure, liver impairment, the elderly and those taking diuretics. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state. Inadequate fluid/blood replacement during
surgery, leading to hypovolemia, may lead to renal dysfunction which could be exacerbated when Toradol is administered. Therefore, volume depletion should be corrected and close monitoring of serum urea and creatinine and urine output is recommended
until the patient is normovolemic. In patients on renal dialysis, ketorolac tromethamine clearance was reduced to approximately half the normal rate and terminal half-life increased approximately three-fold.
Fluid retention and edema: Fluid retention and edema have been reported with the use of Toradol and it should therefore be used with caution in patients with cardiac decompensation,
hypertension or similar conditions.
Hepatic effects: Borderline elevations of one or more liver function tests may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued therapy. Meaningful elevations (greater than 3 times normal) of serum glutamate
pyruvate transaminase (SGPT/ALT) or serum glutamate oxaloacetate transaminase (SGOT/AST) occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations
occur, Toradol should be discontinued.
Hematological effects: Patients with coagulation disorders should not receive Toradol. Patients on anticoagulation therapy may be at increased risk of bleeding if given Toradol concurrently. The concomitant use of ketorolac tromethamine and prophylactic
low-dose heparin (2,500-5,000 units 12-hourly) has not been studied extensively and may also be associated with an increased risk of bleeding. Patients already on anticoagulants or who require low-dose heparin should not receive ketorolac tromethamine.
Patients who are receiving other drug therapy that interferes with hemostasis should be carefully observed. In controlled clinical studies, the incidence of clinically significant postoperative bleeding was less than 1%.
Ketorolac tromethamine inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding times were raised, but not outside the normal range of 2-11 minutes. Unlike the prolonged effects from aspirin, platelet
function returns to normal within 24-48 hours after ketorolac tromethamine is discontinued.
Pregnancy, nursing mothers:
The safety of Toradol in human pregnancy has not been established. Toradol is therefore contraindicated during pregnancy, labor or delivery. As ketorolac tromethamine has been detected in human milk at low levels, it is also contraindicated in mothers who are
breast-feeding. (There was no evidence of teratogenicity in rats or rabbits studied at maternally-toxic doses of ketorolac tromethamine.)
Gastrointestinal tract: abdominal discomfort, constipation, diarrhea, dyspepsia, eructation, flatulence, fullness, gastritis, gastrointestinal bleeding, gastrointestinal pain, nausea, pancreatitis, peptic ulcer, perforation, stomatitis, vomiting.
Central nervous/musculoskeletal systems: abnormal dreams, abnormal taste and vision, abnormal thinking, aseptic meningitis, convulsions, depression, dizziness, drowsiness, dry mouth, euphoria, excessive thirst, functional disorders, hallucinations, headache,
hearing loss, hyperkinesia, inability to concentrate, insomnia, myalgia, nervousness, paresthesia, stimulation, sweating, tinnitus, vertigo.
Urinary tract and kidneys: acute renal failure, flank pain (with or without hematuria), glomerular nephritis, hemolytic uremic syndrome, hyperkalemia, hyponatremia, increased urinary frequency, interstitial nephritis, nephrotic syndrome, oliguria, raised serum urea
and creatinine, renal papillary necrosis.
Cardiovascular/hematological systems: bradycardia, flushing, hypertension, pallor, purpura, thrombocytopenia.
Respiratory system: asthma, dyspnea, pulmonary edema.
Skin: exfoliative dermatitis, Lyellâ€™s syndrome, maculopapular rash, pruritus, Stevens-Johnson syndrome, urticaria.
Hypersensitivity reactions: anaphylaxis, bronchospasm, flushing and rash, hypotension, laryngeal edema. Such reactions may occur in patients with or without known sensitivity to Toradol or other NSAIDs.
Bleeding: epistaxis, hematomata, postoperative wound hemorrhage.
Other: abnormal liver function tests, asthenia, edema, injection site pain, weight gain.
Concurrent treatment with probenecid is contraindicated because of increases in ketorolac tromethamine plasma level and half-life.
Because of an increased tendency to bleeding when oxpentifylline is administered concurrently, this combination is contraindicated.
Concurrent treatment with lithium is contraindicated because there is a possible inhibition of renal lithium clearance, increased plasma lithium concentration, and potential lithium toxicity.
Toradol should not be used with other NSAIDs because of the potential for additive side effects.
Ketorolac tromethamine is highly bound to human plasma protein (>99 %) and binding is concentration-independent. Because ketorolac tromethamine is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace
other protein-bound drugs significantly.
Ketorolac tromethamine did not alter digoxin protein binding. In-vitro studies indicated that at therapeutic concentrations and above of salicylate (â‰¥300 Î¼g/ml), the binding of ketorolac tromethamine was reduced from approximately 99.2-97.5%. Therapeutic
concentrations of digoxin, warfarin, paracetamol, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding.
There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence Toradol would not be expected to alter the pharmacokinetics of other drugs due to
enzyme induction or inhibition mechanisms.
In normovolemic healthy volunteers, ketorolac tromethamine reduces the diuretic response to frusemide by approximately 20%, so particular care should be taken in patients with cardiac decompensation.
There is an increased risk of renal impairment when ketorolac tromethamine is administered concurrently with ACE inhibitors, particularly in volume-depleted patients.
Caution is advised when methotrexate is administered concurrently, since some prostaglandin synthesis-inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.
Store below 30 ÂºC.
This medicine must not be used after the expiry date (EXP) shown on the pack.