INDICATIONS AND USAGE
Adult Patients: TORADOL is indicated for the short-term (=5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with TORADOLIV/IM, and TORADOLORALis to be used only as continuation treatment, if necessary. Combined use of TORADOLIV/IMand TORADOLORALis not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ADVERSE REACTIONS). Patients should be switched to alternative analgesics as soon as possible, but TORADOL therapy is not to exceed 5 days.
Pediatric Patients: The safety and effectiveness of single doses of TORADOLIV/IMhave been established in pediatric patients between the ages of 2 and 16 years. TORADOL, as a single injectable dose, has been shown to be effective in the management of moderately severe acute pain that requires analgesia at the opioid level, usually in the postoperative setting. There is limited data available to support the use of multiple doses of TORADOL in pediatric patients. Safety and effectiveness have not been established in pediatric patients below the age of 2 years. Use of TORADOL in pediatric patients is supported by evidence from adequate and well-controlled studies of TORADOL in adults with additional pharmacokinetic, efficacy and safety data on its use in pediatric patients available in the published literature (see CLINICAL PHARMACOLOGY: Clinical Studies, WARNINGS, and PRECAUTIONS).
TORADOLIV/IMhas been used concomitantly with morphine and meperidine and has shown an opioid-sparing effect. For breakthrough pain, it is recommended to supplement the lower end of the TORADOLIV/IMdosage range with low doses of narcotics prn, unless otherwise contraindicated. TORADOLIV/IMand narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION: Pharmaceutical Information for TORADOLIV/IM).
CONTRAINDICATIONS (SEE ALSO BOX WARNING):
- TORADOL is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.
- TORADOL is CONTRAINDICATED in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see WARNINGS for correction of volume depletion).
- TORADOL is CONTRAINDICATED in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.
- The use of TORADOL is CONTRAINDICATED in nursing mothers because of the potential adverse events of prostaglandin-inhibiting drugs on neonates.
- TORADOL is CONTRAINDICATED in patients with pre-viously demonstrated hypersensitivity to ketorolac tromethamine, allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
- TORADOL is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.
- TORADOL inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).
- TORADOL is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
- TORADOLIV/IMis CONTRAINDICATED for neuraxial (epidural or intrathecal) administration due to its alcohol content.
- The concomitant use of TORADOL and probenecid is CONTRAINDICATED.
WARNINGS (SEE ALSO BOX WARNING):
The combined use of TORADOLIV/IMand TORADOLORALis not to exceed 5 days in adults. Only single doses of TORADOLIV/IMare recommended for use in pediatric patients.
The most serious risks associated with TORADOL are:
- Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation: TORADOL is CONTRAINDICATED in patients with previously documented peptic ulcers and/or GI bleeding. Serious gastrointestinal toxicity, such as bleeding, ulceration and perforation, can occur at any time, with or without warning symptoms, in patients treated with TORADOL. Studies to date with NSAIDs have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Postmarketing experience with parenterally administered TORADOL suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding and perforation in the elderly.
The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, TORADOL. In a nonrandomized, in-hospital postmarketing surveillance study comparing parenteral TORADOL to parenteral opioids, higher rates of clinically serious GI bleeding were seen in adult patients <65 years of age who received an average total daily dose of more than 90 mg of TORADOLIV/IMper day (see CLINICAL PHARMACOLOGY: Postmarketing Surveillance Study).
The same study showed that elderly (>/=65 years of age) and debilitated patients are more susceptible to gastrointestinal complications. A history of peptic ulcer disease was revealed as another risk factor that increases the possibility of developing serious gastrointestinal complications during TORADOL therapy (see Tables 3A and 3B).
- Hemorrhage: Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of TORADOL in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (eg, heparin or dicumarol derivatives) have an increased risk of bleeding complications if given TORADOL concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of TORADOL and prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular
hematoma formation from administered TORADOLIM(see PRECAUTIONS: Drug Interactions). Patients receiving therapy that affects hemostasis should be monitored closely.
In postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of TORADOLIV/IM. Therefore, perioperative use of TORADOL should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGS and PRECAUTIONS).
- Pediatrics and Tonsillectomy: Physicians should consider the increased risk of bleeding before deciding to administer TORADOL in patients following tonsillectomy. TORADOLIV/IMis not recommended for use in pediatric patients below the age of 2 years. In a retrospective analysis of patients having undergone tonsillectomy with or without adenoidectomy, the risk of bleeding was 10.1% in patients administered TORADOLIV/IMcompared to 2.2% in those receiving opioids. The postoperative hemorrhage rate in patients 12 years and younger was 6.5% and 3.3% with and without TORADOL, respectively. In a prospective study of TORADOL in pediatric patients (ages 3 to 9 years) undergoing tonsillectomy with or without adenoidectomy, the overall incidence of bleeding was similar between the patients receiving TORADOL and morphine (16.3% versus 17%, respectively). However, during the first 24 hours after surgery, a higher incidence of bleeding was observed in the TORADOLIV/IMgroup (14.3%) versus the morphine group (4.2%).
- Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, TORADOL or other NSAIDs, or in individuals with a history of angioedema, bronchospastic reactivity (eg, asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
- Impaired Renal Function: TORADOL should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Renal toxicity with TORADOL has been seen 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 TORADOL may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of TORADOL therapy is usually followed by recovery to the pretreatment state.
Renal Effects: TORADOL and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see CLINICAL PHARMACOLOGY). Therefore, TORADOL should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION) and such patients should be followed closely. With the use of TORADOL, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome.
Because patients with underlying renal insufficiency are at increased risk of developing acute renal failure, the risks and benefits should be assessed prior to giving TORADOL to these patients. Hence, in patients with moderately elevated serum creatinine, it is recommended that the daily dose of TORADOLIV/IMbe reduced by half, not to exceed 60 mg/day. TORADOL IS CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS).
Hypovolemia should be corrected
treatment with TORADOL is initiated.
- Fluid Retention and Edema: Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with TORADOL. Therefore, TORADOL should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.
- Pregnancy: In late pregnancy, as with other NSAIDs, TORADOL should be avoided because it may cause premature closure of the ductus arteriosus.
· Hepatic Effects: TORADOL should be used with caution in patients with impaired hepatic function or a history of liver disease. Treatment with TORADOL may cause elevations of liver enzymes, and, in patients with pre-existing liver dysfunction, it may lead to the development of a more severe hepatic reaction. The administration of TORADOL should be discontinued in patients in whom an abnormal liver test has occurred as a result of TORADOL therapy.
· Hematologic Effects: TORADOL inhibits platelet aggregation and may prolong bleeding time; therefore, it is contraindicated as a preoperative medication, and caution should be used when hemostasis is critical. Unlike aspirin, the inhibition of platelet function by TORADOL disappears within 24 to 48 hours after the drug is discontinued. TORADOL does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where TORADOL was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for TORADOL compared to 0.2% in the control groups receiving narcotic analgesics.
Information for Patients: TORADOL is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome.
Physicians, when prescribing TORADOL, should inform their patients or their guardians of the potential risk of TORADOL treatment (see BOX WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections). Advise patients not to given TORADOLORALto other family members and to discard any unused drug.
Remember that the total duration of TORADOL therapy is not to exceed 5 days in adults or a single dose in pediatric patients ages 2 to 16 years.
Drug Interactions: Ketorolac is highly bound to human plasma protein (mean 99.2%).
WARFARIN, DIGOXIN, SALICYLATE, AND HEPARIN
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 µg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 µg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding.
In a study involving 12 adult volunteers, TORADOLORALwas coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, TORADOLIV/IMwas given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between TORADOL and warfarin or heparin, the administration of TORADOL to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGS and PRECAUTIONS).
TORADOLIV/IMreduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).
Concomitant administration of TORADOLORALand probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 µg/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of TORADOL and probenecid is contraindicated.
Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of TORADOL on plasma lithium has not been studied, but cases of increased lithium plasma levels during TORADOL therapy have been reported.
Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of TORADOL on methotrexate clearance has not been studied.
NONDEPOLARIZING MUSCLE RELAXANTS
In postmarketing experience there have been reports of a possible interaction between TORADOLIV/IMand nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of TORADOL with muscle relaxants has not been formally studied.
Concomitant use of ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients.
Sporadic cases of seizures have been reported during concomitant use of TORADOL and antiepileptic drugs (phenytoin, carbamazepine).
Hallucinations have been reported when TORADOL was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).
TORADOLIV/IMhas been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix TORADOL and morphine in the same syringe.
There is no evidence in animal or human studies that TORADOL induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.
Carcinogenesis, Mutagenesis and Impairment of Fertility: An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times of human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.
Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 µg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.
Pregnancy: Pregnancy Category C. Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation Day 17, caused dystocia and higher pup mortality in rats. There are no adequate and well-controlled studies of TORADOL in pregnant women. TORADOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The use of TORADOL is contraindicated in labor and delivery because, through its pro-staglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).
Lactation and Nursing: After a single administration of 10 mg of TORADOLORALto humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.
Pediatric Use: The safety and effectiveness of single doses of TORADOLIV/IMhave been established in pediatric patients between the ages of 2 and 16 years. TORADOLIV/IMhas been shown to be effective in the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Safety and efficacy in pediatric patients below the age of 2 have not been established. Therefore, TORADOLIV/IMis not recommended in pediatric patients below the age of 2. The risk of bleeding was greater in those patients administered TORADOLIV/IMfollowing tonsillectomy. Physicians should consider the increased risk of bleeding before deciding to administer TORADOLIV/IMin patients following tonsillectomy (see WARNINGS: Hemorrhage and Pediatrics and Tonsillectomy).
The risks identified in the adult population with TORADOLIV/IMuse also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when prescribing TORADOLIV/IMto pediatric patients.
Geriatric Use (>/=65 years of age): Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the adverse effects of NSAIDs (see WARNINGS: Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with TORADOLIV/IM. The lower end of the TORADOLIV/IMdosage range is recommended for patients over 65 years of age, and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, TORADOL.