KETOROLOC TROMETHAMINE
WARNING
TOROLAC, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days) management of moderately severe acute pain that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. TOROLAC is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom TOROLAC is indicated, especially when the drug is used inappropriately. Increasing the dose of TOROLAC beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events.
GASTROINTESTINAL EFFECTS
TOROLAC can cause peptic ulcers, gastrointestinal bleeding and/or perforation. Therefore, TOROLAC 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.
RENAL EFFECTS
TOROLAC is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS ).
RISK OF BLEEDING
TOROLAC inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS ).
TOROLAC is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.
HYPERSENSITIVITY
Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of TOROLAC IV/IM (see CONTRAINDICATIONS and WARNINGS ). TOROLAC is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
INTRATHECAL OR EPIDURAL ADMINISTRATION
TOROLAC is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.
LABOR, DELIVERY AND NURSING
The use of TOROLAC in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.
The use of TOROLAC is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
CONCOMITANT USE WITH NSAIDs
TOROLAC is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.
DOSAGE AND ADMINISTRATION
TOROLAC ORAL
TOROLAC ORAL is indicated only as continuation therapy to TOROLAC IV/IM , and the combined duration of use of TOROLAC IV/IM and TOROLAC ORAL is not to exceed 5 days because of the increased risk of serious adverse events.
The recommended total daily dose of TOROLAC ORAL (maximum 40 mg) is significantly lower than for TOROLAC IV/IM (maximum 120 mg) (see DOSAGE AND ADMINISTRATION and Transition from TOROLAC IV/IM to TOROLAC ORAL ).
SPECIAL POPULATIONS
Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION ) and for patients with moderately elevated serum creatinine (see WARNINGS). Doses of TOROLAC IV/IM are not to exceed 60 mg (total dose per day) in these patients.
DESCRIPTION
TOROLAC (ketorolac tromethamine) is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol.
TOROLAC is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41.
TOROLAC is available for intravenous (IV) or intramuscular (IM) administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in sterile solution; 60 mg in 2 mL (3%) of ketorolac tromethamine in sterile solution is available for IM administration only. For the TUBEX syringe units, the solutions contain 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg and 8.70 mg, respectively, of sodium chloride in sterile water. For the vials, the solutions contain 0.1% citric acid, 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg and 8.70 mg, respectively, of sodium chloride in sterile water. The pH is adjusted with sodium hydroxide or hydrochloric acid, and the solutions are packaged with nitrogen. The sterile solutions are clear and slightly yellow in color.
TOROLAC ORAL is available as round, white, film-coated, red-printed tablets. Each tablet contains 10 mg ketorolac tromethamine, the active ingredient, with added lactose, magnesium stearate and microcrystalline cellulose. The white film-coating contains hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.
The tablets are printed with red ink that includes FD&C Red #40 Aluminum lake as the colorant. There is a large T printed on both sides of the tablet, as well as the word TOROLAC on one side, and the word ROCHE on the other.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID). Ketorolac tromethamine inhibits synthesis of prostaglandins and may be considered a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.
Pain relief was statistically different after TOROLAC dosing from that of placebo at 1 / 2 hour (the first time point at which it was measured) following the largest recommended doses of TOROLAC and by 1 hour following the smallest recommended doses. The peak analgesic effect occurred within 2 to 3 hours and was not statistically significantly different over the recommended dosage range of TOROLAC. The greatest difference between large and small doses of TOROLAC by either route was in the duration of analgesia.
Pharmacokinetics: Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.
Comparison of IV, IM and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine, following IV, IM and oral doses of TOROLAC, are compared in Table 1. The extent of bioavailability following administration of the oral and IM forms of TOROLAC was equal to that following an IV bolus.
Linear Kinetics: Following administration of single ORAL, IM or IV doses of TOROLAC in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in humans, following single or multiple IM, IV or recommended oral doses of TOROLAC, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.
Binding and Distribution: The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, even plasma concentrations as high as 10 µg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations.
The mean apparent volume (V(beta)) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data.
Metabolism: Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.
Clearance and Excretion: A single-dose study with 10 mg TOROLAC (n=9) demonstrated that the S-enantiomer is cleared approximately two times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in Table 2.
The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.
Accumulation: TOROLAC administered as an IV bolus every 6 hours for 5 days to healthy subjects (n=13), showed no significant difference in C max on Day 1 and Day 5. Trough levels averaged 0.29 µg/mL (SD ± 0.13) on Day 1 and 0.55 µg/mL (SD ± 0.23) on Day 6. Steady state was approached after the fourth dose.
Accumulation of ketorolac tromethamine has not been studied in special populations (elderly patients, renal failure patients or hepatic disease patients).
Effect of Food: Oral administration of TOROLAC after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of absorption.
Kinetics in Special Populations: Elderly Patients: Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the C max for the two groups (elderly, 2.52 µg/mL ± 0.77; young, 2.99 µg/mL ± 1.03) (see PRECAUTIONS -- Use in the Elderly ).
Renally Impaired Patients: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r=0.5).
In patients with renal disease, the AUC infinity of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction.
The AUC infinity -ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see WARNINGS -- Renal Effects ).
Hepatic Effects: There was no significant difference in estimates of half-life, AUC infinity and C max in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS -- Hepatic Effects).
Clinical Studies: The analgesic efficacy of intramuscularly, intravenously and orally administered TOROLAC was investigated in two postoperative pain models: general surgery (orthopedic, gynecologic and abdominal) and oral surgery (removal of impacted third molars). The studies were double-blind, single- and multiple-dose, parallel trial designs in patients with moderate to severe pain at baseline. TOROLAC IV/IM was compared as follows: IM to meperidine or morphine administered intramuscularly and IV to morphine administered either directly IV or through a PCA (Patient-Controlled Analgesia) pump.
Short-Term Use (up to 5 days) Studies: In the comparisons of intramuscular administration during the first hour, the onset of analgesic action was similar for TOROLAC and the narcotics, but the duration of analgesia was longer with TOROLAC than with the opioid comparators meperidine or morphine.
In a multidose, postoperative (general surgery) double-blind trial of TOROLAC IM 30 mg versus morphine 6 and 12 mg IM, each drug given on an as needed basis for up to 5 days, the overall analgesic effect of TOROLAC IM 30 mg was between that of morphine 6 and 12 mg. The majority of patients treated with either TOROLAC or morphine were dosed for up to 3 days; a small percentage of patients received 5 days of dosing.
In clinical settings where perioperative morphine was allowed, TOROLAC IV 30 mg, given once or twice as needed, provided analgesia comparable to morphine 4 mg IV once or twice as needed.
There was relatively limited experience with 5 consecutive days of TOROLAC IV use in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with IV-administered TOROLAC were similar to those observed with IM-administered TOROLAC, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of IV and IM routes of TOROLAC administration.
Clinical Studies with Concomitant Use of Opioids: Clinical studies in postoperative pain management have demonstrated that TOROLAC IV/IM , when used in combination with opioids, significantly reduced opioid consumption. This combination may be useful in the subpopulation of patients especially prone to opioid-related complications. TOROLAC and narcotics should not be administered in the same syringe.
In a postoperative study, where all patients received morphine by a PCA device, patients treated with TOROLAC IV as fixed intermittent boluses (eg, 30 mg initial dose followed by 15 mg q3h), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving TOROLAC IV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.
Postmarketing Surveillance Study: A large postmarketing observational, nonrandomized study, involving approximately 10,000 patients receiving TOROLAC, demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of TOROLAC
INDICATIONS AND USAGE
TOROLAC 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 TOROLAC IV/IM , and TOROLAC ORAL is to be used only as continuation treatment, if necessary. Combined use of TOROLAC IV/IM and TOROLAC ORAL is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS , PRECAUTIONS , DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS ). Patients should be switched to alternative analgesics as soon as possible, but TOROLAC therapy is not to exceed 5 days.
TOROLAC IV/IM has 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 TOROLAC IV/IM dosage range with low doses of narcotics prn, unless otherwise contraindicated. TOROLAC IV/IM and narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION : Pharmaceutical Information for TOROLAC IV/IM ).
CONTRAINDICATIONS
(see also Boxed WARNING):
TOROLAC 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.
TOROLAC 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).
TOROLAC 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 TOROLAC is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
TOROLAC is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine, allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
TOROLAC is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.
TOROLAC 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 ).
TOROLAC is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
TOROLAC IV/IM is CONTRAINDICATED for neuraxial (epidural or intrathecal) administration due to its alcohol content.
The concomitant use of TOROLAC and probenecid is CONTRAINDICATED.
WARNINGS
(see also Boxed WARNING):
The combined use of TOROLAC IV/IM and TOROLAC ORAL is not to exceed 5 days.
The most serious risks associated with TOROLAC are:
Gastrointestinal Ulcerations, Bleeding and Perforation: TOROLAC 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 TOROLAC. 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 TOROLAC 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, TOROLAC. In a nonrandomized, in-hospital postmarketing surveillance study comparing parenteral TOROLAC to parenteral opioids, higher rates of clinically serious GI bleeding were seen in patients <65 years of age who received an average total daily dose of more than 90 mg of TOROLAC IV/IM per 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 TOROLAC therapy (see Tables 3A and 3B).
Impaired Renal Function: TOROLAC 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 TOROLAC 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 TOROLAC 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 TOROLAC therapy is usually followed by recovery to the pretreatment state.
Renal Effects: TOROLAC 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, TOROLAC 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 TOROLAC, there have been reports of acute renal failure, 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 TOROLAC to these patients. Hence, in patients with moderately elevated serum creatinine, it is recommended that the daily dose of TOROLAC IV/IM be reduced by half, not to exceed 60 mg/day. TOROLAC IS CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS ).
Hypovolemia should be corrected before treatment with TOROLAC 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 TOROLAC. Therefore, TOROLAC should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.
Hemorrhage: Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of TOROLAC 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 TOROLAC concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of TOROLAC 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 TOROLAC IM (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 TOROLAC IV/IM . Therefore, perioperative use of TOROLAC should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGS and PRECAUTIONS ).
Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, TOROLAC 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.
PRECAUTIONS
General:
Hepatic Effects: TOROLAC should be used with caution in patients with impaired hepatic function or a history of liver disease. Treatment with TOROLAC 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 TOROLAC should be discontinued in patients in whom an abnormal liver test has occurred as a result of TOROLAC therapy.
Hematologic Effects: TOROLAC 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 TOROLAC disappears within 24 to 48 hours after the drug is discontinued. TOROLAC does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where TOROLAC was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for TOROLAC compared to 0.2% in the control groups receiving narcotic analgesics.
Information for Patients: TOROLAC 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 TOROLAC, should inform their patients of the potential risks of TOROLAC treatment (see Boxed WARNING , WARNINGS , PRECAUTIONS and ADVERSE REACTIONS sections). Advise patients not to give TOROLAC ORAL to other family members and to discard any unused drug.
Remember that the total duration of TOROLAC therapy is not to exceed 5 days.
Drug Interactions: Ketorolac is highly bound to human plasma protein (mean 99.2%).
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 volunteers, TOROLAC ORAL was coadministered with a single dose of 25 mg warfarin , causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, TOROLAC IV/IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between TOROLAC and warfarin or heparin, the administration of TOROLAC to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGS and PRECAUTIONS ).
TOROLAC IV/IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).
Concomitant administration of TOROLAC ORAL and 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 TOROLAC 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 TOROLAC on plasma lithium has not been studied, but cases of increased lithium plasma levels during TOROLAC 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 TOROLAC on methotrexate clearance has not been studied.
In postmarketing experience there have been reports of a possible interaction between TOROLAC IV/IM and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of TOROLAC 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 TOROLAC and antiepileptic drugs (phenytoin, carbamazepine).
Hallucinations have been reported when TOROLAC was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).
TOROLAC IV/IM has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix TOROLAC and morphine in the same syringe.
There is no evidence in animal or human studies that TOROLAC 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 the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.
Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 µg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.
Pregnancy: 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 TOROLAC in pregnant women. TOROLAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The use of TOROLAC 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 ).
Lactation and Nursing: After a single administration of 10 mg of TOROLAC ORAL to humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.
Pediatric Use: Safety and efficacy in children (less than 16 years of age) have not been established. Therefore, use of TOROLAC in children is not recommended.
Use in the Elderly (>/=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 TOROLAC IV/IM . The lower end of the TOROLAC IV/IM dosage 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, TOROLAC.
ADVERSE REACTIONS
Adverse reaction rates increase with higher doses of TOROLAC. Practitioners should be alert for the severe complications of treatment with TOROLAC, such as GI ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (see Boxed WARNING , WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION ). These NSAID-related complications can be serious in certain patients for whom TOROLAC is indicated, especially when the drug is used inappropriately.
The Adverse Reactions Listed Below Were Reported In Clinical Trials As Probably Related To TOROLAC:
Incidence Greater Than 1%
Percentage of incidence in parentheses for those events reported in 3% or more patients.
Body as a Whole: edema (4%)
Cardiovascular: hypertension
Dermatologic: pruritus, rash
Gastrointestinal: nausea (12%), dyspepsia (12%), gastrointestinal pain (13%), diarrhea (7%), constipation, flatulence, gastrointestinal fullness, vomiting, stomatitis
Hemic and Lymphatic: purpura
Nervous System: headache (17%), drowsiness (6%), dizziness (7%), sweating
Injection-site pain was reported by 2% of patients in multidose studies.
Incidence 1% or Less
Body as a Whole: weight gain, fever, infections, asthenia
Cardiovascular: palpitation, pallor, syncope
Dermatologic: urticaria
Gastrointestinal: gastritis, rectal bleeding, eructation, anorexia, increased appetite
Hemic and Lymphatic: epistaxis, anemia, eosinophilia
Nervous System: tremors, abnormal dreams, hallucinations, euphoria, extrapyramidal symptoms, vertigo, paresthesia, depression, insomnia, nervousness, excessive thirst, dry mouth, abnormal thinking, inability to concentrate, hyperkinesis, stupor
Respiratory: dyspnea, pulmonary edema, rhinitis, cough
Special Senses: abnormal taste, abnormal vision, blurred vision, tinnitus, hearing loss
Urogenital: hematuria, proteinuria, oliguria, urinary retention, polyuria, increased urinary frequency
The Following Adverse Events Were Reported From Postmarketing Experience:
Body as a Whole: hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see Boxed WARNING, WARNINGS), myalgia
Cardiovascular: hypotension, flushing
Dermatologic: Lyell' syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria
Gastrointestinal: peptic ulceration, GI hemorrhage, GI perforation (see Boxed WARNING, WARNINGS), melena, acute pancreatitis
Hemic and Lymphatic: postoperative wound hemorrhage (rarely requiring blood transfusion--see Boxed WARNING, WARNINGS and PRECAUTIONS), thrombocytopenia, leukopenia
Hepatic: hepatitis, liver failure, cholestatic jaundice
Nervous System: convulsions, psychosis, aseptic meningitis
Respiratory: asthma, bronchospasm
Urogenital: acute renal failure (see Boxed WARNING, WARNINGS), flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome
OVERDOSAGE
In controlled overdosage, daily doses of 360 mg of TOROLAC IV/IM given for 5 days (three times the highest recommended dose), caused abdominal pain and peptic ulcers which healed after discontinuation of dosing. Metabolic acidosis has been reported following intentional overdosage.
Dialysis does not significantly clear ketorolac tromethamine from the blood stream.
DOSAGE AND ADMINISTRATION
THE COMBINED DURATION OF USE OF TOROLAC IV/IM AND TOROLAC ORAL IS NOT TO EXCEED 5 DAYS.
THE USE OF TOROLAC ORAL IS ONLY INDICATED AS CONTINUATION THERAPY TO TOROLAC IV/IM .
TOROLAC IV/IM
TOROLAC IV/IM may be used as a single or multiple dose on a regular or prn schedule for the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Hypovolemia should be corrected prior to the administration of TOROLAC (see WARNINGS : Renal Effects ). Patients should be switched to alternative analgesics as soon as possible, but TOROLAC therapy is not to exceed 5 days.
When administering TOROLAC IV/IM , the IV bolus must be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins in 30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours.
Single-Dose Treatment: The Following Regimen Should Be Limited To Single Administration Use Only
IM Dosing:
Patients <65 years of age: One dose of 60 mg.
Patients >/=65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: dose of 30 mg.
IV Dosing:
Patients <65 years of age: One dose of 30 mg.
Patients >/=65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: dose of 15 mg.
Multiple-Dose Treatment (IV or IM)
Patients <65 years of age: The recommended dose is 30 mg TOROLAC IV/IM every 6 hours. The maximum daily dose should not exceed 120 mg.
For Patients >/=65 years of age, renally impaired patients (see WARNINGS ) and patients less than 50 kg (110 lbs): The recommended dose is 15 mg TOROLAC IV/IM every 6 hours. The maximum daily dose for these populations should not exceed 60 mg.
For breakthrough pain do not increase the dose or the frequency of TOROLAC. Consideration should be given to supplementing these regimens with low doses of opioids prn unless otherwise contraindicated.
Pharmaceutical Information for TOROLAC IV/IM : Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
TOROLAC IV/IM should not be mixed in a small volume (eg, in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution.
TOROLAC ORAL is indicated ONLY as continuation therapy to TOROLAC IV/IM for the management of moderately severe acute pain that requires analgesia at the opioid level (see also PRECAUTIONS : Information for Patients ).
Transition from TOROLAC IV/IM to TOROLAC ORAL : The recommended TOROLAC ORAL dose is as follows:
Patients <65 years of age: 2 tablets as a first oral dose for patients who received 60 mg IM single dose, 30 mg IV single dose or 30 mg multiple dose. TOROLAC IV/IM followed by 1 tablet TOROLAC ORAL every 4 to 6 hours, not to exceed 40 mg/24 h of TOROLAC ORAL
Patients >/=65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: 1 tablet as a first oral dose for patients who received 30 mg IM single dose, 15 mg IV single dose or 15 mg multiple dose. TOROLAC IV/IM followed by 1 tablet TOROLAC ORAL every 4 to 6 hours, not to exceed 40 mg/24 h of TOROLAC ORAL .
Shortening the recommended dosing intervals may result in increased frequency and severity of adverse reactions.
The maximum combined duration of use (parenteral and oral TOROLAC) is limited to 5 days.