KETOROLAC TROMETHAMINE- ketorolac tromethamine injection, solution
General Injectables and Vaccines, Inc.
FOR INTRAVENOUS (IV)/ INTRAMUSCULAR (IM) USE (15 mg and 30 mg)
FOR INTRAMUSCULAR (IM) USE ONLY (60 mg)
Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.
Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.
Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac tromethamine 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. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).
CARDIOVASCULAR THROMBOTIC EVENTS
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS).
Ketorolac Tromethamine Injection, USP is CONTRAINDICATED in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS).
Ketorolac tromethamine 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
Ketorolac tromethamine 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).
Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery.
Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection (see CONTRAINDICATIONS and WARNINGS). Ketorolac tromethamine 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
Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.
RISK DURING LABOR AND DELIVERY
The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.
CONCOMITANT USE WITH NSAIDs
Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.
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 ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients.
DOSAGE AND ADMINISTRATION
Ketorolac Tromethamine Tablets
Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events.The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION).
Ketorolac Tromethamine Injection, USP 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 (1:1), and the structural formula is presented in FIGURE 1.
Ketorolac tromethamine 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 376.40.
Ketorolac Tromethamine Injection, USP 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. 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. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear to slightly yellow in color.
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. The biological activity of ketorolac tromethamine is associated with the S-form.
Ketorolac tromethamine possesses no sedative or anxiolytic properties.
The peak analgesic effect of ketorolac tromethamine occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine by either route is in the duration of analgesia.
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 PharmacokineticsThe pharmacokinetics of ketorolac tromethamine, following IV, IM and oral doses of ketorolac tromethamine are compared in TABLE 1. In adults, the extent of bioavailability following administration of the ORAL and IM forms of ketorolac tromethamine was equal to that following an IV bolus.
Table 1 Table of Approximate Average Pharmacokinetic Parameters (Mean±SD) Following Oral, Intramuscular and Intravenous Dose of Ketorolac Tromethamine
In adults, following administration of single ORAL, IM or IV doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple IM, IV or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.
The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/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.
Ketorolac tromethamine is excreted in human milk (see PRECAUTIONS, NURSING MOTHERS).
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.
The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac tromethamine (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 (see CLINICAL PHARMACOLOGY, KINETICS IN SPECIAL POPULATIONS).
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.
Ketorolac tromethamine administered as an IV bolus, every 6 hours, for 5 days, to healthy subjects (n=13), showed no significant difference in Cmax on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD±0.13) on Day 1 and 0.55 mcg/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 (geriatric, pediatric, renal failure or hepatic disease patients).
Kinetics in Special Populations
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 Cmax for the two groups (elderly, 2.52 mcg/mL±0.77; young, 2.99 mcg/mL±1.03) (see PRECAUTIONS, GERIATRIC USE).
Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8±1.6 hours, the average clearance was 0.042±0.01 L/hr/kg, the volume of distribution during the terminal phase (Vβ) was 0.34±0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26±0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see TABLE 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the IM route in pediatric 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∞ 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∞-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).
There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS, HEPATIC EFFECTS and TABLE 2).
RacePharmacokinetic differences due to race have not been identified.
Table 2 The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM1 and ORAL2) in Adult Populations
IV-Administration: In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4.0 to 7.9) hours (see KINETICS IN SPECIAL POPULATIONS for use of IV dosing of ketorolac tromethamine in pediatric patients).
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