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 ketorolac tromethamine dosing from that of placebo at 1/2 hour (the first time point at which it was measured) following the largest recommended doses of ketorolac tromethamine, 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 ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine 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 I.V., I.M., and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine following I.V., I.M., and oral doses of ketorolac tromethamine, are compared in TABLE 1. The extent of bioavailability following administration of the oral and I.M. forms of ketorolac tromethamine was equal to that following an I.V. bolus.
Linear Kinetics
Following administration of single oral, I.M., or I.V. 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 humans, following single or multiple I.M., I.V., 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.
Binding and Distribution
The ketorolac tromethamine racemate has been shown to be highly protein-bound (99%). Nevertheless, even 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.
The mean apparent volume (Vß) 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 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.
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
Ketorolac tromethamine administered as an I.V. 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 (elderly patients, renal failure patients, or hepatic disease patients).
Effects of Food
Oral administration of ketorolac tromethamine tablets 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 Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS, Geriatric Use).
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 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).
Hepatic Effects
There was no significant difference in estimates of half-life, AUC, Cmax, in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS, Hepatic Effects).
TABLE 1: Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine | Pharmacokinetic Parameters (units) | Oral+ | Intramuscular§ | Intravenous Bolus * |
| | 10 mg | 15 mg | 30 mg | 60 mg | 15 mg | 30 mg |
| Bioavailability (extent) | 100% |
| Tmax1(min) | 44 ± 34 | 33 ± 21** | 44 ± 29 | 33 ± 21** | 1.1 ± 0.7** | 2.9 ± 1.8 |
| Cmax2(mcg/mL) [single-dose] | 0.87 ± 0.22 | 1.14 ± 0.32** | 2.42 ± 0.68 | 4.55 ± 1.27** | 2.47 ± 0.51** | 4.65 ± 0.96 |
| Cmax (mcg/mL) [steady state q.i.d.] | 1.05 ± 0.26** | 1.56 ± 0.44** | 3.11 ± 0.87** | N/A++ | 3.09 ± 1.17** | 6.85 ± 2.61 |
| Cmin3(mcg/mL) [steady state q.i.d.] | 0.29 ± 0.07** | 0.47 ± 0.13** | 0.93 ± 0.26** | N/A | 0.61 ± 0.21** | 1.04 ± 0.35 |
| Cave4(mcg/mL) [steady state q.i.d.] | 0.59 ± 0.2** | 0.94 ± 0.29** | 1.88 ± 0.59** | N/A | 1.09 ± 0.3** | 2.17 ± 0.59 |
| Vß5(L/kg) | 0.175 ± 0.039 | 0.21 ± 0.044 |
% Dose metabolized ≤ 50 % Dose excreted in feces = 6
% Dose excreted in urine = 91 % Plasma protein binding = 99
TABLE 2: The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-Life of Ketorolac Tromethamine (I.M.1 and Oral2) | Total Clearance [in L/h/kg] 3 | Terminal Half-life [in hours] |
| Types of Subjects | I.M. Mean (range) | ORAL Mean (range) | I.M. Mean (range) | ORAL Mean (range) |
| Normal Subjects I.M.(n = 54) mean age = 32, range = 18 to 60 Oral (n = 77) mean age = 32, range = 20 to 60 | 0.023 (0.01 to 0.046) | 0.025 (0.013 to 0.05) | 5.3 (3.5 to 9.2) | 5.3 (2.4 to 9) |
| Healthy Elderly Subjects I.M.(n = 13), Oral (n = 12) mean age = 72, range = 65 to 78 | 0.019 (0.013 to 0.034) | 0.024 (0.018 to 0.034) | 7 (4.7 to 8.6) | 6.1 (4.3 to 7.6) |
| Patients with Hepatic Dysfunction I.M. and Oral (n = 7) mean age = 51, range = 43 to 64 | 0.029 (0.013 to 0.066) | 0.033 (0.019 to 0.051) | 5.4 (2.2 to 6.9) | 4.5 (1.6 to 7.6) |
| Patients with Renal Impairment I.M.(n = 25), Oral (n = 9) serum creatinine = 1.9 to 5 mg/dL, mean age (I.M.) = 54, range = 35 to 71 mean age (oral) = 57, range = 39 to 70 | 0.015 (0.005 to 0.043) | 0.016 (0.007 to 0.052) | 10.3 (5.9 to 19.2) | 10.8 (3.4 to 18.9) |
| Renal Dialysis Patients I.M. and Oral (n = 9), mean age = 40, range = 27 to 63 | 0.016 (0.003 to 0.036) | -- | 13.6 (8 to 39.1) | -- |
I.V. Administration: In normal subjects (n = 37), the total clearance of 30 mg I.V. administered ketorolac tromethamine was 0.03 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4 to 7.9) hours.
Clinical Studies
The analgesic efficacy of intramuscularly, intravenously and orally administered ketorolac tromethamine 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. Ketorolac tromethamine-I.V./I.M. was compared as follows: I.M. to meperidine or morphine administered intramuscularly, and I.V. to morphine administered either directly I.V. 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 ketorolac tromethamine and the narcotics, but the duration of analgesia was longer with ketorolac tromethamine than with the opioid comparators meperidine or morphine.
In a multi-dose, postoperative (general surgery) double-blind trial of ketorolac tromethamine-I.M.30 mg versus morphine 6 and 12 mg I.M., each drug given on an "as needed" basis for up to 5 days, the overall analgesic effect of ketorolac tromethamine-I.M. 30 mg was between that of morphine 6 and 12 mg. The majority of patients treated with either ketorolac tromethamine 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, ketorolac tromethamine-I.V. 30 mg, given once or twice as needed, provided analgesia comparable to morphine 4 mg I.V. once or twice as needed.
There was relatively limited experience with 5 consecutive days of ketorolac tromethamine-I.V. use in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with I.V.-administered ketorolac tromethamine were similar to those observed with I.M.-administered ketorolac tromethamine, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of I.V. and I.M. routes of ketorolac tromethamine administration.
Clinical Studies with Concomitant Use of Opioids
Clinical studies in postoperative pain management have demonstrated that ketorolac tromethamine-I.V./I.M., 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. Ketorolac tromethamine 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 ketorolac tromethamine-I.V. as fixed intermittent boluses (e.g., 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 ketorolac tromethamine-I.V. plus PCA morphine as compared to patients receiving PCA-administered morphine alone.
Postmarketing Surveillance Study
A large postmarketing observational, non-randomized study, involving approximately 10,000 patients receiving ketorolac tromethamine, demonstrated that the risk of clinically serious gastrointestinal (G.I.) bleeding was dose-dependent (see TABLE 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine (TABLE 3A).
TABLE 3: Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose, and History of G.I. Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatment with Ketorolac Tromethamine-I.V./I.M. | A. Patients without a History of PUB |
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine-I.V./I.M. |
| ≤ 60 mg | > 60 to 90 mg | > 90 to 120 mg | > 120 mg |
| < 65 years of age | 0.4% | 0.4% | 0.9% | 4.6% |
| ≥ 65 years of age | 1.2% | 2.8% | 2.2% | 7.7% |
| B. Patients with History of PUB |
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine-I.V./I.M. |
| ≤ 60 mg | > 60 to 90 mg | > 90 to 120 mg | > 120 mg |
| < 65 years of age | 0.4% | 0.4% | 0.9% | 4.6% |
| ≥ 65 years of age | 1.2% | 2.8% | 2.2% | 7.7% |
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