KETOROLAC TROMETHAMINE (Page 2 of 8)

Kinetics in Special Populations

Geriatric 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).

Pediatric Patients: 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.

Renally Insufficiency: 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 Insufficiency: 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).

Race: Pharmacokinetic differences due to race have not been identified.

1 Estimated from 30 mg single IM doses of ketorolac tromethamine

2 Estimated from 10 mg single oral doses of ketorolac tromethamine

3 Liters/hours/kilogram

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
Total Clearance [in L/h/kg]3 Terminal Half-life [in hours]
Type of Subjects IM ORAL IM ORAL
Mean (range) Mean (range) Mean (range) Mean (range)
Normal Subjects Intramuscular (n=54) mean age=32, range=18 to 60 Oral (n=77) mean age=32, range=20 to 60 0.023 (0.010 to 0.046) 0.025 (0.013 to 0.050) 5.3 (3.5 to 9.2) 5.3 (2.4 to 9)
Healthy Elderly Subjects Intramuscular (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 Intramuscular 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 Intramuscular (n=25), Oral (n=9) serum creatinine=1.9 to 5 mg/dL, mean age (Intramuscular)=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 Intramuscular and Oral (n=9) mean age=40, range=27 to 63 0.016 (0.003 to 0.036) - 13.6 (8 to 39.1) -

IV Administration: In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) hours. (See Kinetics in Special Populations for use of IV dosing of ketorolac tromethamine in pediatric patients.)

CLINICAL STUDIES

Adult Patients: In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine IV 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 IV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ketorolac tromethamine and other treatment options before deciding to use ketorolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Acute Pain in Adult Patients

Ketorolac tromethamine 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 IV or IM dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary.

The total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine 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 ketorolac tromethamine therapy is not to exceed 5 days.

Ketorolac tromethamine injection 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 ketorolac tromethamine injection dosage range with low doses of narcotics prn, unless otherwise contraindicated. Ketorolac tromethamine injection and narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION — Pharmaceutical Information for Ketorolac Tromethamine Injection).

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