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 intramuscular route in pediatric patients.

Renal 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.

Table 2: The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (Intramuscular1 and Oral2) in Adult Populations
1 Estimated from 30 mg single intramuscular doses of ketorolac tromethamine2 Estimated from 10 mg single oral doses of ketorolac tromethamine3 Liters/hour/kilogram
Total Clearance [in L/h/kg]3 Terminal Half-life [in hours]
Type of Subjects Intramuscular Mean (range) Oral Mean (range) Intramuscular Mean (range) Oral Mean (range)
Normal SubjectsIntramuscular (n = 54)mean age = 32, range = 18 to 60Oral (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 HepaticDysfunctionIntramuscular 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 ImpairmentIntramuscular (n = 25), Oral (n = 9)serum creatinine = 1.9 to 5.0 mg/dL,mean age (Intramuscular) = 54, range = 35 to 71mean 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 PatientsIntramuscular and Oral (n = 9)mean age = 40, range = 27 to 63 0.016(0.003 to 0.036) 13.6(8.0 to 39.1)

Intravenous-Administration: In normal subjects (n=37), the total clearance of 30 mg intravenous-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 intravenous 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 intravenous 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 intravenous 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 intravenous or intramuscular 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.

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