Pharmacodynamics
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.
Pharmacokinetics
Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S‑form having analgesic activity.
Comparison of Intravenous, Intramuscular and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following intravenous, intramuscular, and oral doses of ketorolac tromethamine are compared in Table 1. In adults, the extent of bioavailability following administration of the oral and intramuscular forms of ketorolac tromethamine was equal to that following an intravenous bolus.
Oral† | Intramuscular* | Intravenous Bolus‡ | ||||
Pharmacokinetic Parameters (units) | 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 qid] | 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 qid] | 0.29±0.07** | 0.47±0.13** | 0.93±0.26** | N/A | 0.61±0.21** | 1.04±0.35 |
Cavg4 (mcg/mL) [steady state qid] | 0.59±0.2** | 0.94±0.29** | 1.88±0.59** | N/A | 1.09±0.3** | 2.17±0.59 |
Vβ5 (L/kg) | ———— 0.175±0.039 ———— | 0.210±0.044 | ||||
% Dose metabolized = <50 % Dose excreted in urine = 91 | % Dose excreted in feces = 6 % Plasma protein binding = 99 | 1 Time-to-peak plasma 2 Peak plasma concentration 3 Trough plasma concentration 4 Average plasma concentration 5 Volume of distribution | ||||
† Derived from oral pharmacokinetic studies in 77 normal fasted volunteers * Derived from intramuscular pharmacokinetic studies in 54 normal volunteers ‡ Derived from intravenous pharmacokinetic studies in 24 normal volunteers †† Not applicable because 60 mg is only recommended as a single dose ** Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data | ||||||
Linear Kinetics
In adults, following administration of single oral, intramuscular or intravenous 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 intramuscular, intravenous, 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.
Distribution
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).
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.
Excretion
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.
Accumulation
Ketorolac tromethamine administered as an intravenous 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 patients, or hepatic disease patients).
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.
| 1 Estimated from 30 mg single intramuscular doses of ketorolac tromethamine 2 Estimated from 10 mg single oral doses of ketorolac tromethamine 3 Liters/hour/kilogram | ||||
Total Clearance | Terminal Half-life | |||
Type of Subjects | Intramuscular Mean (range) | Oral Mean (range) | Intramuscular Mean (range) | Oral Mean (range) |
Normal Subjects | 0.023 0.046) | 0.025 0.050) | 5.3 | 5.3 |
Healthy Elderly Subjects | 0.019 0.034) | 0.024 0.034) | 7 | 6.1 |
Patients with Hepatic Dysfunction | 0.029 0.066) | 0.033 0.051) | 5.4 | 4.5 |
Patients with Renal Impairment mean age (Oral) = 57, | 0.015 0.043) | 0.016 0.052) | 10.3 | 10.8 |
Renal Dialysis Patients | 0.016 0.036) | – | 13.6 | – |
Intravenous-Administration:
In normal subjects (n=37), the total clearance of 30 mg intravenous‑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 intravenous dosing of ketorolac tromethamine in pediatric patients.)
Pharmacodynamics
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.
Pharmacokinetics
Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S‑form having analgesic activity.
Comparison of Intravenous, Intramuscular and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following intravenous, intramuscular, and oral doses of ketorolac tromethamine are compared in Table 1. In adults, the extent of bioavailability following administration of the oral and intramuscular forms of ketorolac tromethamine was equal to that following an intravenous bolus.
Oral† | Intramuscular* | Intravenous Bolus‡ | ||||
Pharmacokinetic Parameters (units) | 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 qid] | 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 qid] | 0.29±0.07** | 0.47±0.13** | 0.93±0.26** | N/A | 0.61±0.21** | 1.04±0.35 |
Cavg4 (mcg/mL) [steady state qid] | 0.59±0.2** | 0.94±0.29** | 1.88±0.59** | N/A | 1.09±0.3** | 2.17±0.59 |
Vβ5 (L/kg) | ———— 0.175±0.039 ———— | 0.210±0.044 | ||||
% Dose metabolized = <50 % Dose excreted in urine = 91 | % Dose excreted in feces = 6 % Plasma protein binding = 99 | 1 Time-to-peak plasma 2 Peak plasma concentration 3 Trough plasma concentration 4 Average plasma concentration 5 Volume of distribution | ||||
† Derived from oral pharmacokinetic studies in 77 normal fasted volunteers * Derived from intramuscular pharmacokinetic studies in 54 normal volunteers ‡ Derived from intravenous pharmacokinetic studies in 24 normal volunteers †† Not applicable because 60 mg is only recommended as a single dose ** Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data | ||||||
Linear Kinetics
In adults, following administration of single oral, intramuscular or intravenous 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 intramuscular, intravenous, 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.
Distribution
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).
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.
Excretion
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.
Accumulation
Ketorolac tromethamine administered as an intravenous 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 patients, or hepatic disease patients).
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.
| 1 Estimated from 30 mg single intramuscular doses of ketorolac tromethamine 2 Estimated from 10 mg single oral doses of ketorolac tromethamine 3 Liters/hour/kilogram | ||||
Total Clearance | Terminal Half-life | |||
Type of Subjects | Intramuscular Mean (range) | Oral Mean (range) | Intramuscular Mean (range) | Oral Mean (range) |
Normal Subjects | 0.023 0.046) | 0.025 0.050) | 5.3 | 5.3 |
Healthy Elderly Subjects | 0.019 0.034) | 0.024 0.034) | 7 | 6.1 |
Patients with Hepatic Dysfunction | 0.029 0.066) | 0.033 0.051) | 5.4 | 4.5 |
Patients with Renal Impairment mean age (Oral) = 57, | 0.015 0.043) | 0.016 0.052) | 10.3 | 10.8 |
Renal Dialysis Patients | 0.016 0.036) | – | 13.6 | – |
Intravenous-Administration:
In normal subjects (n=37), the total clearance of 30 mg intravenous‑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 intravenous dosing of ketorolac tromethamine in pediatric patients.)
{{section_body_html_patient}}
Chat online with Pfizer Medical Information regarding your inquiry on a Pfizer medicine.
*Speak with a Pfizer Medical Information Professional regarding your medical inquiry. Available 9AM-5PM ET Monday to Friday; excluding holidays.
Submit a medical question for Pfizer prescription products.
Pfizer Safety
To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:
Pfizer Safety Reporting Site*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.
If you cannot use the above website, or would like to report an adverse event related to a different Pfizer product, please call Pfizer Safety at (800) 438-1985.
FDA Medwatch
You may also contact the U.S. Food and Drug Administration (FDA) directly to report adverse events or product quality concerns either online at www.fda.gov/medwatch or call (800) 822-7967.