Prescription Drug Information: Ketorolac Tromethamine
KETOROLAC TROMETHAMINE- ketorolac tromethamine tablet, film coated
Zydus Pharmaceuticals (USA) Inc.
WARNING
Ketorolac tromethamine tablets, a nonsteroidal anti-inflammatory drug (NSAID), are indicated for the short-term (up to 5 days in adults), management of moderately severe acute pain that requires analgesia at the opioid level and only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of ketorolac tromethamine tablets and ketorolac tromethamine should not exceed 5 days. Ketorolac tromethamine tablets are not indicated for use in pediatric patients and they are NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine tablets beyond a daily maximum of 40 mg in adults will not provide better efficacy but will increase the risk of developing serious adverse events. GASTROINTESTINAL RISK
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DESCRIPTION
Ketorolac tromethamine tablets, USP are a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine, USP is (±)-5-benzoyl-2,3-dihydro-1H -pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). The structural formula is:
C15 H13 NO3 . C4 H11 NO3 M.W. 376.40
Ketorolac tromethamine, USP is a racemic mixture of [-]S and [+]R ketorolac tromethamine, USP. Ketorolac tromethamine, USP may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine, USP has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26.
Ketorolac tromethamine tablets, USP are white to off-white, round, biconvex, film-coated tablets. Each tablet, for oral administration, contains 10 mg ketorolac tromethamine, USP, the active ingredient. In addition, each tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methyl cellulose, titanium dioxide and macrogol.
CLINICAL PHARMACOLOGY
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 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 IV, IM and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of ketorolac tromethamine and oral doses of ketorolac tromethamine, are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL form of ketorolac tromethamine and the IM form of ketorolac tromethamine was equal to that following an IV bolus.
Linear Kinetics
In adults, following administration of single ORAL doses of ketorolac tromethamine or 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 or IV doses of ketorolac tromethamine 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.
Absorption
Ketorolac tromethamine is 100% absorbed after oral administration (see Table 1). Oral administration of ketorolac tromethamine 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.
Distribution
The mean apparent volume (Vß ) 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 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 (≥ 65 Years of Age)).
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.
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 Effect and Table 2).
Race
Pharmacokinetic differences due to race have not been identified.
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Pharmacokinetic Parameters (units) | Oral * | Intramuscular † | Intravenous Bolus ‡ | |||||
10 mg | 15 mg | 30 mg | 60 mg | 15 mg | 30 mg | |||
Bioavailability (extent) | 100% | |||||||
Tmax § (min) | 44 ± 34 | 33 ± 21¶ | 44 ± 29 | 33 ± 21¶ | 1.1 ± 0.7¶ | 2.9 ± 1.8 | ||
Cmax # (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 Þ | 3.09 ± 1.17¶ | 6.85 ± 2.61 | ||
Cmin 8 (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 | ||
Cavg ß (mcg/mL) [steady state qid] | 0.59 ± 0.20¶ | 0.94 ± 0.29¶ | 1.88 ± 0.59¶ | N/A | 1.09 ± 0.30¶ | 2.17 ± 0.59 | ||
Vβà (L/kg) | 0.175 ± 0.039 | 0.210 ±0.044 | ||||||
% Dose metabolized ≤ 50 | % Dose excreted in feces = 6 | |||||||
% Dose excreted in urine = 91 | % Plasma protein binding = 99 |
Total Clearance [in L/h/kg]‡ | Terminal Half-Life [in hours] | |||
Type of Subjects | IM | ORAL | IM | ORAL |
Mean (range) | Mean (range) | Mean (range) | Mean (range) | |
Normal Subjects IM (n = 54) mean age = 32, range = 18 to 60 Oral (n = 77) mean age = 32, range = 20 to 60 | 0.023 | 0.025 | 5.3 | 5.3 |
(0.010 to 0.046) | (0.013 to 0.050) | (3.5 to 9.2) | (2.4 to 9) | |
Healthy Elderly Subjects IM (n = 13), Oral (n = 12) mean age = 72, range = 65 to 78 | 0.019 | 0.024 | 7 | 6.1 |
(0.013 to 0.034) | (0.018 to 0.034) | (4.7 to 8.6) | (4.3 to 7.6) | |
Patients with Hepatic Dysfunction IM and Oral (n = 7) mean age = 51, range = 43 to 64 | 0.029 | 0.033 | 5.4 | 4.5 |
(0.013 to 0.066) | (0.019 to 0.051) | (2.2 to 6.9) | (1.6 to 7.6) | |
Patients with Renal Impairment IM (n = 25), Oral (n = 9) serum creatinine = 1.9 to 5 mg/dL, mean age (IM) = 54, range = 35 to 71 mean age (Oral) = 57, range = 39 to 70 | 0.015 | 0.016 | 10.3 | 10.8 |
(0.005 to 0.043) | (0.007 to 0.052) | (5.9 to 19.2) | (3.4 to 18.9) | |
Renal Dialysis Patients IM and Oral (n = 9) mean age = 40, range = 27 to 63 | 0.016 | — | 13.6 | — |
(0.003 to 0.036) | (8 to 39.1) |
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