Ketorolac Tromethamine

KETOROLAC TROMETHAMINE- ketorolac tromethamine tablet, film coated
Burel Pharmaceuticals, LLC

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 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

  • Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

CARDIOVASCULAR THROMBOTIC EVENTS

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS).
  • Ketorolac tromethamine tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS).

RENAL RISK

  • Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS).

RISK OF BLEEDING

  • Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).

Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery.

RISK DURING LABOR AND DELIVERY

  • The use of ketorolac tromethamine in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions.

CONCOMITANT USE WITH NSAIDs

  • Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.

SPECIAL POPULATIONS

  • Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see WARNINGS).

DESCRIPTION

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-Benzoyl-2,3-dihydro-1H — pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol, and the structural formula is:

123
(click image for full-size original)

C15 H13 NO3 • C4 H11 NO3

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41.

Each tablet for oral administration contains 10 mg ketorolac tromethamine, USP. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80, shellac glaze, isopropyl alcohol, black iron oxide, N-butyl alcohol, propylene glycol and ammonium hydroxide.

FDA approved dissolution test specifications differ from USP.

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, IM and oral doses of ketorolac tromethamine tablets, are compared in Table 1. In adults, the extent of bioavailability following administration of the oral and IM forms of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics
In adults, following administration of single oral, 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, IV 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 (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 2 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

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.

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 seven patients with liver disease compared to healthy volunteers (see PRECAUTIONS: General: Hepatic Effect and Table 2).

Race Pharmacokinetic differences due to race have not been identified.

TABLE 1 Table of Approximate Average Pharmacokinetic Parameters (Mean ±SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine
% Dose metabolized = < 50
% Dose excreted in urine = 91
% Dose excreted in feces = 6
% Plasma protein binding = 99
* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers
Derived from IM pharmacokinetic studies in 54 normal volunteers
Derived from IV pharmacokinetic studies in 24 normal volunteers
§ Time-to-peak plasma concentration
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.
# Peak plasma concentration
Þ Not Applicable because 60 mg is only recommended as a single-dose
ß Trough plasma concentration
à Average plasma concentration
è Volume of Distribution

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 q.i.d.]

1.05 ± 0.26

1.56 ± 0.44

3.11 ± 0.87

N/AÞ

3.09 ± 1.17

6.85 ± 2.61

Cmin ß (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

Cavg à (mcg/mL) [steady state q.i.d.]

0.59 ± 0.20

0.94 ± 0.29

1.88 ± 0.59

N/A

1.09 ± 0.30

2.17 ± 0.59

è (L/kg)

0.175 ± 0.039

0.210 ± 0.044

TABLE 2 The Influence of Age, Liver and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM* and Oral) in Adult Populations
* Estimated from 30 mg single IM doses of ketorolac tromethamine
Estimated from 10 mg single oral doses of ketorolac tromethamine
Liters/hour/kilogram

Types of Subjects

Total Clearance [in L/h/kg]

Terminal Half-Life [in hours]

IM Mean (range)

ORAL Mean (range)

IM Mean (range)

ORAL Mean (range)

Normal SubjectsIM (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 SubjectsIM (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 IM 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 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 (0.005 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 IM and Oral (n =9), mean age = 40, range = 27 to 63

0.016 (0.003 to 0.036)

――

13.6 (8 to 39.1)

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IV Administration
In normal adult subjects (n = 37), the total clearance of 30 mg IV administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4 to 7.9) hours. (see Kinetics in Special Populations for use of IV dosing of ketorolac tromethamine in pediatric patients).

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