A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Toradol Pharmacology, Pharmacokinetics, Studies, Metabolism - Ketorolac
Toradol Pharmacology, Pharmacokinetics, Studies, Metabolism - Ketorolac
CLINICAL PHARMACOLOGY
Pharmacodynamics: Ketorolac is a nonsteroidal anti-inflammatory
drug (NSAID). Ketorolac
tromethamine inhibits
synthesis of prostaglandins and may be considered a peripherally-acting
analgesic. The biological
activity of ketorolac
is associated with the S-form. Ketorolac tromethamine
possesses no sedative
or anxiolytic properties.
Pain relief was statistically
different after ketorolac tromethamine dosing from that of placebo
at 1/2 hour (the first time
point at which it was
measured) following the largest recommended doses of ketorolac tromethamine,
and by 1 hour following the smallest recommended doses. The peak
analgesic effect occurred within 2 to 3 hours and was 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 was 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, are compared in TABLE 1. 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: 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
humans, 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.
Binding and Distribution: The ketorolac tromethamine
racemate has been shown to be highly protein-bound (99%). Nevertheless,
even 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.
The mean apparent
volume (Vbeta)
of ketorolac tromethamine following complete distribution
was approximately 13 liters. This parameter was determined from
single-dose data.
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.
Clearance and Excretion: 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.
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 5-6 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 (elderly patients, renal
failure patients, or
hepatic disease patients).
Effects of Food: 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.
Kinetics in Special Populations Elderly Patients: Based
on single-dose data only, the half-life
of the ketorolac tromethamine
racemate increased
from 5 to 7 hours in the elderly (65-78 years) compared with young
healthy volunteers (24-35 years) (see TABLE 2). There was little
difference in the C maxfor the two groups (elderly, 2.52
mcg/,l ± 1.03) (see PRECAUTIONS,
Use in the Elderly.)
Renally Impaired Patients: Based on single-dose data only,
the mean half-life
of ketorolac tromethamine
in renally impaired patients in between 6 and 19 hours, and is dependent
on the extent of the impairment. There is p.o.
correlation between
creatine clearance
and total ketorolac tromethamine clearance
in the elderly and populations with renal
impairment (r=0.5).
In patients with renal
disease, the AUC0-¥
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 PRECAUTIONS, Hepatic
Effects).
Hepatic Effects: There was no
significant difference
in estimates of half-life
AUC0-¥ 'Cmax'
in 7 patients with liver
disease compared to
healthy volunteers (see
PRECAUTIONS, Hepatic Effects).
TABLE 1A - Table of Approximate Average Pharmacokinetic
Parameters (Mean ± SD) Oral, Intramuscular and Intravenous
Doses of Ketorolac Tromethamine
| Oral †
|
| Pharmacokinetic Parameter (units) |
10 mg |
|
Bioavailability (extent)
|
100% |
|
Tmax1 (min)
|
44 ± 34 |
|
Cmax2(mcg/ml)[single
dose]
|
0.87 ± 0.22 |
|
Cmax (mcg/ml)[steady state
qid]
|
1.05 ± 0.26** |
|
Cmin3 (mcg/ml)[steady
state qid]
|
0.29 ± 0.07** |
|
Cavg4 (mcg/ml)[steady
state qid]
|
0.59 ± 0.20** |
|
Vbeta5 (L/kg)
|
--0.175 ± 0.039-- |
TABLE 1B - Table of Approximate Average Pharmacokinetic
Parameters (Mean ± SD) Oral, Intramuscular and Intravenous
Doses of Ketorolac Tromethamine
| Intramuscular* |
| Pharmacokinetic Parameter (units) |
15 mg |
30 mg |
60 mg |
|
Bioavailability (extent)
|
--- 100% --- |
|
Tmax1 (min)
|
33 ± 21** |
44 ± 29 |
33 ± 21** |
|
Cmax2(mcg/ml)[single
dose]
|
1.14 ± 0.32** |
2.42 ± 0.68 |
4.55 ± 1.27** |
|
Cmax (mcg/ml)[steady state
qid]
|
1.56 ± 0.44** |
3.11 ± 0.87** |
N/A††
|
|
Cmin3 (mcg/ml)[steady
state qid]
|
0.47 ± 0.13** |
0.93 ± 0.26** |
N/A |
|
Cavg4 (mcg/ml)[steady
state qid]
|
0.94 ± 0.29** |
1.88 ± 0.59** |
N/A |
|
Vbeta5 (L/kg)
|
--- 0.175-0.039--- |
TABLE 1C - Table of Approximate Average Pharmacokinetic
Parameters (Mean ± SD) Oral, Intramuscular and Intravenous
Doses of Ketorolac Tromethamine
| Intravenous Bolus †
|
| Pharmacokinetic Parameter (units) |
15 mg |
30 mg |
|
Bioavailability (extent)
|
100% |
|
Tmax1 (min)
|
1.1 ± 0.7** |
2.9 ± 1.8 |
|
Cmax2 (mcg/ml)[single
dose]
|
2.47 ± 0.51** |
4.65 ± 0.96 |
|
Cmax (mcg/ml)[steady state
qid]
|
3.09 ± 1.17** |
6.85 ± 2.61 |
|
Cmin3 (mcg/ml)[steady
state qid]
|
0.61 ± 0.21** |
1.04 ± 0.35 |
|
Cavg4 (mcg/ml)[steady
state qid]
|
1.09 ± 0.30** |
2.17 ± 0.59 |
|
Vbeta5 (L/kg)
|
0.210 ± 0.044 |
|
% Dose metabolized £50
|
% Dose excreted in feces
= 6 |
|
% Dose excreted in urine
= 91
|
% Plasma protein
binding = 99 |
|
† Derived from PO pharmacokinetic
studies in 77 normal
fasted volunteers.
|
|
* Derived from IM pharmacokinetic studies
in 54 normal volunteers.
|
|
†† Not applicable because 60 mg
is only recommended as a single dose.
|
|
‡ Derived from IV
pharmacokinetic studies in 24 normal
volunteers.
|
|
** 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
|
|
1 Time-to-peak plasma
concentration
|
|
2 Peak plasma
concentration
|
|
3 Trough plasma
concentration
|
|
4 Average plasma
concentration
|
|
5 Volume of distribution
|
TABLE 2 - The Influence of Age, Liver and Kidney
Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine
(IM1and ORAL2)
|
Total Clearance |
Terminal Half-life |
|
[in l/h/kg]3 |
[in hours] |
| Type of Subjects |
IM |
Oral |
IM |
Oral |
| |
Mean |
Mean |
Mean |
Mean |
| |
(range) |
(range) |
(range) |
(range) |
|
Normal Subjects
|
0.023 |
0.025 |
5.3 |
5.3 |
|
IM (n=54)
|
(0.010-0.046) |
(0.013-0.050) |
(3.5-9.2) |
(2.4-9.0) |
| mean range=32, range=18-60, (n=77),
mean age=32, range=20-60 |
|
Healthy Elderly
|
0.019 |
0.024 |
7.0 |
6.1 |
|
Subjects IM (n=13),
|
(0.013-0.034) |
(0.018-0.034) |
(4.7-8.6) |
(4.3-7.6) |
| Oral (n=12) (mean age=72, range=65-78) |
|
Patients with Hepatic
|
0.029 |
0.033 |
5.4 |
4.5 |
|
Dysfunction IM
|
(0.013-0.066) |
(0.019-0.051) |
(2.2-6.9) |
(1.6-7.6) |
| Oral (n=7) (mean age=51, range=43-64) |
|
Patients with Renal
|
0.015 |
0.016 |
10.3 |
10.8 |
|
Impairment IM and Oral (n=9) serum
creatinine
1.9-5.0mg/dl
|
(0.005-0.043) |
(0.007-0.052) |
(5.9-19.2) |
(3.4-18.9) |
| (mean age
(IM)=54, range=35-71 mean
age (Oral)=5, range=39-70) |
|
Renal Dialysis
|
0.016 |
- |
13.6 |
- |
|
Patients IM and Oral
|
(0.003-0.036) |
(8.0-39.1) |
- |
|
| (n=9) mean
age=40, range=27-63 |
|
1 Estimated from 30 mg
single IM doses of ketorolac tromethamine
|
|
2 Estimated from 10 mg
single oral doses
of ketorolac tromethamine
|
|
3 Liters/hour/kilogram IV-Administration:
In normal
studies (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.
|
CLINICAL STUDIES
The analgesic efficacy
of intramuscularly, intravenously and orally administered ketorolac
tromethamine was
investigated in two postoperative pain models: general surgery
(orthopedic, gynecologic
and abdominal) and oral surgery
(removal of impacted
third molars). The studies were primarily double-blind, single-
and multi-dose, parallel trial designs, in patients with moderate
to severe pain at baseline.
Ketorolac tromethamine
IV/IM was compared as follows: IM to meperidine or morphine
administered intramuscularly, and IV
to morphine administered
either directly IV or through
a PCA (Patient-Controlled Analgesia) pump.
Short Term Use (up to 5 days): In
the comparisons of intramuscular administration during the first
hour, the onset of analgesic
action was similar for
ketorolac tromethamine
and the narcotics, but the duration of analgesia
was longer with ketorolac tromethamine
than with the opioid comparators meperidine or morphine.
In a multi-dose, postoperative (general surgery) double-blind trial
of ketorolac tromethamine
IM 30 mg versus morphine
6 and 12 mg IM, each drug
given on an "as needed" basis
for up to 5 days, the overall analgesic effect
of ketorolac tromethamine
IM 30 mg was in between that
of morphine 6 and 12
mg. Ketorolac tromethamine
30 mg caused less drowsiness,
nausea and vomiting
than morphine 12 mg.
The majority of patients treated with either ketorolac tromethamine
or morphine were dosed
for up to 3 days; a small percentage of patients received 5 days
of dosing.
In clinical settings
where perioperative
morphine was allowed,
ketorolac tromethamine IV
30 mg, given once or twice as needed, provided analgesia comparable
to morphine 4 mg
IV once or twice as needed.
There was relatively limited experience
with 5 consecutive days of ketorolac tromethamine IV
use in controlled clinical
trials, as most patients were given the drug
for 3 days or less. The adverse events seen with IV- administered
ketorolac tromethamine
were similar to those observed with IM-administered ketorolac tromethamine,
as would be expected based on the similar pharmacokinetics and bioequivalence
(AUC, clearance, plasma
half-life) of IV and IM routes
of ketorolac tromethamine
administration.
Clinical Studies with Concomitant Use of Opioids: Clinical
studies in postoperative pain
management have demonstrated that ketorolac tromethamine IV/IM,
when used in combination with opioids, significantly reduced opioid
consumption. This combination may be useful in the subpopulation
of patients especially prone
to opioid-related complications. Ketorolac tromethamine and narcotics
should not be administered in the same syringe.
In 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.
Postmarketing Surveillance Study: A large postmarketing
observational, non-randomized study, involving approximately 10,000
patients receiving ketorolac tromethamine, demonstrated that the
risk of clinically serious
gastrointestinal
(G.I.) bleeding was
dose-dependent (see TABLE 3A and 3B). This was particularly true
in elderly patients who received an average
daily dose greater than 60 mg/day of ketorolac tromethamine
(TABLE 3A).
TABLE 3A - Incidence of Clinically Serious G.I.
Bleeding as Related to Age, Total Daily Dose, and History of G.I.
Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatment
with Ketorolac Tromethamine IV/IM A. Patients without History of
PUB
| Age of Patients |
Total Daily Dose of Ketorolac TromethamineIV/IM |
| £60 mg |
>60 to 90 mg |
>90 to 120 mg |
>120 mg |
| <65 years of age |
0.4% |
0.4% |
0.9% |
4.6% |
| ³65 years of
age |
1.2% |
2.8% |
2.2% |
7.7% |
TABLE 3B - Incidence of Clinically Serious G.I.
Bleeding as Related to Age, Total Daily Dose, and History of G.I.
Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatment
with Ketorolac Tromethamine IV/IM B. Patients with History of PUB
| Age of Patients |
Total Daily Dose of ketorolac tromethamine
IV/IM |
| £60 mg |
>60 to 90 mg |
>90 to 120 mg |
>120 mg |
| <65 years of age |
2.1% |
4.6% |
7.8% |
15.4% |
| ³65 years of
age |
4.7% |
3.7% |
2.8% |
25.0% |
Ophthalmic Solution: Ocular administration
of ketorolac tromethamine reduces the prostaglandin
E2 levels in aqueous
humor. The mean concentration of PGE2 was 80 pg/ml in
the aqueous humor
of the eyes receiving vehicle
and 28 pg/ml in the eyes receiving 0.5% Acular (ketorolac tromethamine)
ophthalmic solution.
Ketorolac tromethamine
given systemically does not cause
pupil constriction.
Results from clinical
studies indicate that Acular ophthalmic
solution has no significant
effect upon intraocular
pressure.
Two controlled studies showed that Acular (ketorolac tromethamine)
ophthalmic solution was significantly more effective than its vehicle
in receiving ocular itch
caused by seasonal allergic
conjunctivitis. Two drops (0.1 ml) of 0.5% Acular (ketorolac tromethamine)
ophthalmic solution
instilled into the patient
12 hours and 1 hour prior to cataract
extraction achieved
measurable levels in 8 of 9 patients' eyes (mean ketorolac concentration
95 ng/ml aqueous humor,
range 40 to 170 ng/ml).
One drop (0.05 ml) of
0.5% of Acular ophthalmic
solution was instilled
into one eye and one drop
of vehicle into the
other eye tid in 26 normal
subjects. Only 5 of 26 subjects had a detectable amount of ketorolac
in their plasma (range
10.7 to 22.5 ng/ml) at Day 10 during topical
ocular treatment. When ketorolac tromethamine
10 mg is administered systemically
every 6 hours, peak plasma
levels at steady state
are round 960 ng/ml.
Acular ophthalmic
solution has been safely
administered in conjunction with other ophthalmic
medications, such as antibiotics,
beta blockers, carbonic
anhydrase inhibitors,
cycloplegics, and mydriatics.
ANIMAL PHARMACOLOGY
Ophthalmic Solution Only: Ketorolac tromethamine
prevented the development of increased intraocular
pressure induced
in rabbits with topically applied arachidonic acid. Ketorolac did
not inhibit rabbit lens
aldose reductase in vivo.
Ketorolac tromethamine
ophthalmic solution
did not enhance the spread of ocular
infections induced in
rabbits with Candida albicans, Herpes Simplex virus
type one, or pseudomonas
aeruginosa.
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