Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2123
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Ketorolac Tromethamine (Injection, Solution)
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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 presented in Figure 1. 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. Ketorolac
tromethamine is available for intravenous (IV) or intramuscular (IM) administration
as 15 mg per mL (1.5%) and 30 mg per mL (3%) in sterile solution; 60 mg per
2 mL (3%) of ketorolac tromethamine in sterile solution is available for IM
administration only. The solutions contain 10% (w/v) alcohol, and 6.68 mg,
4.35 mg, and 8.7 mg, respectively, of sodium chloride in sterile water. May
contain sodium hydroxide and/or hydrochloric acid for pH adjustment, pH 7.4
(6.9 to 7.9). The sterile solutions are clear and slightly yellow in color.
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PHARMACODYNAMICS Ketorolac
tromethamine 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 tromethamine 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 dose 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 (V) 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 Con 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). 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 Cfor the
two groups (elderly, 2.52 mcg/mL��0.77; young, 2.99 mcg/mL��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 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 Effects There
was no significant difference in estimates of half-life, AUC���, C,
in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS���Hepatic Effects).
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(see also Boxed WARNING)
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Ketorolac Tromethamine Injection, USP is supplied as follows: *FOR
IM USE ONLY. Store at 20 to 25��C (68
to 77��F). [See USP Controlled Room Temperature.] HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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WARNING Ketorolac tromethamine, a nonsteroidal anti-inflammatory
drug (NSAID), is indicated for the short-term (up to 5 days) management of
moderately severe, acute pain, that requires analgesia at the opioid level.
It is NOT indicated for minor or chronic painful conditions. Ketorolac tromethamine
is a potent NSAID analgesic, and its administration carries many risks. The
resulting NSAID-related adverse events can be serious in certain patients
for whom ketorolac tromethamine is indicated, especially when the drug is
used inappropriately. Increasing the dose of ketorolac tromethamine beyond
the label recommendations will not provide better efficacy but will result
in increasing the risk of developing serious adverse events. Gastrointestinal Effects Renal Effects Risk of Bleeding Hypersensitivity Intrathecal or Epidural Administration Labor, Delivery and NURSING Concomitant Use with NSAIDs DOSAGE AND ADMINISTRATION Ketorolac Tromethamine
Tablets Special Populations
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GENERAL:<br/>INFORMATION FOR PATIENTS: Ketorolac tromethamine is a potent NSAID and may cause serious
side effects such as gastrointestinal bleeding or kidney failure, which may
result in hospitalization and even fatal outcome. Physicians,
when prescribing ketorolac tromethamine, should inform their patients of the
potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS,
PRECAUTIONS, and ADVERSE REACTIONS sections). Advise patients not to give
ketorolac tromethamine tablets to other family members and to discard any
unused drug. Remember that the total duration of ketorolac
tromethamine therapy is not to exceed 5 (five) days.<br/>DRUG INTERACTIONS: Ketorolac is highly bound to human plasma protein (mean 99.2%). The in vitro binding ofwarfarin to plasma proteins is only slightly reduced by ketorolac tromethamine
(99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL.
Ketorolac does not alter digoxin protein
binding. In vitro studies indicate
that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately
99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac
plasma levels. Therapeutic concentrations of digoxin,
warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac tromethamine
protein binding. In a study involving 12 volunteers,
ketorolac tromethamine tablets were co-administered with a single dose of
25 mg warfarin, causing no significant
changes in pharmacokinetics or pharmacodynamics of warfarin. In another study,
ketorolac tromethamine injection was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting
in a mean template bleeding time of 6.4 minutes (3.2-11.4 min) compared to
a mean of 6.0 minutes (3.4-7.5 min) for heparin alone and 5.1 minutes (3.5-8.5
min) for placebo. Although these results do not indicate a significant interaction
between ketorolac tromethamine and warfarin or heparin, the administration
of ketorolac tromethamine to patients taking anticoagulants should be done
extremely cautiously and patients should be closely monitored (see WARNINGS
and PRECAUTIONS). Ketorolac tromethamine injection reduced
the diuretic response to furosemide in
normo-volemic healthy subjects by approximately 20% (mean sodium and urinary
output decreased 17%). Concomitant administration of
ketorolac tromethamine tablets and probenecid resulted in decreased clearance of ketorolac and significant increases
in ketorolac plasma levels (total AUC increased approximately 3-fold from
5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately 2-fold
from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine
and probenecid is contraindicated. Inhibition of renal lithium clearance, leading to an increase
in plasma lithium concentration, has been reported with some prostaglandin
synthesis-inhibiting drugs. The effect of ketorolac tromethamine on plasma
lithium has not been studied, but cases of increased lithium plasma levels
during ketorolac tromethamine therapy have been reported. Concomitant
administration of methotrexate and
some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing
the toxicity of methotrexate. The effect of ketorolac tromethamine on methotrexate
clearance has not been studied. In postmarketing experience,
there have been reports of a possible interaction between ketorolac tromethamine
injection and non-depolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine
with muscle relaxants has not been formally studied. Concomitant
use of ACE inhibitors may increase
the risk of renal impairment, particularly in volume depleted patients. Sporadic
cases of seizures have been reported during concomitant use of ketorolac tromethamine
and antiepileptic drugs (phenytoin, carbamazepine). Hallucinations
have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine,
thiothixene, alprazolam) . Ketorolac tromethamine
injection has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence
of adverse interactions. Do not mix ketorolac tromethamine and morphine in
the same syringe. There is no evidence, in animal or
human studies, that ketorolac tromethamine induces or inhibits hepatic enzymes
capable of metabolizing itself or other
drugs.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: An 18-month study in mice with ketorolac tromethamine tablets
at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM
or IV dose of 30 mg qid, based on area-under-the-plasma concentration curve
[AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC),
showed no evidence of tumorigenicity. Ketorolac tromethamine
was not mutagenic in the Ames test, unscheduled DNA synthesis and repair,
and in forward mutation assays. Ketorolac tromethamine did not cause chromosome
breakage in the in vivo mouse micronucleus
assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine
increased the incidence of chromosomal aberrations in Chinese hamster ovarian
cells. Impairment of fertility did not occur in male
or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg
(1.6 times the human AUC) of ketorolac tromethamine, respectively.<br/>Pregnancy: Pregnancy Category C. Reproduction
studies have been performed during organogenesis, using daily doses of ketorolac
tromethamine tablets at 3.6 mg/kg (0.37 times the human AUC) in rabbits and
at 10 mg/kg (1 times the human AUC) in rats. Results of these studies did
not reveal evidence of teratogenicity to the fetus. Doses of ketorolac tromethamine
tablets at 1.5 mg/kg (0.14 times the human AUC), administered after gestation
day 17, caused dystocia and higher pup mortality in rats. There are no adequate
and well-controlled studies of ketorolac tromethamine in pregnant women. Ketorolac
tromethamine should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.<br/>Labor and Delivery: The use of ketorolac tromethamine is contraindicated in labor
and delivery because, through its prostaglandin synthesis inhibitory effect,
it may adversely affect fetal circulation and inhibit uterine musculature,
thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).<br/>Lactation and Nursing: After a single administration of a 10 mg ketorolac tromethamine
tablet to humans, the maximum milk concentration observed was 7.3 ng/mL and
the maximum milk-to-plasma ratio was 0.037. After one day of dosing (qid),
the maximum milk concentration was 7.9 ng/mL and the maximum milk-to-plasma
ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting
drugs on neonates, use in nursing mothers is CONTRAINDICATED.<br/>Pediatric Use: Safety and efficacy in pediatric patients (less than 16 years
of age) have not been established. Therefore, use of ketorolac tromethamine
in pediatric patients is not recommended.<br/>Use in the Elderly (���65 Years of Age): Because ketorolac tromethamine may be cleared more slowly
by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to
the adverse effects of NSAIDs (see WARNINGS���Renal Effects), extra
caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when
treating the elderly with ketorolac tromethamine injection. The lower end
of the ketorolac tromethamine injection dosage range is recommended for patients
over 65 years of age and total daily dose is not to exceed 60 mg. The incidence
and severity of gastrointestinal complications increases with increasing dose
of, and duration of treatment with, ketorolac tromethamine.
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In controlled overdosage, daily doses of 360 mg of ketorolac
tromethamine injection given for five days (3 times the highest recommended
dose), caused abdominal pain and peptic ulcers which healed after discontinuation
of dosing. Metabolic acidosis has been reported following intentional overdosage. Dialysis
does not significantly clear ketorolac tromethamine from the blood stream.
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Ketorolac Tromethamine
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Ketorolac Tromethamine (Injection, Solution)
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Adverse reaction rates increase with higher doses of ketorolac
tromethamine. Practitioners should be alert for the severe complications of
treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and
perforation, postoperative bleeding, acute renal failure, anaphylactic and
anaphylactoid reactions, and liver failure (see Boxed WARNING, WARNINGS, PRECAUTIONS,
and DOSAGE AND ADMINISTRATION). These NSAID-related complications can be serious
in certain patients for whom ketorolac tromethamine is indicated, especially
when the drug is used inappropriately. The
adverse reactions listed below were reported in clinical trials as probably
related to ketorolac tromethamine. The following adverse events were
reported from postmarketing experience. Body as a Whole: hypersensitivity reactions such
as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see
Boxed WARNING, WARNINGS), myalgia. Cardiovascular: hypotension and flushing. Dermatologic: Lyell's syndrome, Stevens-Johnson syndrome, exfoliative
dermatitis, maculo-papular rash, urticaria. Gastrointestinal: peptic ulceration, G.I. hemorrhage,
G.I. perforation (see Boxed WARNING, WARNINGS), melena, acute pancreatitis. Hemic and Lymphatic: postoperative wound hemorrhage
(rarely requiring blood transfusion-see Boxed WARNING, WARNINGS and PRECAUTIONS),
thrombocytopenia, leukopenia. Hepatic: hepatitis, liver failure, cholestatic jaundice. Nervous System: convulsions, psychosis, aseptic
meningitis Respiratory: asthma,
bronchospasm. Urogenital: acute renal failure (see Boxed WARNING, WARNINGS), flank pain with
or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia,
hemolytic uremic syndrome.
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(see also Boxed WARNING) ���The combined use of ketorolac tromethamine injection and tablets is not to
exceed 5 days. The most serious risks associated with
ketorolac tromethamine are: Renal Effects: Ketorolac
tromethamine and its metabolites are eliminated primarily by the kidneys,
which, in patients with reduced creatinine clearance, will result in diminished
clearance of the drug (see CLINICAL PHARMACOLOGY). Therefore, ketorolac tromethamine
should be used with caution in patients with impaired renal function (see
DOSAGE AND ADMINISTRATION) and suchpatients should be followed closely. With
the use of ketorolac tromethamine, there have been reports of acute renal
failure, nephritis, and nephrotic syndrome. Because
patients with underlying renal insufficiency are at increased risk of developing
acute renal failure, the risks and benefits should be assessed prior to giving
ketorolac tromethamine to these patients. Hence, in patients with moderately
elevated serum creatinine, it is recommended that the daily dose of ketorolac
tromethamine injection be reduced by half, not to exceed 60 mg/day. Ketorolac
tromethamine is CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS
INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS). Hypovolemia should be corrected before treatment
with ketorolac tromethamine is initiated.
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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 ketorolac tromethamine injection, and ketorolac tromethamine
tablets are to be used only as continuation treatment, if necessary. Combined
use of ketorolac tromethamine injection and tablets 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. Ketorolac tromethamine
injection has been used concomitantly with morphine and meperidine, and has
shown an opioid-sparing effect. For breakthrough pain, it is recommended to
supplement the lower end of the ketorolac tromethamine injection dosage range
with low doses of narcotics prn, unless otherwise contraindicated. Ketorolac
tromethamine injection and narcotics should not be administered in the same
syringe (see DOSAGE AND ADMINISTRATION���Pharmaceutical
Information for Ketorolac tromethamine injection).
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Ketorolac Tromethamine
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