Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/406
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Ketorolac Tromethamine (Injection, Solution)
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IN ADULTS, THE
COMBINED DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND
KETOROLAC TROMETHAMINE TABLETS IS NOT TO EXCEED FIVE (5) DAYS. IN
ADULTS, THE USE OF KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS
CONTINUATION THERAPY TO KETOROLAC TROMETHAMINE INJECTION.<br/>Ketorolac
Tromethamine Injection:<br/>Adult
Patients: Ketorolac Tromethamine Injection may be used as a
single or multiple dose on a regular or���prn���schedule
for the management of moderately severe acute pain that
requires analgesia at the opioid level, usually in a
postoperative setting. Hypovolemia should be corrected
prior to the administration of ketorolac tromethamine
. Patients
should be switched to alternative analgesics as soon as
possible, but ketorolac tromethamine therapy is not to
exceed five (5) days. When administering Ketorolac Tromethamine Injection,
the IV bolus must be given over no less than 15 seconds.
The IM administration should be given slowly and deeply
into the muscle. The analgesic effect begins in ~30
minutes with maximum effect in 1 to 2 hours after dosing
IV or IM. Duration of analgesic effect is usually 4 to 6
hours.<br/>Single-Dose
Treatment: The Following Regimen Should Be Limited to Single
Administration Use Only:<br/>Adult
Patients:<br/>Pediatric
Patients (2 to 16 Years of Age): The
pediatric population should receive only a single dose
of Ketorolac Tromethamine Injection, as
follows:<br/>Multiple-Dose
Treatment (IV or IM) in Adults:<br/>Patients<65 Years of Age: The
recommended dose is 30 mg Ketorolac Tromethamine
Injection every 6 hours. The maximum daily dose should
not exceed 120 mg.<br/>For
Patients���65 Years of Age, Renally Impaired Patients and
Patients Less Than 50 Kg (110 lbs): The
recommended dose is 15 mg Ketorolac Tromethamine
Injection every 6 hours. The maximum daily dose for
these populations should not exceed 60 mg. For
breakthrough pain do not increase the dose or the
frequency of ketorolac tromethamine. Consideration
should be given to supplementing these regimens with low
doses of opioids prn unless otherwise
contraindicated.<br/>Pharmaceutical
Information for Ketorolac Tromethamine Injection: Parenteral
drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever
solution and container permit. Ketorolac
Tromethamine Injection should not be mixed in a small volume
(e.g., in a syringe) with morphine sulfate, meperidine
hydrochloride, promethazine hydrochloride or hydroxyzine
hydrochloride; this will result in precipitation of ketorolac
from solution. Shortening
the recommended dosing intervals may result in increased
frequency and severity of adverse reactions.
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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 (1:1), and
the chemical structure is: 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. Its molecular
formula is CHNO. Ketorolac
tromethamine is available for intravenous (IV) or intramuscular (IM)
administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in
sterile solution; 60 mg in 2 mL (3%) of ketorolac tromethamine in
sterile solution is available for IM administration only. The solutions
contain 0.1% citric acid, 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg
and 8.70 mg, respectively, of sodium chloride in sterile water. The pH
is adjusted with sodium hydroxide or hydrochloric acid, and the
solutions are packaged with nitrogen. The sterile solutions are clear
and slightly yellow in color.
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Pharmacodynamics: Ketorolac
tromethamine is a nonsteroidal anti-inflammatory drug (NSAID)
that exhibits analgesic activity in animal models. 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. The peak
analgesic effect of ketorolac tromethamine occurs 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.<br/>Pharmacokinetics: Ketorolac
tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric
forms, with the S-form having analgesic activity.<br/>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. 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.<br/>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.<br/>Distribution: The
mean apparent volume (V) 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, 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. Ketorolac tromethamine is excreted in human milk (seePRECAUTIONS, Lactation and
Nursing).<br/>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.<br/>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.<br/>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 (geriatric, pediatric,
renal failure or hepatic disease patients).<br/>Kinetics in
Special Populations:<br/>Clinical Studies:<br/>Adult
Patients: 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 double-blind, single- and multiple-dose, parallel
trial designs in patients with moderate to severe pain
at baseline. Ketorolac Tromethamine Injection 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.<br/>Short-Term
Use (Up to 5 Days) Studies: In
adults, 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 30 mg IM
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 30 mg IM was between
that of morphine 6 and 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 30 mg IV, 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.<br/>Pediatric
Patients: The
analgesic efficacy of single doses of Ketorolac
Tromethamine Injection has been demonstrated by showing
a decrease in the need for supplemental narcotic in
pediatric patients receiving ketorolac as compared to
placebo. See discussion of these results under Clinical Studies With Concomitant Use of Opioids
below.<br/>Clinical
Studies With Concomitant Use of Opioids:<br/>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 (GI) bleeding was
dose-dependent (see Tables 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).
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(see also Boxed
WARNING)
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Ketorolac
Tromethamine Injection, USP is available as follows: For IV or IM Single Dose use: NDC 10019-029-02, 2
mL vials containing 1 mL of 15 mg/mL Ketorolac Tromethamine, USP,
available in boxes of 25. NDC 10019-030-03, 2
mL vials containing 1 mL of 30 mg/mL Ketorolac Tromethamine, USP,
available in boxes of 25. For IM Single Dose use only: NDC 10019-030-04,
60 mg/2 mL, 2 mL vials containing 2 mL of 30 mg/mL Ketorolac
Tromethamine, USP, (60 mg), available in boxes of 25. Store at 20��-25��C (68��-77��F), excursions permitted to 15��-30��C (59��-86��F) [see USP Controlled Room
Temperature]. PROTECT FROM LIGHT Retain in carton until time of use. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015
USA For Product Inquiry
1 800 ANA DRUG (1-800-262-3784) MLT-01480/1.0
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WARNING: Ketorolac tromethamine, a nonsteroidal
anti-inflammatory drug (NSAID), is indicated for the short-term (up
to 5 days in adults) 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.<br/>Gastrointestinal
Effects:<br/>Renal Effects:<br/>Risk of Bleeding:<br/>Hypersensitivity:<br/>Intrathecal or
Epidural Administration:<br/>Labor, Delivery and
Nursing:<br/>Concomitant Use
With NSAIDs:<br/>Dosage and
Administration:<br/>Ketorolac
Tromethamine Tablets:<br/>Special Populations:
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General:<br/>Hepatic
Effects: Ketorolac tromethamine
should be used with caution in patients with
impaired hepatic function or a history of liver
disease. Treatment with ketorolac
tromethamine may cause elevations of liver enzymes, and,
in patients with pre-existing liver dysfunction, it may
lead to the development of a more severe hepatic
reaction. The administration of ketorolac tromethamine
should be discontinued in patients in whom an abnormal
liver test has occurred as a result of ketorolac
tromethamine therapy.<br/>Hematologic
Effects: Ketorolac tromethamine inhibits platelet aggregation
and may prolong bleeding time; therefore, it is
contraindicated as a preoperative medication, and
caution should be used when hemostasis is critical.
Unlike aspirin, the inhibition of platelet function by
ketorolac tromethamine disappears within 24 to 48 hours
after the drug is discontinued. Ketorolac tromethamine
does not appear to affect platelet count, prothrombin
time (PT) or partial thromboplastin time (PTT). In
controlled clinical studies, where ketorolac
tromethamine was administered intramuscularly or
intravenously postoperatively, the incidence of
clinically significant postoperative bleeding was 0.4%
for ketorolac tromethamine compared to 0.2% in the
control groups receiving narcotic
analgesics.<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 or their guardians 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 five (5) days in adults or a single dose in pediatric
patients ages 2 to 16 years.<br/>Drug Interactions: Ketorolac
is highly bound to human plasma protein (mean
99.2%).<br/>Warfarin,
Digoxin, Salicylate, and Heparin: Thein vitro
binding of warfarin 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 vitrostudies 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 ofdigoxin,warfarin, ibuprofen, naproxen,piroxicam, acetaminophen, phenytoin andtolbutamide did not alter ketorolac
tromethamine protein binding. In
a study involving 12 adult volunteers, ketorolac
tromethamine tablets were coadministered 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 to 11.4 min) compared
to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin
alone and 5.1 minutes (3.5 to 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 .<br/>Furosemide: Ketorolac Tromethamine Injection reduced the diuretic
response to furosemide in normovolemic healthy subjects
by approximately 20% (mean sodium and urinary output
decreased 17%).<br/>Probenecid: 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 three-fold
from 5.4 to 17.8 mcg/h/mL) and terminal half-life
increased approximately two-fold from 6.6 to 15.1 hours.
Therefore, concomitant use of ketorolac tromethamine and
probenecid is contraindicated.<br/>Lithium: 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.<br/>Methotrexate: 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.<br/>Nondepolarizing Muscle Relaxants: In
postmarketing experience there have been reports of a
possible interaction between Ketorolac Tromethamine
Injection and nondepolarizing muscle relaxants that
resulted in apnea. The concurrent use of ketorolac
tromethamine with muscle relaxants has not been formally
studied.<br/>ACE
Inhibitors: Concomitant use of ACE inhibitors may increase the risk of
renal impairment, particularly in volume-depleted
patients.<br/>Antiepileptic Drugs: Sporadic cases of seizures have been reported during
concomitant use of ketorolac tromethamine and antiepileptic
drugs (phenytoin, carbamazepine).<br/>Psychoactive Drugs: Hallucinations have been reported when ketorolac
tromethamine was used in patients taking psychoactive
drugs (fluoxetine, thiothixene,
alprazolam).<br/>Morphine: 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 and
Mutagenesis and Impairment of Fertility: An 18-month
study in mice with oral doses of ketorolac tromethamine 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:<br/>Pregnancy
Category C: Reproduction studies have been performed during
organogenesis using daily oral doses of ketorolac
tromethamine at 3.6 mg/kg (0.37 times the human AUC) in
rabbits and at 10 mg/kg (1.0 times the human AUC) in
rats. Results of these studies did not reveal evidence
of teratogenicity to the fetus. Oral doses of ketorolac
tromethamine 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
contractions, thus increasing the risk of uterine hemorrhage
.<br/>Lactation and
Nursing: After a
single administration of 10 mg of ketorolac tromethamine tablets
to humans, the maximum milk concentration observed was 7.3
ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1
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: The safety
and effectiveness of single doses of Ketorolac Tromethamine
Injection have been established in pediatric patients between
the ages of 2 and 16 years. Ketorolac Tromethamine Injection has
been shown to be effective in the management of moderately
severe acute pain that requires analgesia at the opioid level,
usually in a postoperative setting. Safety and efficacy in
pediatric patients below the age of 2 have not been established.
Therefore, Ketorolac Tromethamine Injection is not recommended
in pediatric patients below the age of 2. The risk of bleeding
was greater in those patients administered Ketorolac
Tromethamine Injection following tonsillectomy. Physicians
should consider the increased risk of bleeding before deciding
to administer Ketorolac Tromethamine Injection in patients
following tonsillectomy (see WARNINGS,
Hemorrhage and Pediatrics and Tonsillectomy). The risks
identified in the adult population with Ketorolac Tromethamine
Injection use also apply to pediatric patients. Therefore,
consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE
REACTIONS sections when prescribing Ketorolac
Tromethamine Injection to pediatric patients.<br/>Geriatric Use (���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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Symptoms following
acute NSAIDs overdoses are usually limited to lethargy, drowsiness,
nausea, vomiting, and epigastric pain, which are generally reversible
with supportive care. Gastrointestinal bleeding can occur. Hypertension,
acute renal failure, respiratory depression and coma may occur, but are
rare. Anaphylactoid reactions have been reported with therapeutic
ingestion of NSAIDs, and may occur following an overdose. Patients should be
managed by symptomatic and supportive care following a NSAIDs overdose.
There are no specific antidotes. Emesis and/or activated charcoal (60 g
to 100 g in adults, 1 g/kg to 2 g/kg in children) and/or osmotic
cathartic may be indicated in patients seen within 4 hours of ingestion
with symptoms or following a large oral overdose (5 to 10 times the
usual dose). In controlled
overdosage, daily doses of 360 mg of Ketorolac Tromethamine Injection
given for five (5) days (three 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. Single overdoses of
ketorolac tromethamine have been variously associated with abdominal
pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive
gastritis and renal dysfunction which have resolved after
discontinuation of dosing. 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 GI 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.<br/>The Adverse
Reactions Listed Below Were Reported In Clinical Trials As Probably
Related To Ketorolac Tromethamine::<br/>Incidence
Greater Than 1%: Percentage of incidence in parentheses for those events
reported in 3% or more patients Body as a
Whole: edema (4%) Cardiovascular:
hypertension Dermatologic:
pruritus, rash Gastrointestinal: nausea (12%), dyspepsia
(12%), gastrointestinal pain (13%), diarrhea (7%),
constipation, flatulence, gastrointestinal fullness,
vomiting, stomatitis Hemic and
Lymphatic: purpura Nervous System:
headache (17%), drowsiness (6%), dizziness (7%),
sweating Injection-site
pain was reported by 2% of patients in
multi-dose studies.<br/>Incidence
1% or Less: Body as a
Whole: weight gain, fever, infections,
asthenia Cardiovascular:
palpitation, pallor, syncope Dermatologic:
urticaria Gastrointestinal: gastritis, rectal bleeding,
eructation, anorexia, increased appetite Hemic and
Lymphatic: epistaxis, anemia, eosinophilia Nervous System:
tremors, abnormal dreams, hallucinations, euphoria,
extrapyramidal symptoms, vertigo, paresthesia,
depression, insomnia, nervousness, excessive thirst, dry
mouth, abnormal thinking, inability to concentrate,
hyperkinesis, stupor Respiratory:
dyspnea, pulmonary edema, rhinitis, cough Special Senses:
abnormal taste, abnormal vision, blurred vision,
tinnitus, hearing loss Urogenital:
hematuria, proteinuria, oliguria, urinary retention,
polyuria, increased urinary frequency<br/>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), angioedema, myalgia Cardiovascular: hypotension,
flushing Dermatologic: Lyell's syndrome,
Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular
rash, urticaria Gastrointestinal: peptic
ulceration, GI hemorrhage, GI perforation (see Boxed
WARNING, WARNINGS), melena, acute pancreatitis, hematemesis,
esophagitis 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, interstitial nephritis, hyponatremia,
hyperkalemia, hemolytic uremic syndrome
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(see also Boxed
WARNING) The combined use of
Ketorolac Tromethamine Injection and ketorolac tromethamine tablets are
not to exceed 5 days in adults. Only single doses of Ketorolac
Tromethamine Injection are recommended for use in pediatric patients. The most serious
risks associated with ketorolac tromethamine are:<br/>Gastrointestinal
(GI) Effects���Risk of GI Ulceration, Bleeding and Perforation: Ketorolac
tromethamine is CONTRAINDICATED in patients with previously
documented peptic ulcers and/or GI bleeding. Serious
gastrointestinal toxicity, such as bleeding, ulceration and
perforation, can occur at any time, with or without warning
symptoms, in patients treated with ketorolac tromethamine.
Studies to date with NSAIDs have not identified any subset of
patients not at risk of developing peptic ulceration and
bleeding. Elderly or debilitated patients seem to tolerate
ulceration or bleeding less well than other individuals, and
most spontaneous reports of fatal GI events are in this
population. Postmarketing experience with parenterally
administered ketorolac tromethamine suggests that there may be a
greater risk of gastrointestinal ulcerations, bleeding and
perforation in the elderly. The
incidence and severity of gastrointestinal complications
increases with increasing dose of, and duration of treatment
with, ketorolac tromethamine. In a non-randomized, in-hospital
postmarketing surveillance study comparing parenteral ketorolac
tromethamine to parenteral opioids, higher rates of clinically
serious GI bleeding were seen in adult patients<65 years
of age who received an average total daily dose of more than 90
mg of Ketorolac Tromethamine Injection per day (see CLINICAL PHARMACOLOGY,
Postmarketing Surveillance Study). The same
study showed that elderly (���65 years of age) and debilitated
patients are more susceptible to gastrointestinal complications.
A history of peptic ulcer disease was revealed as another risk
factor that increases the possibility of developing serious
gastrointestinal complications during ketorolac tromethamine
therapy (see Tables 3A and 3B).<br/>Hemorrhage: Because
prostaglandins play an important role in hemostasis and NSAIDs
affect platelet aggregation as well, use of ketorolac
tromethamine in patients who have coagulation disorders should
be undertaken very cautiously, and those patients should be
carefully monitored. Patients on therapeutic doses of
anticoagulants (e.g., heparin or dicumarol derivatives) have an
increased risk of bleeding complications if given ketorolac
tromethamine concurrently; therefore, physicians should
administer such concomitant therapy only extremely cautiously.
The concurrent use of ketorolac tromethamine and prophylactic
low-dose heparin (2500 to 5000 units q12h), warfarin and
dextrans have not been studied extensively, but may also be
associated with an increased risk of bleeding. Until data from
such studies are available, physicians should carefully weigh
the benefits against the risks and use such concomitant therapy
in these patients only extremely cautiously. In patients who
receive anticoagulants for any reason, there is an increased
risk of intramuscular hematoma formation from administered
ketorolac tromethamine IM (seePRECAUTIONS
- Drug Interactions). Patients receiving therapy
that affects hemostasis should be monitored closely. In
postmarketing experience, postoperative hematomas and other
signs of wound bleeding have been reported in association with
the perioperative use of Ketorolac Tromethamine Injection.
Therefore, perioperative use of ketorolac tromethamine should be
avoided and postoperative use be undertaken with caution when
hemostasis is critical .<br/>Pediatrics and
Tonsillectomy: Physicians
should consider the increased risk of bleeding before deciding
to administer ketorolac tromethamine in patients following
tonsillectomy. Ketorolac Tromethamine Injection is not
recommended for use in pediatric patients below the age of 2
years. In a retrospective analysis of patients having undergone
tonsillectomy with or without adenoidectomy, the risk of
bleeding was 10.1% in patients administered Ketorolac
Tromethamine Injection compared to 2.2% in those receving
opioids. The postoperative hemorrhage rate in patients 12 years
and younger was 6.5% and 3.3% with and without ketorolac
tromethamine, respectively. In a prospective study of ketorolac
tromethamine in pediatric patients (ages 3 to 9 years)
undergoing tonsillectomy with or without adenoidectomy, the
overall incidence of bleeding was similar between the patients
receiving ketorolac tromethamine and morphine (16.3% versus 17%,
respectively). However, during the first 24 hours after surgery,
a higher incidence of bleeding was observed in the Ketorolac Tromethamine Injection group (14.3%) versus the morphine group
(4.2%).<br/>Anaphylactoid
Reactions: Anaphylactoid reactions may occur in patients without a known
previous exposure or hypersensitivity to aspirin, ketorolac
tromethamine or other NSAIDs, or in individuals with a history
of angioedema, bronchospastic reactivity (e.g., asthma) and
nasal polyps. Anaphylactoid reactions, like anaphylaxis, may
have a fatal outcome.<br/>Impaired Renal
Function: Ketorolac tromethamine should be used with
caution in patients with impaired renal function or a
history of kidney disease because it is a potent inhibitor
of prostaglandin synthesis. Renal toxicity with
ketorolac tromethamine has been seen in patients with conditions
leading to a reduction in blood volume and/or renal blood flow
where renal prostaglandins have a supportive role in the
maintenance of renal perfusion. In these patients administration
of ketorolac tromethamine may cause a dose-dependent reduction
in renal prostaglandin formation and may precipitate acute renal
failure. Patients at greatest risk of this reaction are those
with impaired renal function, dehydration, heart failure, liver
dysfunction, those taking diuretics and the elderly.
Discontinuation of ketorolac tromethamine therapy is usually
followed by recovery to the pretreatment state.<br/>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 . Therefore,
ketorolac tromethamine should be used with caution in
patients with impaired renal function and such
patients 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 . Hypovolemia should be
corrected before treatment with ketorolac
tromethamine is initiated.<br/>Fluid Retention and
Edema: Fluid
retention, edema, retention of NaCl, oliguria, elevations of
serum urea nitrogen and creatinine have been reported in
clinical trials with ketorolac tromethamine. Therefore,
ketorolac tromethamine should be used only very cautiously in
patients with cardiac decompensation, hypertension or similar
conditions.<br/>Pregnancy: In late
pregnancy, as with other NSAIDs, ketorolac tromethamine should
be avoided because it may cause premature closure of the ductus
arteriosus.
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Adult Patients: 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 ketorolac
tromethamine 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 (seeWARNINGS, 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.<br/>Pediatric Patients: The safety
and effectiveness of single doses of Ketorolac Tromethamine
Injection have been established in pediatric patients between
the ages of 2 and 16 years. Ketorolac tromethamine, as a single
injectable dose, has been shown to be effective in the
management of moderately severe acute pain that requiresanalgesia at the opioid level, usually in the postoperative
setting. There is limited data available to support the use of
multiple doses of ketorolac tromethamine in pediatric patients.
Safety and effectiveness have not been established in pediatric
patients below the age of 2 years. Use of ketorolac tromethamine
in pediatric patients is supported by evidence from adequate and
well-controlled studies of ketorolac tromethamine in adults with
additional pharmacokinetic, efficacy and safety data on its use
inpediatric patients available in the published literature (seeCLINICAL
PHARMACOLOGY, Clinical Studies, WARNINGS, and PRECAUTIONS). 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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