Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/328
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Ketorolac Tromethamine (Injection, Solution)
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THE COMBINED
DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND KETOROLAC
TROMETHAMINE TABLETS IS NOT TO EXCEED FIVE (5) DAYS. THE USE OF
KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS CONTINUATION THERAPY
TO KETOROLAC TROMETHAMINE INJECTION.<br/>Ketorolac
Tromethamine Injection: 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/>IM Dosing::<br/>IV Dosing::<br/>Multiple-Dose
Treatment (IV or IM):<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 (see
WARNINGS) 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.
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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. 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 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 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 and/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).
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.<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. 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: 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 inthe concentrations of free and
bound racemate.<br/>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.<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/>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 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 (elderly patients, renal
failure patients or hepatic disease
patients).<br/>Kinetics in
Special Populations:<br/>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 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
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. Ina 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/>Clinical
Studies With Concomitant Use of Opioids:: Clinical studies in postoperative pain management have
demonstrated that Ketorolac Tromethamine Injection, 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 a 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 alone.<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 in pre-filled syringes as
follows:<br/>For IV or IM
Single-Dose use:: A syringe
containing 1 mL of 15 mg/mL Ketorolac Tromethamine, USP, NDC
10019-021-09, available in boxes of 10. A syringe containing 1 mL of 30 mg/mL Ketorolac Tromethamine, USP, NDC
10019-022-09, available in boxes of 10.<br/>For IM Single-Dose
use only:: A syringe
containing 2 mL of 30 mg/mL Ketorolac Tromethamine, USP, (60
mg), NDC 10019-022-32, available in boxes of 10. Each
disposable syringe is supplied with an individually wrapped 22gauge, 1 1/2 inch needle.<br/>Directions for use:: Peel back
needle wrapping and expose needle hub; avoid touching hub.
Aseptically remove rubber protective cap from the syringe.
Attach needle to syringe hub with a twist, keeping needle sheath
intact. Remove needle sheath and inject medication. To prevent
needle-stick injuries, needles should not be recapped, purposelybent, or broken by hand. Dispose of used syringe in accordance
with applicable medical waste regulations and guidelines. Store at controlled room temperature
15��-30��C (59��-86��F). PROTECT FROM LIGHT Retain in carton until time of
use. Manufactured for Baxter Healthcare
Corporation Deerfield,
IL 60015 USA by: Taylor
Pharmaceuticals Decatur, IL
62525 For Product
Inquiry 1 800 ANA DRUG (1-800-262-3784) 400-657-02 MLT-01572/1.0
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WARNING: Ketorolac tromethamine, a nonsteroidal
anti-inflammatory drug (NSAID), is indicated for the short-term (up
to 5 days) 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 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.<br/>Drug Interactions: Ketorolac
is highly bound to human plasma protein (mean 99.2%). Thein 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 alterdigoxin 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
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)
forheparin 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 . 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
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 ketorolactromethamine and
probenecid is contraindicated. Inhibition
of renal lithiumclearance, 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 methotrexateand 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 andnondepolarizing muscle relaxants that resulted in apnea. The concurrent
use of ketorolac tromethamine with muscle relaxants has not been
formally studied. Concomitant
use of ACE inhibitorsmay 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 withmorphine 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 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 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: 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 (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. 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:: 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. 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), myalgia Cardiovascular: hypotension,
flushing Dermatologic: Lyell's syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculo-papular
rash, urticaria Gastrointestinal: peptic
ulceration, GI hemorrhage, GI 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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The combined use of
Ketorolac Tromethamine Injecton and ketorolac tromethamine tablets are
not to exceed 5 days. The most serious
risks associated with ketorolac tromethamine are:<br/>Gastrointestinal
Ulcerations, 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 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/>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/>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 (see PRECAUTIONS
- 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/>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.
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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
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 (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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| dailymed-instance:name |
Ketorolac Tromethamine
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