A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Toradol Warnings, Precautions, Pregnancy, Nursing, Abuse - Ketorolac
Toradol Warnings, Precautions, Pregnancy, Nursing, Abuse - Ketorolac
WARNINGS
(see also BOXED WARNING)
The combined use of ketorolac tromethamine
IV/IM and oral ketorolac
tromethamine is not to exceed 5 days.
The most serious risks associated ketorolac tromethamine
are:
- Gastrointestinal Ulcerations. Bleeding and Perforation:
Ketorolac tromethamine is CONTRAINDICATED in patients with previously
documented peptic ulcers and/or G.I. 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
compilations increases with increasing dose
of, and duration of
treatment with, ketorolac
tromethamine. In a non-randomized, in-hospital postmarketing surveillance
study, comparing parental ketorolac tromethamine
to parental opioids, higher rates of clinically serious G.I. bleeding
were seen in patients <65 years of age
who received an average
total daily dose of more
than 90 mg of ketorolac tromethamine
IV/IM 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 B).
- Impaired Renal Function: Ketorolac tromethamine
should be 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.
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 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
IV/IM 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.
- Fluid Retention and Edema: Fluid Retention, edema,
retention of NaCl, oliguria,
elevations of serum
urea nitrogen
and creatine 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.
- 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 (2500-5000
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 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
IV/IM. Therefore, perioperative
use of ketorolac tromethamine should be avoided and postoperative
use be undertaken with caution when hemostasis
is critical (see PRECAUTIONS
).
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.
Ophthalmic Solution: There is potential
for cross sensitivity
to acetylsalicylic acid,
phenylacetic acid derivatives,
and other nonsteroidal anti-inflammatory agents. Therefore, caution
should be used when treating individuals who have previously exhibited
sensitivities to these drugs.
PRECAUTIONS
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.
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.
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
, and ADVERSE
REACTIONS). Advise patients not to give oral
ketorolac tromethamine 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.
Carcinogenesis Mutagenesis, and Impairment of Fertility
(For ALL forms including Ophthalmic Solution) 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
q.d. 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 Ames test, unscheduled DNA synthesis and repair,
and in forward mutation
assays. Ketorolac tromethamine did not cause
chromosome breakage
in the in vivomouse 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
A.C. and 16 mg/kg (1.6
times the human A.C. of
ketorolac tromethamine, respectively.
Pregnancy
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
A.C. in rabbits and at
10 mg/kg (1.0 times the human
A.C. 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.
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
(see CONTRAINDICATIONS).
Lactation and Nursing
After a single administration
of 10 mg of oral ketorolac
tromethamine 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.
Pediatric Use
(For ALL forms including Ophthalmic Solution)
Safety and efficacy
in children (less than 16 years of age) have not been established.
Therefore, use of ketorolac tromethamine
is not recommended for use in children is not recommended.
Acular: Safety and efficacy
in children have not been established.
Use in the Elderly (³65 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 tromethamineIV/IM. The lower 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.
Additional Precautions for the Ophthalmic Solution
It is recommended that Acular (ketorolac tromethamine) 0.5% Sterile
Ophthalmic Solution be used with caution in patients with known
bleeding tendencies
or who are receiving other medication
which may prolong bleeding
time.
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