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KETOTOLAC TROMETHAMINE
Overview
What is KETOTOLAC TROMETHAMINE?
Ketorolac tromethamine is a member of the pyrrolo-pyrrole group
of non-steroidal anti-inflammatory drugs (NSAIDs). The chemical name for
ketorolac tromethamine is (±)-5-Benzoyl-2,3-dihydro-1-pyrrolizine-1-carboxylic acid, compound with
2-amino-2-(hydroxymethyl)-1,3-propanediol, and the structural formula 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.
Each tablet for oral administration contains 10 mg ketorolac tromethamine,
USP. In addition, each tablet contains the following inactive ingredients:
anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium,
hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin.
What does KETOTOLAC TROMETHAMINE look like?
What are the available doses of KETOTOLAC TROMETHAMINE?
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What should I talk to my health care provider before I take KETOTOLAC TROMETHAMINE?
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How should I use KETOTOLAC TROMETHAMINE?
Carefully consider the potential benefits and risks of ketorolac
tromethamine and other treatment options before deciding to use ketorolac
tromethamine. Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals.
Ketorolac tromethamine tablets are 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-IV or IM and ketorolac tromethamine
tablets are to be used only as continuation treatment, if necessary.
The total combined duration of use of ketorolac tromethamine-IV/IM 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 , ,
and ). Patients should be switched to alternative analgesics as soon as
possible, but ketorolac tromethamine tablet therapy is not to exceed 5 days.
Carefully consider the potential benefits and
risks of ketorolac tromethamine and other treatment options before deciding to
use ketorolac tromethamine. Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals. In adults, the
combined duration of use of IV or IM dosing of ketorolac tromethamine and
ketorolac tromethamine tablets is not to exceed 5 days. In adults, the use of
ketorolac tromethamine tablets is only indicated as continuation therapy to IV
or IM dosing of ketorolac tromethamine.
Oral formulation
not
as an initial dose
Use minimum effective dose
Do of 4 to 6 hours
Total duration of treatment in adult patients:
The following table summarizes ketorolac tromethamine tablets dosing
instructions in terms of age group:
What interacts with KETOTOLAC TROMETHAMINE?
(see also Boxed WARNING)
Ketorolac tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine.
Ketorolac tromethamine is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.
Ketorolac tromethamine should not be given to patients who have experienced asthma, urticaria or allergic-type reactions after taking aspirin or other NSAIDS. Severe, rarely fatal, anaphylactic-like reactions to NSAIDS have been reported in such patients (see and ).
Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.
Ketorolac tromethamine is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Ketorolac tromethamine is contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see for correction of volume depletion).
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.
The use of ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis and those at high risk of bleeding (see and ).
Ketorolac tromethamine is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
The concomitant use of ketorolac tromethamine and probenecid is contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.
What are the warnings of KETOTOLAC TROMETHAMINE?
The possibility of rapid emergence of resistant meningococci restricts the use of rifampin to short-term treatment of the asymptomatic carrier state. .
(see also Boxed WARNING)
The total combined duration of use of ketorolac tromethamine-IV/IM and
ketorolac tromethamine tablets is not to exceed 5 days in adults. Ketorolac
tromethamine tablets are not indicated for use in pediatric patients.
The most serious risks associated with ketorolac tromethamine are:
Ketorolac tromethamine is contraindicated in patients with
previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine
can cause serious gastrointestinal (GI) adverse events including bleeding,
ulceration and perforation, of the stomach, small intestine or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or
without warning symptoms, in patients treated with ketorolac tromethamine.
Only one in five patients who develop a serious upper GI adverse event on
NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as
dyspepsia, are common and may also occur at any time during NSAID therapy. The
incidence and severity of gastrointestinal complications increases with
increasing dose of, and duration of treatment with, ketorolac tromethamine. Do
not use ketorolac tromethamine for more than 5 days. However, even short-term
therapy is not without risk. In addition to past history of ulcer disease, other
factors that increase the risk for GI bleeding in patients treated with NSAIDs
include concomitant use of oral corticosteroids, or anticoagulants, longer
duration of NSAID therapy, smoking, use of alcohol, older age and poor general
health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating
this population.
To minimize the potential risk for an adverse GI event, the
lowest effective dose should be used for the shortest possible duration.
NSAIDs should be given with care to patients with a history of inflammatory
bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be
exacerbated.
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 therapy that
affects hemostasis, including 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.
Patients receiving therapy that affects hemostasis should be monitored
closely.
In post-marketing experience, postoperative hematomas and other signs of
wound bleeding have been reported in association with the perioperative use of
IV or IM dosing of ketorolac tromethamine. Therefore, perioperative use of
ketorolac tromethamine should be avoided and postoperative use be undertaken
with caution when hemostasis is critical (see ).
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a NSAID may
cause a dose-dependent reduction in prostaglandin formation and, secondarily, in
renal blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function, heart
failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
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 ). Therefore, ketorolac tromethamine should be used with caution
in patients with impaired renal function (see ) and such patients should be followed closely. With the use
of ketorolac tromethamine, there have been reports of acute renal failure,
interstitial nephritis and nephrotic syndrome.
Ketorolac tromethamine contraindicated
in patients with serum creatinine concentrations indicating advanced renal
impairment (see ).
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. Because patients with underlying renal insufficiency
are at increased risk of developing acute renal decompensation or failure, the
risks and benefits should be assessed prior to giving ketorolac tromethamine to
these patients.
As with other NSAIDs, anaphylactoid reactions may occur in
patients without a known previous exposure or hypersensitivity to ketorolac
tromethamine. Ketorolac tromethamine should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe,
potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
and ). Anaphylactoid reactions, like anaphylaxis, may have a
fatal outcome. Emergency help should be sought in cases where an anaphylactoid
reaction occurs.
Clinical trials of several COX-2 selective and nonselective
NSAIDs of up to 3 years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which
can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may
be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for the
shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV events
and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use. The
concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see ). Two large,
controlled clinical trials of a COX-2 selective NSAID for the treatment of pain
in the first 10 to 14 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see ).
NSAIDs, including ketorolac tromethamine, can lead to onset of
new hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazides or
loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including ketorolac tromethamine, should be used with caution in
patients with hypertension. Blood pressure (BP) should be monitored closely
during the initiation of NSAID treatment and throughout the course of
therapy.
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.
NSAIDS, including ketorolac tromethamine, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS)
and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Patients should be informed about the signs and
symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash, mucosal lesions or any other
sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, ketorolac tromethamine
should be avoided because it may cause premature closure of the ductus
arteriosus.
What are the precautions of KETOTOLAC TROMETHAMINE?
Ketorolac tromethamine cannot be expected to substitute for
corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation
of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is
made to discontinue corticosteroids.
The pharmacological activity of ketorolac tromethamine in reducing
inflammation may diminish the utility of this diagnostic sign in detecting
complications of presumed noninfectious, painful conditions.
Ketorolac tromethamine should be used with caution in patients
with impaired hepatic function or a history of liver disease. Borderline
elevations of one or more liver tests may occur in up to 15% of patients taking
NSAIDs including ketorolac tromethamine. These laboratory abnormalities may
progress, may remain unchanged or may be transient with continuing therapy.
Notable elevations of ALT or AST (approximately 3 or more times the upper limit
of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including
jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some
of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom
an abnormal liver test has occurred, should be evaluated for evidence of the
development of a more severe hepatic reaction while on therapy with ketorolac
tromethamine. If clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.),
ketorolac tromethamine should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including
ketorolac tromethamine. This may be due to fluid retention, occult or gross GI
blood loss, or an incompletely described effect upon erythropoiesis. Patients on
long-term treatment with NSAIDs, including ketorolac tromethamine, should have
their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of
anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong
bleeding time in some patients. Unlike aspirin, their effect on platelet
function is quantitatively less, of shorter duration, and reversible. Patients
receiving ketorolac tromethamine who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients
receiving anticoagulants, should be carefully monitored.
Patients with asthma may have aspirin-sensitive asthma. The use
of aspirin in patients with aspirin-sensitive asthma has been associated with
severe bronchospasm which can be fatal. Since cross-reactivity, including
bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, ketorolac tromethamine
should not be administered to patients with this form of aspirin sensitivity and
should be used with caution in patients with preexisting asthma.
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, ,
and sections), instruct patients to seek medical advice if they
develop treatment-related adverse events, and
Remember that the total combined duration of use of ketorolac tromethamine
tablet and ketorolac tromethamine IV or IM dosing is not to exceed 5 days in
adults. Ketorolac tromethamine tablets are not indicated for use in pediatric
patients.
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
Because serious GI tract ulcerations and bleeding can occur
without warning symptoms, physicians should monitor for signs or symptoms of GI
bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and
a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur
(e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
ketorolac tromethamine should be discontinued.
Ketorolac is highly bound to human plasma protein (mean 99.2%).
There is no evidence in animal or human studies that ketorolac tromethamine
induces or inhibits hepatic enzymes capable of metabolizing itself or other
drugs.
Warfarin, Digoxin, Salicylate and Heparin
The binding of 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 protein binding. studies indicate that, at therapeutic
concentrations of
(300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to
97.5%, representing a potential 2-fold increase in unbound ketorolac plasma
levels. Therapeutic concentrations of and 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 ,causing no significant changes in
pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac
tromethamine dosed IV or IM was given with two doses of 5000 U of 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 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
(see and ).
The effects of warfarin and NSAIDs, in general, on GI bleeding are
synergistic, such that the users of both drugs together have a risk of serious
GI bleeding higher than the users of either drug alone.
When ketorolac tromethamine is administered with aspirin, its
protein binding is reduced, although the clearance of free ketorolac
tromethamine is not altered. The clinical significance of this interaction is
not known; however, as with other NSAIDs, concomitant administration of
ketorolac tromethamine and aspirin is not generally recommended because of the
potential of increased adverse effects.
Clinical studies, as well as post-marketing observations, have
shown that ketorolac tromethamine can reduce the natriuretic effect of
furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis. During concomitant therapy with
NSAIDs, the patient should be observed closely for signs of renal failure (see
), as well as to assure diuretic efficacy.
Concomitant administration of ketorolac tromethamine tablets and
resulted in
decreased clearance and volume of distribution 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
tablets and probenecid is contraindicated.
NSAIDs have produced an elevation of plasma lithium levels and a
reduction in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the renal clearance was decreased by approximately 20%. These
effects have been attributed to inhibition of renal prostaglandin synthesis by
the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects
should be observed carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. This may indicate that they could enhance
the toxicity of methotrexate. Caution should be used when NSAIDs are
administered concomitantly with methotrexate.
Concomitant use of may
increase the risk of renal impairment, particularly in volume-depleted patients.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE
inhibitors and/or angiotension II receptor antagonists. This interaction should
be given consideration in patients taking NSAIDs concomitantly with ACE
inhibitors and/or angiotension II receptor antagonists.
Sporadic cases of seizures have been reported during concomitant
use of ketorolac tromethamine and (phenytoin,
carbamazepine).
Hallucinations have been reported when ketorolac tromethamine was
used in patients taking (fluoxetine, thiothixene, alprazolam).
When ketorolac tromethamine is administered concurrently with
pentoxifylline, there is an increased tendency to bleeding.
In post-marketing experience there have been reports of a
possible interaction between ketorolac tromethamine IV/IM and that resulted in apnea. The concurrent use of ketorolac
tromethamine with muscle relaxants has not been formally studied.
There is an increased risk of gastrointestinal bleeding when
selective serotonin re-uptake inhibitors (SSRIs) are combined with NSAIDs.
Caution should be used when NSAIDs are administered concomitantly with
SSRIs.
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.i.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 the Ames test, unscheduled DNA
synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did
not cause chromosome breakage in the 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.
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.
However, animal reproduction studies are not always predictive of human
response.
Because of the known effects of non-steroidal anti-inflammatory
drugs on the fetal cardiovascular system (closure of ductus arteriosus), use
during pregnancy (particularly late pregnancy) should be avoided. 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.
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 ).
The use of ketorolac tromethamine, as with any drug known to
inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not
recommended in women attempting to conceive. In women who have difficulty
conceiving or are undergoing investigation of infertility, withdrawal of
ketorolac tromethamine should be considered.
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
(q.i.d.), 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.
Ketorolac tromethamine tablets are not indicated for use in
pediatric patients. The safety and effectiveness of ketorolac tromethamine
tablets in pediatric patients below the age of 17 have not been
established.
Because ketorolac tromethamine may be cleared more slowly by the
elderly (see ) who are also more sensitive to the dose related adverse
effects of NSAIDs (see ),
extreme caution, reduced dosages (see ) and careful clinical monitoring must be used when treating
the elderly with ketorolac tromethamine.
- Ketorolac tromethamine, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see ).
- Ketorolac tromethamine, like other NSAIDs, can cause GI discomfort and rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena and hematemesis. Patients should be apprised of the importance of this follow-up (see ).
- Ketorolac tromethamine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see ).
- In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it will cause premature closure of the ductus arteriosus.
What are the side effects of KETOTOLAC TROMETHAMINE?
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, , ,
and ). These NSAID-related complications can be serious in
certain patients for whom ketorolac tromethamine is indicated, especially when
the drug is used inappropriately.
In patients taking ketorolac tromethamine or other NSAIDs in clinical trials,
the most frequently reported adverse experiences in approximately 1% to 10% of
patients are:
Additional adverse experiences reported occasionally (<1% in patients
taking ketorolac tromethamine or other NSAIDs in clinical trials) include:
Body as a Whole:
Cardiovascular:
Dermatologic:
Gastrointestinal:
Hemic and Lymphatic:
Metabolic and Nutritional:
Nervous System:
Reproductive, female:
Respiratory:
Special Senses:
Urogenital:
Other rarely observed reactions (reported from post-marketing experience in
patients taking ketorolac tromethamine or other NSAIDs) are:
Body as a Whole:
Cardiovascular:
Dermatologic:
Gastrointestinal:
Hemic and Lymphatic:
Metabolic and Nutritional:
Nervous System:
Respiratory:
Special Senses:
Urogenital:
Post-Marketing Surveillance Study:
| Abdominal Pain | Constipation/Diarrhea | Dyspepsia* | ||
| Flatulence | GI Fullness | GI Ulcers (gastric/duodenal) | ||
| Gross Bleeding/Perforation | Heartburn | Nausea* | ||
| Stomatitis | Vomiting | |||
| Abnormal Renal Function | Anemia | Dizziness | ||
| Drowsiness | Edema | Elevated Liver Enzymes | ||
| Headaches* | Hypertension | Increased Bleeding Time | ||
| Injection Site Pain | Pruritus | Purpura | ||
| Rashes | Tinnitus | Sweating | ||
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine IV/IM | |||
| < | > 60 to 90 mg | > 90 to 120 mg | > 120 mg | |
| < 65 years of age | 0.4% | 0.4% | 0.9% | 4.6% |
| > | 1.2% | 2.8% | 2.2% | 7.7% |
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine IV/IM | |||
| < | > 60 to 90 mg | > 90 to 120 mg | > 120 mg | |
| < 65 years of age | 2.1% | 4.6% | 7.8% | 15.4% |
| > | 4.7% | 3.7% | 2.8% | 25% |
What should I look out for while using KETOTOLAC TROMETHAMINE?
(see also Boxed WARNING)
Ketorolac tromethamine is contraindicated in patients with previously
demonstrated hypersensitivity to ketorolac tromethamine.
Ketorolac tromethamine is contraindicated in patients with active peptic
ulcer disease, in patients with recent gastrointestinal bleeding or perforation,
and in patients with a history of peptic ulcer disease or gastrointestinal
bleeding.
Ketorolac tromethamine should not be given to patients who have experienced
asthma, urticaria or allergic-type reactions after taking aspirin or other
NSAIDS. Severe, rarely fatal, anaphylactic-like reactions to NSAIDS have been
reported in such patients (see and ).
Ketorolac tromethamine is contraindicated as prophylactic analgesic before
any major surgery.
Ketorolac tromethamine is contraindicated for the treatment of perioperative
pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Ketorolac tromethamine is contraindicated in patients with advanced renal
impairment or in patients at risk for renal failure due to volume depletion (see
for
correction of volume depletion).
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.
The use of ketorolac tromethamine is contraindicated in nursing mothers
because of the potential adverse effects of prostaglandin-inhibiting drugs on
neonates.
Ketorolac tromethamine inhibits platelet function and is, therefore,
contraindicated in patients with suspected or confirmed cerebrovascular
bleeding, hemorrhagic diathesis, incomplete homeostasis and those at high risk
of bleeding (see and ).
Ketorolac tromethamine is contraindicated in patients currently receiving
aspirin or NSAIDs because of the cumulative risks of inducing serious
NSAID-related adverse events.
The concomitant use of ketorolac tromethamine and probenecid is
contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is
contraindicated.
(see also Boxed WARNING)
The total combined duration of use of ketorolac tromethamine-IV/IM and
ketorolac tromethamine tablets is not to exceed 5 days in adults. Ketorolac
tromethamine tablets are not indicated for use in pediatric patients.
The most serious risks associated with ketorolac tromethamine are:
Ketorolac tromethamine is contraindicated in patients with
previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine
can cause serious gastrointestinal (GI) adverse events including bleeding,
ulceration and perforation, of the stomach, small intestine or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or
without warning symptoms, in patients treated with ketorolac tromethamine.
Only one in five patients who develop a serious upper GI adverse event on
NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as
dyspepsia, are common and may also occur at any time during NSAID therapy. The
incidence and severity of gastrointestinal complications increases with
increasing dose of, and duration of treatment with, ketorolac tromethamine. Do
not use ketorolac tromethamine for more than 5 days. However, even short-term
therapy is not without risk. In addition to past history of ulcer disease, other
factors that increase the risk for GI bleeding in patients treated with NSAIDs
include concomitant use of oral corticosteroids, or anticoagulants, longer
duration of NSAID therapy, smoking, use of alcohol, older age and poor general
health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating
this population.
To minimize the potential risk for an adverse GI event, the
lowest effective dose should be used for the shortest possible duration.
NSAIDs should be given with care to patients with a history of inflammatory
bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be
exacerbated.
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 therapy that
affects hemostasis, including 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.
Patients receiving therapy that affects hemostasis should be monitored
closely.
In post-marketing experience, postoperative hematomas and other signs of
wound bleeding have been reported in association with the perioperative use of
IV or IM dosing of ketorolac tromethamine. Therefore, perioperative use of
ketorolac tromethamine should be avoided and postoperative use be undertaken
with caution when hemostasis is critical (see ).
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a NSAID may
cause a dose-dependent reduction in prostaglandin formation and, secondarily, in
renal blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function, heart
failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
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 ). Therefore, ketorolac tromethamine should be used with caution
in patients with impaired renal function (see ) and such patients should be followed closely. With the use
of ketorolac tromethamine, there have been reports of acute renal failure,
interstitial nephritis and nephrotic syndrome.
Ketorolac tromethamine contraindicated
in patients with serum creatinine concentrations indicating advanced renal
impairment (see ).
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. Because patients with underlying renal insufficiency
are at increased risk of developing acute renal decompensation or failure, the
risks and benefits should be assessed prior to giving ketorolac tromethamine to
these patients.
As with other NSAIDs, anaphylactoid reactions may occur in
patients without a known previous exposure or hypersensitivity to ketorolac
tromethamine. Ketorolac tromethamine should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe,
potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
and ). Anaphylactoid reactions, like anaphylaxis, may have a
fatal outcome. Emergency help should be sought in cases where an anaphylactoid
reaction occurs.
Clinical trials of several COX-2 selective and nonselective
NSAIDs of up to 3 years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which
can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may
be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for the
shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV events
and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use. The
concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see ). Two large,
controlled clinical trials of a COX-2 selective NSAID for the treatment of pain
in the first 10 to 14 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see ).
NSAIDs, including ketorolac tromethamine, can lead to onset of
new hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazides or
loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including ketorolac tromethamine, should be used with caution in
patients with hypertension. Blood pressure (BP) should be monitored closely
during the initiation of NSAID treatment and throughout the course of
therapy.
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.
NSAIDS, including ketorolac tromethamine, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS)
and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Patients should be informed about the signs and
symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash, mucosal lesions or any other
sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, ketorolac tromethamine
should be avoided because it may cause premature closure of the ductus
arteriosus.
What might happen if I take too much KETOTOLAC TROMETHAMINE?
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). Forced diuresis, alkalization of urine, hemodialysis or
hemoperfusion may not be useful due to high protein binding.
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.
How should I store and handle KETOTOLAC TROMETHAMINE?
Storage and HandlingStore at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).Storage and HandlingStore at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine, USP. The tablets are white film-coated, round, unscored tablets debossed with over on one side and blank on the other side. They are available as follows:Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2008KTLC:R6mcRelabeling and Repackaging by:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Ketorolac tromethamine is a non-steroidal anti-inflammatory drug
(NSAID) that exhibits analgesic activity in animal models. The mechanism of
action of ketorolac, like that of other NSAIDs, is not completely understood but
may be related to prostaglandin synthetase inhibition. 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 is not statistically significantly different over the recommended
dosage range of ketorolac tromethamine. The greatest difference between large
and small doses of ketorolac tromethamine is in the duration of analgesia.
Ketorolac tromethamine is a racemic mixture of [-]S- and
[+]R-enantiomeric forms, with the S-form having analgesic activity.
The pharmacokinetics of ketorolac tromethamine, following IV, IM
and oral doses of ketorolac tromethamine tablets, are compared in . 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.
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.
Ketorolac tromethamine is 100% absorbed after oral administration
(see ). Oral
administration of ketorolac tromethamine after a high-fat meal resulted in
decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine
by about one hour. Antacids did not affect the extent of absorption.
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, 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 (see ).
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.
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
2 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 (see ).
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.
Ketorolac tromethamine administered as an IV bolus every 6 hours
for 5 days to healthy subjects (n = 13), showed no significant difference in
C on Day 1 and Day 5. Trough levels averaged 0.29
mcg/mL (SD ± 0.13) on Day 1 and 0.55 mcg/mL (SD ± 0.23) on Day 6. Steady-state
was approached after the fourth dose.
Accumulation of ketorolac tromethamine has not been studied in special
populations (geriatric, pediatric, renal failure or hepatic disease
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 to 78
years) compared with young healthy volunteers (24 to 35 years) (see ). There was little
difference in the C for the two groups (elderly, 2.52
mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see ).
Limited information is available regarding the pharmacokinetics
of dosing of ketorolac tromethamine in the pediatric population. Following a
single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the
half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg,
the volume of distribution during the terminal phase (V)
was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (V) was 0.26 ± 0.08 L/kg. The volume of distribution and
clearance of ketorolac in pediatric patients was higher than those observed in
adult subjects (see ). There are no pharmacokinetic data available for administration of
ketorolac tromethamine by the IM route in pediatric 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 ).
There was no significant difference in estimates of half-life,
AUCand C in seven patients
with liver disease compared to healthy volunteers (see and ).
Pharmacokinetic differences due to race have not been
identified.
In normal subjects (n = 37), the total clearance of 30 mg IV
administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The
terminal half-life was 5.6 (4 to 7.9) hours. (see for use of IV dosing of ketorolac tromethamine in pediatric
patients).
Non-Clinical Toxicology
(see also Boxed WARNING)Ketorolac tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine.
Ketorolac tromethamine is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.
Ketorolac tromethamine should not be given to patients who have experienced asthma, urticaria or allergic-type reactions after taking aspirin or other NSAIDS. Severe, rarely fatal, anaphylactic-like reactions to NSAIDS have been reported in such patients (see and ).
Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.
Ketorolac tromethamine is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Ketorolac tromethamine is contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see for correction of volume depletion).
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.
The use of ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis and those at high risk of bleeding (see and ).
Ketorolac tromethamine is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
The concomitant use of ketorolac tromethamine and probenecid is contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.
(see also Boxed WARNING)
The total combined duration of use of ketorolac tromethamine-IV/IM and ketorolac tromethamine tablets is not to exceed 5 days in adults. Ketorolac tromethamine tablets are not indicated for use in pediatric patients.
The most serious risks associated with ketorolac tromethamine are:
Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration and perforation, of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. Do not use ketorolac tromethamine for more than 5 days. However, even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration.
NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
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 therapy that affects hemostasis, including 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. Patients receiving therapy that affects hemostasis should be monitored closely.
In post-marketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of IV or IM dosing of ketorolac tromethamine. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see ).
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
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 ). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see ) and such patients should be followed closely. With the use of ketorolac tromethamine, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome.
Ketorolac tromethamine contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see ). 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. Because patients with underlying renal insufficiency are at increased risk of developing acute renal decompensation or failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients.
As with other NSAIDs, anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to ketorolac tromethamine. Ketorolac tromethamine should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see and ). Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see ). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see ).
NSAIDs, including ketorolac tromethamine, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ketorolac tromethamine, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
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.
NSAIDS, including ketorolac tromethamine, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it may cause premature closure of the ductus arteriosus.
Ketorolac tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of ketorolac tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions.
Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ketorolac tromethamine. These laboratory abnormalities may progress, may remain unchanged or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ketorolac tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketorolac tromethamine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketorolac tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ketorolac tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
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, , and sections), instruct patients to seek medical advice if they develop treatment-related adverse events, and
Remember that the total combined duration of use of ketorolac tromethamine tablet and ketorolac tromethamine IV or IM dosing is not to exceed 5 days in adults. Ketorolac tromethamine tablets are not indicated for use in pediatric patients.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine should be discontinued.
Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.
Warfarin, Digoxin, Salicylate and Heparin
The binding of 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 protein binding. studies indicate that, at therapeutic concentrations of (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential 2-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of and 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 ,causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed IV or IM was given with two doses of 5000 U of 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 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 (see and ).
The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.
When ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects.
Clinical studies, as well as post-marketing observations, have shown that ketorolac tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see ), as well as to assure diuretic efficacy.
Concomitant administration of ketorolac tromethamine tablets and resulted in decreased clearance and volume of distribution 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 tablets and probenecid is contraindicated.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Concomitant use of may increase the risk of renal impairment, particularly in volume-depleted patients.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotension II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotension II receptor antagonists.
Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and (phenytoin, carbamazepine).
Hallucinations have been reported when ketorolac tromethamine was used in patients taking (fluoxetine, thiothixene, alprazolam).
When ketorolac tromethamine is administered concurrently with pentoxifylline, there is an increased tendency to bleeding.
In post-marketing experience there have been reports of a possible interaction between ketorolac tromethamine IV/IM and that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.
There is an increased risk of gastrointestinal bleeding when selective serotonin re-uptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs.
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.i.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 the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the 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.
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. However, animal reproduction studies are not always predictive of human response.
Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. 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.
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 ).
The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered.
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 (q.i.d.), 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.
Ketorolac tromethamine tablets are not indicated for use in pediatric patients. The safety and effectiveness of ketorolac tromethamine tablets in pediatric patients below the age of 17 have not been established.
Because ketorolac tromethamine may be cleared more slowly by the elderly (see ) who are also more sensitive to the dose related adverse effects of NSAIDs (see ), extreme caution, reduced dosages (see ) and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.
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, , , and ). These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately.
In patients taking ketorolac tromethamine or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:
Additional adverse experiences reported occasionally (<1% in patients taking ketorolac tromethamine or other NSAIDs in clinical trials) include:
Body as a Whole:
Cardiovascular:
Dermatologic:
Gastrointestinal:
Hemic and Lymphatic:
Metabolic and Nutritional:
Nervous System:
Reproductive, female:
Respiratory:
Special Senses:
Urogenital:
Other rarely observed reactions (reported from post-marketing experience in patients taking ketorolac tromethamine or other NSAIDs) are:
Body as a Whole:
Cardiovascular:
Dermatologic:
Gastrointestinal:
Hemic and Lymphatic:
Metabolic and Nutritional:
Nervous System:
Respiratory:
Special Senses:
Urogenital:
Post-Marketing Surveillance Study:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).