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TORADOL

 * Generic Name: ketorolac tromethamine
 * Brand Name: Toradol

Last updated on RxList: 10/16/2020

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 * Drug Description
 * Indications
 * Dosage
 * Side Effects
 * Drug Interactions
 * Warnings
 * Precautions
 * Overdose
 * Contraindications
 * Clinical Pharmacology
 * Medication Guide

Drug Description

WHAT IS TORADOL AND HOW IS IT USED?

Toradol (ketorolac tromethamine) is a nonsteroidal anti-inflammatory drug
(NSAID) that is used to treat moderately severe pain and inflammation, usually
after surgery. Toradol works by blocking the production of prostaglandins,
compounds that cause pain, fever, and inflammation. The brand name Toradol is no
longer available in the U.S. Generic versions may be available.

WHAT ARE SIDE EFFECTS OF TORADOL?

Common side effects of Toradol include:

 * headache,
 * heartburn,
 * upset stomach,
 * nausea,
 * vomiting,
 * diarrhea,
 * stomach pain,
 * bloating,
 * gas,
 * constipation,
 * dizziness,
 * drowsiness,
 * sweating,
 * and ringing in the ears.

TORADOL®
(ketorolac tromethamine) Tablets

WARNING

TORADOLORAL (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug
(NSAID), is indicated for the short-term (up to 5 days in adults), management of
moderately severe acute pain that requires analgesia at the opioid level and
only as continuation treatment following IV or IM dosing of ketorolac
tromethamine, if necessary. The total combined duration of use of TORADOLORAL
and ketorolac tromethamine should not exceed 5 days.

TORADOL (ketorolac tromethamine) ORAL is not indicated for use in pediatric
patients and it is NOT indicated for minor or chronic painful conditions.
Increasing the dose of TORADOL (ketorolac tromethamine) ORAL beyond a daily
maximum of 40 mg in adults will not provide better efficacy but will increase
the risk of developing serious adverse events.

GASTROINTESTINAL RISK

 * Ketorolac tromethamine, including TORADOL (ketorolac tromethamine) can cause
   peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or
   intestines, which can be fatal. These events can occur at any time during use
   and without warning symptoms. Therefore, TORADOL (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. Elderly
   patients are at greater risk for serious gastrointestinal events (see
   WARNINGS).

CARDIOVASCULAR RISK

 * NSAIDs may cause an increased risk of serious cardiovascular thrombotic
   events, myocardial infarction, and stroke, which can be fatal. This risk may
   increase with duration of use. Patients with cardiovascular disease or risk
   factors for cardiovascular disease may be at greater risk (see WARNINGS and
   CLINICAL TRIALS).
 * TORADOL (ketorolac tromethamine) is CONTRAINDICATED for the treatment of
   peri-operative pain in the setting of coronary artery bypass graft (CABG)
   surgery (see WARNINGS).

RENAL RISK

 * TORADOL (ketorolac tromethamine) is CONTRAINDICATED in patients with advanced
   renal impairment and in patients at risk for renal failure due to volume
   depletion (see WARNINGS).

RISK OF BLEEDING

 * TORADOL (ketorolac tromethamine) inhibits platelet function and is,
   therefore, CONTRAINDICATED in patients with suspected or confirmed
   cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete
   hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).

TORADOL (ketorolac tromethamine) is CONTRAINDICATED as prophylactic analgesic
before any major surgery.

RISK DURING LABOR AND DELIVERY

 * The use of TORADOL (ketorolac tromethamine) in labor and delivery is
   contraindicated because it may adversely affect fetal circulation and inhibit
   uterine contractions. The use of TORADOL (ketorolac tromethamine) is
   contraindicated in nursing mothers because of the potential adverse effects
   of prostaglandin-inhibiting drugs on neonates.

CONCOMITANT USE WITH NSAIDS

 * TORADOL (ketorolac tromethamine) is CONTRAINDICATED in patients currently
   receiving aspirin or NSAIDs because of the cumulative risk of inducing
   serious NSAID-related side effects.

SPECIAL POPULATIONS

Dosage should be adjusted for patients 65 years or older, for patients under 50
kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for patients
with moderately elevated serum creatinine (see WARNINGS).


DESCRIPTION

TORADOL (ketorolac tromethamine) is a member of the pyrrolo-pyrrole group of
nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac
tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid,
compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical
structure is:







Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac
tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms
are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an
n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac
tromethamine is 376.41. Its molecular formula is C19H24N2O6.

TORADOL (ketorolac tromethamine) ORAL is available as round, white, film-coated,
red-printed tablets. Each tablet contains 10 mg ketorolac tromethamine, the
active ingredient, with added lactose, magnesium stearate and microcrystalline
cellulose. The white film-coating contains hydroxypropyl methylcellulose,
polyethylene glycol and titanium dioxide.

The tablets are printed with red ink that includes FD&C Red #40 Aluminum Lake as
the colorant. There is a large T printed on both sides of the tablet, as well as
the word TORADOL (ketorolac tromethamine) on one side, and the word ROCHE on the
other.


Indications


INDICATIONS

Carefully consider the potential benefits and risks of TORADOL (ketorolac
tromethamine) and other treatment options before deciding to use TORADOL
(ketorolac tromethamine) . Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals.

ACUTE PAIN IN ADULT PATIENTS

TORADOL (ketorolac tromethamine) ORAL is indicated for the short-term ( ≤ 5
days) management of moderately severe acute pain that requires analgesia at the
opioid level, usually in a postoperative setting. Therapy should always be
initiated with IV or IM dosing of ketorolac tromethamine, and TORADOL (ketorolac
tromethamine) ORAL is to be used only as continuation treatment, if necessary.

The total combined duration of use of TORADOL (ketorolac tromethamine) ORAL and
ketorolac tromethamine is not to exceed 5 days of use because of the potential
of increasing the frequency and severity of adverse reactions associated with
the recommended doses (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION, and
ADVERSE REACTIONS). Patients should be switched to alternative analgesics as
soon as possible, but TORADOL (ketorolac tromethamine) ORAL therapy is not to
exceed 5 days.

SLIDESHOW

Back Pain: 16 Back Pain Truths and Myths See Slideshow
Dosage


DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of TORADOL (ketorolac
tromethamine) and other treatment options before deciding to use TORADOL
(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
TORADOL (ketorolac tromethamine) ORAL is not to exceed 5 days. In adults, the
use of TORADOL (ketorolac tromethamine) ORAL is only indicated as continuation
therapy to IV or IM dosing of ketorolac tromethamine.

Transition from IV or IM dosing of ketorolac tromethamine (single- or
multiple-dose) to multiple-dose TORADOL (ketorolac tromethamine) ORAL:

Patients age 17 to 64: 20 mg PO once followed by 10 mg q4-6 hours prn not > 40
mg/day

Patients age ≥ 65, renally impaired, and/or weight < 50 kg (110 lbs): 10 mg PO
once followed by 10 mg q4-6 hours prn not > 40 mg/day

Note:

Oral formulation should not be given as an initial dose

Use minimum effective dose for the individual patient

Do not shorten dosing interval of 4 to 6 hours

Total duration of treatment in adult patients: the combined duration of use of
IV or IM dosing of ketorolac tromethamine and TORADOL (ketorolac tromethamine)
ORAL is not to exceed 5 days.

The following table summarizes TORADOL (ketorolac tromethamine) ORAL dosing
instructions in terms of age group:

Table 4 :Summary of Dosing Instructions



Patient Population TORADOLORA L(following IV or IM dosing of ketorolac
tromethamine) Age < 17 years Oral not approved Adult Age 17 to 64 years 20 mg
once, then 10 mg q4-6 hours prn not > 40 mg/day Adult Age ≥ 65 years, renally
impaired, and/or weight < 50 kg 10 mg once, then 10 mg q4-6 hours prn not > 40
mg/day




HOW SUPPLIED

TORADOL (ketorolac tromethamine) ORAL10 mg tablets are round, white, film-coate
d, red printed tablets. There is a large T printed on both sides of the tablet,
with TORADOL (ketorolac tromethamine) on one side, and ROCHE on the other,
available in bottles of 100 tablets (NDC 0004-0273-01).

STORAGE

Store bottles at 15°to 30°C (59°to 86°F).

Distributed by: Roche Laboratories Inc.340 Kingsland Street, Nutley, New Jersey
07110 - 1199. FDA revision date: 11/13/2007


Side Effects


SIDE EFFECTS

Adverse reaction rates increase with higher doses of TORADOL (ketorolac
tromethamine) . Practitioners should be alert for the severe complications of
treatment with TORADOL (ketorolac tromethamine) , such as GI ulceration,
bleeding and perforation, postoperative bleeding, acute renal failure,
anaphylactic and anaphylactoid reactions and liver failure (see BOXED WARNING,
WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). These NSAID-related
complications can be serious in certain patients for whom TORADOL (ketorolac
tromethamine) is indicated, especially when the drug is used inappropriately.

In patients taking TORADOL (ketorolac tromethamine) or other NSAIDs in clinical
trials, the most frequently reported adverse experiences in approximately 1% to
10% of patients are:



Gastrointestinal (GI) experiences including: abdominal pain*
constipation/diarrhea dyspepsia* flatulence GI fullness GI ulcers
(gastric/duodenal) gross bleeding/perforation Heartburn nausea* stomatitis
Vomiting   Other experiences: abnormal renal function Anemia dizziness
drowsiness Edema elevated liver enzymes headaches* Hypertension increased
bleeding time injection site pain Pruritus purpura rashes Tinnitus sweating
*Incidence greater than 10%



Additional adverse experiences reported occasionally ( < 1% in patients taking
TORADOL (ketorolac tromethamine) or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infections, sepsis

Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia,
syncope

Dermatologic: alopecia, photosensitivity, urticaria

Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive
thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite,
jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia,
thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia,
confusion, depression, euphoria, extrapyramidal symptoms, hallucinations,
hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia,
somnolence, stupor, tremors, vertigo, malaise

Reproductive, female: infertility

Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency,
interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary
retention

Other rarely observed reactions (reported from postmarketing experience in
patients taking TORADOL (ketorolac tromethamine) or other NSAIDs) are:

Body as a Whole: angioedema, death, hypersensitivity reactions such as
anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see
WARNINGS), myalgia

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension,
myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome,
bullous reactions including Stevens-Johnson syndrome and toxic epidermal
necrolysis

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis,
exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia,
lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring
blood transfusion - see BOXED WARNING, WARNINGS, and PRECAUTIONS)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic
uremic syndrome

POSTMARKETING SURVEILLANCE STUDY

A large postmarketing observational, nonrandomized study, involving
approximately 10,000 patients receiving ketorolac tromethamineIV/IM,
demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding
was dose-dependent (see Tables 3A and 3B). This was particularly true in elderly
patients who received an average daily dose greater than 60 mg/day of ketorolac
tromethamineIV/IM (see Table 3A).

Table 3 Incidence of Clinically Serious GI Bleeding as Related to Age, Total
Daily Dose, and History of GI Perforation, Ulcer, Bleeding (PUB) After up to 5
Days of Treatment With Ketorolac TromethamineIV/IMA.



A. Adult Patients Without History of PUB Age of Patients Total Daily Dose of
Ketorolac TromethamineIV/IM   ≤ 60 mg > 60 to 90 mg > 90 to 120 mg > 120 mg < 65
years of age 0.4% 0.4% 0.9% 4.6% ≥ 65 years of age 1.2% 2.8% 2.2% 7.7% B. Adult
Patients With History of PUB Age of Patients Total Daily Dose of Ketorolac
TromethamineIV/IM   ≤ 60 mg > 60 to 90 mg > 90 to 120 mg > 120 mg < 65 years of
age 2.1% 4.6% 7.8% 15.4% ≥ 65 years of age 4.7% 3.7% 2.8% 25.0%



QUESTION

Medically speaking, the term "myalgia" refers to what type of pain? See Answer
Drug Interactions


DRUG INTERACTIONS

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no
evidence in animal or human studies that TORADOL (ketorolac tromethamine)
induces or inhibits hepatic enzymes capable of metabolizing itself or other
drugs.

WARFARIN, DIGOXIN, SALICYLATE, AND HEPARIN

The in vitro binding of warfarin to plasma proteins is only slightly reduced by
ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma
concentrations reach 5 to 10 μg/mL. Ketorolac does not alter digoxin protein
binding. In vitro studies indicate that, at therapeutic concentrations of
salicylate (300 μg/mL), the binding of ketorolac was reduced from approximately
99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac
plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen,
naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter
ketorolac tromethamine protein binding.

In a study involving 12 adult volunteers, TORADOL (ketorolac tromethamine) ORAL
was coadministered with a single dose of 25 mg warfarin, 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
heparin to 11 healthy volunteers, resulting in a mean template bleeding time of
6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min)
for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these
results do not indicate a significant interaction between TORADOL (ketorolac
tromethamine) and warfarin or heparin, the administration of TORADOL (ketorolac
tromethamine) to patients taking anticoagulants should be done extremely
cautiously, and patients should be closely monitored (see WARNINGS and
PRECAUTIONS: Hematologic Effect).

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.

ASPIRIN

When TORADOL (ketorolac tromethamine) is administered with aspirin, its protein
binding is reduced, although the clearance of free TORADOL (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.

DIURETICS

Clinical studies, as well as postmarketing observations, have shown that TORADOL
(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 WARNINGS:
Renal Effects), as well as to assure diuretic efficacy.

PROBENECID

Concomitant administration of TORADOL (ketorolac tromethamine) ORAL and
probenecid resulted in decreased clearance and volume of distribution of
ketorolac and significant increases in ketorolac plasma levels (total AUC
increased approximately threefold from 5.4 to 17.8 μg/h/mL) and terminal
half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore,
concomitant use of TORADOL (ketorolac tromethamine) and probenecid is
contraindicated.

LITHIUM

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.

METHOTREXATE

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.

ACE INHIBITORS/ANGIOTENSION II RECEPTOR ANTAGONISTS

Concomitant use of ACE inhibitors and/or angiotension II receptor antagonists
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.

ANTIEPILEPTIC DRUGS

Sporadic cases of seizures have been reported during concomitant use of TORADOL
(ketorolac tromethamine) and antiepileptic drugs (phenytoin, carbamazepine).

PSYCHOACTIVE DRUGS

Hallucinations have been reported when TORADOL (ketorolac tromethamine) was used
in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

PENTOXIFYLLINE

When ketorolac tromethamine is administered concurrently with pentoxifylline,
there is an increased tendency to bleeding.

NONDEPOLARIZING MUSCLE RELAXANTS

In postmarketing experience there have been reports of a possible interaction
between ketorolac tromethamineIV/IM and nondepolarizing muscle relaxants that
resulted in apnea. The concurrent use of ketorolac tromethamine with muscle
relaxants has not been formally studied.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)

There is an increased risk of gastrointestinal bleeding when selective serotonin
reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used
when NSAIDs are administered concomitantly with SSRIs.


Warnings


WARNINGS

(see also BOXED WARNING)

The total combined duration of use of TORADOLORAL and IV or IM dosing of
ketorolac tromethamine is not to exceed 5 days in adults. TORADOL (ketorolac
tromethamine) ORAL is not indicated for use in pediatric patients.

The most serious risks associated with TORADOL (ketorolac tromethamine) are:

GASTROINTESTINAL EFFECTS - RISK OF ULCERATION, BLEEDING, AND PERFORATION

TORADOL (ketorolac tromethamine) is contraindicated in patients with previously
documented peptic ulcers and/or GI bleeding. Toradol (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 TORADOL (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, TORADOL (ketorolac
tromethamine) . Do not use TORADOL (ketorolac tromethamine) for more than five
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. Patients and physicians
should remain alert for signs and symptoms of GI ulceration and bleeding during
NSAID therapy and promptly initiate additional evaluation and treatment if a
serious GI adverse event is suspected. This should include discontinuation of
TORADOL (ketorolac tromethamine) until a serious GI adverse event is ruled out.
For high risk patients, alternate therapies that do not involve NSAIDs should be
considered.

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.

HEMORRHAGE

Because prostaglandins play an important role in hemostasis and NSAIDs affect
platelet aggregation as well, use of TORADOL (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 (eg, heparin or dicumarol derivatives) have an increased risk
of bleeding complications if given TORADOL (ketorolac tromethamine)
concurrently; therefore, physicians should administer such concomitant therapy
only extremely cautiously. The concurrent use of TORADOL (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 postmarketing experience, postoperative hematomas and other signs of wound
bleeding have been reported in association with the peri-operative use of IV or
IM dosing of ketorolac tromethamine. Therefore, peri-operative use of TORADOL
(ketorolac tromethamine) should be avoided and postoperative use be undertaken
with caution when hemostasis is critical (see PRECAUTIONS).

RENAL EFFECTS

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.

TORADOL (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,
TORADOL (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 TORADOL (ketorolac tromethamine) , there
have been reports of acute renal failure, interstitial nephritis and nephrotic
syndrome.

IMPAIRED RENAL FUNCTION

TORADOL (ketorolac tromethamine) is contraindicated in patients with serum
creatinine concentrations indicating advanced renal impairment (see
CONTRAINDICATIONS). TORADOL (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 TORADOL (ketorolac tromethamine) to these patients.

ANAPHYLACTOID REACTIONS

As with other NSAIDs, anaphylactoid reactions may occur in patients without a
known previous exposure or hypersensitivity to TORADOL (ketorolac tromethamine)
. TORADOL (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
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Anaphylactoid reactions,
like anaphylaxis, may have a fatal outcome. Emergency help should be sought in
cases where an anaphylactoid reaction occurs.

CARDIOVASCULAR EFFECTS

CARDIOVASCULAR THROMBOTIC EVENTS

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
three 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 Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation). Two large, controlled clinical trials of a COX-2 selective NSAID
for the treatment of pain in the first 10-14 days following CABG surgery found
an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).

HYPERTENSION

NSAIDs, including TORADOL (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 TORADOL (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.

CONGESTIVE HEART FAILURE AND EDEMA

Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea
nitrogen and creatinine have been reported in clinical trials with TORADOL
(ketorolac tromethamine) . Therefore, TORADOL (ketorolac tromethamine) should be
used only very cautiously in patients with cardiac decompensation, hypertension
or similar conditions.

SKIN REACTIONS

NSAIDS, including TORADOL (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.

PREGNANCY

In late pregnancy, as with other NSAIDs, TORADOL (ketorolac tromethamine) should
be avoided because it may cause premature closure of the ductus arteriosus.

Precautions


PRECAUTIONS

GENERAL

TORADOL (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 TORADOL (ketorolac tromethamine) in reducing
inflammation may diminish the utility of this diagnostic sign in detecting
complications of presumed noninfectious, painful conditions.

HEPATIC EFFECT

TORADOL (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 TORADOL (ketorolac tromethamine) . These laboratory abnormalities may
progress, may remain unchanged, or may be transient with continuing therapy.
Notable elevations of ALT or AST (approximately three 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 TORADOL
(ketorolac tromethamine) . If clinical signs and symptoms consistent with liver
disease develop, or if systemic manifestations occur (eg, eosinophilia, rash,
etc.), TORADOL (ketorolac tromethamine) should be discontinued.

HEMATOLOGIC EFFECT

Anemia is sometimes seen in patients receiving NSAIDs, including TORADOL
(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 TORADOL (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 TORADOL (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.

PREEXISTING ASTHMA

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 nonsteroidal anti-inflammatory drugs has been reported
in such aspirin-sensitive patients, TORADOL (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.

INFORMATION FOR PATIENTS

TORADOL (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 TORADOL (ketorolac tromethamine) , should inform
their patients or their guardians of the potential risks of TORADOL treatment
(see BOXED WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections),
instruct patients to seek medical advice if they develop treatment-related
adverse events, and advise patients not to give TORADOL (ketorolac tromethamine)
ORAL to other family members and to discard any unused drug.

Remember that the total combined duration of use of TORADOLORAL and IV or IM
dosing of ketorolac tromethamine is not to exceed 5 days in adults. TORADOL
(ketorolac tromethamine) ORAL is 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.

 1. TORADOL (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 WARNINGS: Cardiovascular Effects).
 2. TORADOL (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 WARNINGS:
    Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
 3. TORADOL (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.
 4. Patients should promptly report signs or symptoms of unexplained weight gain
    or edema to their physicians.
 5. Patients should be informed of the warning signs and symptoms of
    hepatotoxicity (eg, 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.
 6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
    difficulty breathing, swelling of the face or throat). If these occur,
    patients should be instructed to seek immediate emergency help (see
    WARNINGS).
 7. In late pregnancy, as with other NSAIDs, TORADOL (ketorolac tromethamine)
    should be avoided because it will cause premature closure of the ductus
    arteriosus.

LABORATORY TESTS

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
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
TORADOL (ketorolac tromethamine) should be discontinued.

CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY

An 18-month study in mice with oral doses of ketorolac tromethamine at 2
mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV
dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]),
and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no
evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames
test, unscheduled DNA synthesis and repair, and in forward mutation assays.

Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse
micronucleus assay. At 1590 μg/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.

PREGNANCY

TERATOGENIC EFFECTS: PREGNANCY CATEGORY C

Reproduction studies have been performed during organogenesis using daily oral
doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in
rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these
studies did not reveal evidence of teratogenicity to the fetus. However, animal
reproduction studies are not always predictive of human response.

NONTERATOGENIC EFFECTS

Because of the known effects of nonsteroidal 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 TORADOL (ketorolac
tromethamine) in pregnant women. TORADOL (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 TORADOL (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).

EFFECTS ON FERTILITY

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.

NURSING MOTHERS

After a single administration of 10 mg of TORADOL (ketorolac tromethamine) ORAL
to humans, the maximum milk concentration observed was 7.3 ng/mL, and the
maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum
milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was
0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs
on neonates, use in nursing mothers is contraindicated.

PEDIATRIC USE

TORADOL (ketorolac tromethamine) ORAL is not indicated for use in pediatric
patients. The safety and effectiveness of TORADOL (ketorolac tromethamine) ORAL
in pediatric patients below the age of 17 have not been established.

GERIATRIC USE ( ≥ 65 YEARS OF AGE)

Because ketorolac tromethamine may be cleared more slowly by the elderly (see
CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related adverse
effects of NSAIDs (see WARNINGS: Gastrointestinal Effects - Risk of Ulceration,
Bleeding, and Perforation), extreme caution, reduced dosages (see DOSAGE AND
ADMINISTRATION), and careful clinical monitoring must be used when treating the
elderly with TORADOL (ketorolac tromethamine) .

Overdose


OVERDOSE

SYMPTOMS AND SIGNS

Symptoms following acute NSAID 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.

TREATMENT

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 TORADOL 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.

SLIDESHOW

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Contraindications


CONTRAINDICATIONS

TORADOL is contraindicated in patients with previously demonstrated
hypersensitivity to ketorolac tromethamine.

TORADOL 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.

TORADOL 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 WARNINGS: Anaphylactoid Reactions, and PRECAUTIONS: Preexisting Asthma).

TORADOL is contraindicated as prophylactic analgesic before any major surgery.

TORADOL is contraindicated for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

TORADOL is contraindicated in patients with advanced renal impairment or in
patients at risk for renal failure due to volume depletion (see WARNINGS for
correction of volume depletion).

TORADOL 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.

TORADOL inhibits platelet function and is, therefore, contraindicated in
patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic
diathesis, incomplete hemostasis and those at high risk of bleeding (see
WARNINGS and PRECAUTIONS).

TORADOL 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 TORADOL and probenecid is contraindicated.

The concomitant use of ketorolac tromethamine and pentoxifylline is
contraindicated.

Clinical Pharmacology


CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

Ketorolac tromethamine is a nonsteroidal 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 TORADOL (ketorolac tromethamine) occurs within 2 to
3 hours and is not statistically significantly different over the recommended
dosage range of TORADOL (ketorolac tromethamine) . The greatest difference
between large and small doses of TORADOL (ketorolac tromethamine) is in the
duration of analgesia.

PHARMACOKINETICS

Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric
forms, with the S-form having analgesic activity.

COMPARISON OF IV, IM AND ORAL PHARMACOKINETICS

The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of
ketorolac tromethamine and oral doses of TORADOL (ketorolac tromethamine) , are
compared in Table 1. In adults, the extent of bioavailability following
administration of the ORAL form of TORADOL and the IM form of ketorolac
tromethamine was equal to that following an IV bolus.

LINEAR KINETICS

In adults, following administration of single ORAL doses of TORADOL or 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 or IV doses of
ketorolac tromethamine or recommended oral doses of TORADOL (ketorolac
tromethamine) , are linear. At the higher recommended doses, there is a
proportional increase in the concentrations of free and bound racemate.

ABSORPTION

TORADOL (ketorolac tromethamine) is 100% absorbed after oral administration (see
Table 1). Oral administration of TORADOL (ketorolac tromethamine) after a
high-fat meal resulted in decreased peak and delayed time-to-peak concentrations
of ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of
absorption.

DISTRIBUTION

The mean apparent volume (Vβ) 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
μg/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 PRECAUTIONS: Nursing
Mothers).

METABOLISM

Ketorolac tromethamine is largely metabolized in the liver. The metabolic
products are hydroxylated and conjugated forms of the parent drug. The products
of metabolism, and some unchanged drug, are excreted in the urine.

EXCRETION

The principal route of elimination of ketorolac and its metabolites is renal.
About 92% of a given dose is found in the urine, approximately 40% as
metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is
excreted in the feces. A single-dose study with 10 mg TORADOL (ketorolac
tromethamine) (n=9) demonstrated that the S-enantiomer is cleared approximately
two times faster than the R-enantiomer and that the clearance was independent of
the route of administration. This means that the ratio of S/R plasma
concentrations decreases with time after each dose. There is little or no
inversion of the R- to S- form in humans. The clearance of the racemate in
normal subjects, elderly individuals and in hepatically and renally impaired
patients is outlined in Table 2 (see CLINICAL PHARMACOLOGY: Kinetics in Special
Populations).

The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5
hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other
studies, the half-life for the racemate has been reported to lie within the
range of 5 to 6 hours.

ACCUMULATION

Ketorolac tromethamine administered as an IV bolus every 6 hours for 5 days to
healthy subjects (n=13), showed no significant difference in Cmax on Day 1 and
Day 5. Trough levels averaged 0.29 μg/mL (SD ± 0.13) on Day 1 and 0.55 μg/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).

KINETICS IN SPECIAL POPULATIONS

GERIATRIC 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 Table 2). There was little
difference in the Cmax for the two groups (elderly, 2.52 μg/mL ± 0.77; young,
2.99 μg/mL ± 1.03) (see PRECAUTIONS: Geriatric Use).

PEDIATRIC PATIENTS

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 (Vβ) was 0.34 ± 0.12 L/kg
and the volume of distribution at steady state (Vss) 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 Table 1). There are no
pharmacokinetic data available for administration of ketorolac tromethamine by
the IM route in pediatric patients.

RENAL INSUFFICIENCY

Based on single-dose data only, the mean half-life of ketorolac tromethamine in
renally impaired patients is between 6 and 19 hours and is dependent on the
extent of the impairment. There is poor correlation between creatinine clearance
and total ketorolac tromethamine clearance in the elderly and populations with
renal impairment (r=0.5).

In patients with renal disease, the AUC∞ of each enantiomer increased by
approximately 100% compared with healthy volunteers. The volume of distribution
doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The
increase in volume of distribution of ketorolac tromethamine implies an increase
in unbound fraction.

The AUC∞ -ratio of the ketorolac tromethamine enantiomers in healthy subjects
and patients remained similar, indicating there was no selective excretion of
either enantiomer in patients compared to healthy subjects (see WARNINGS: Renal
Effects).

HEPATIC INSUFFICIENCY

There was no significant difference in estimates of half-life, AUC∞ and Cmax in
7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS:
Hepatic Effect and Table 2).

RACE

Pharmacokinetic differences due to race have not been identified.

Table 1 - Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD)
Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine



Pharmacokinetic Parameters (units) Oral* Intramuscular† Intravenous Bolus‡ 10 mg
15 mg 30 mg 60 mg 15 mg 30 mg Bioavailability (extent) 100% Tmax1 (min) 44 ± 34
33 ± 21§ 44 ± 29 33 ± 21§ 1.1 ± 0.7§ 2.9 ± 1.8 Cmax2 (μg/mL) [single-dose] 0.87
± 0.22 1.14 ± 0.32§ 2.42 ± 0.68 4.55 ± 1.27§ 2.47 ± 0.51§ 4.65 ± 0.96 Cmax
(μg/mL) [steady state qid] 1.05 ± 0.26§ 1.56 ± 0.44§ 3.11 ± 0.87§ N/A|| 3.09 ±
1.17§ 6.85 ± 2.61 Cmin3 (μg/mL) [steady state qid] 0.29 ± 0.07§ 0.47 ± 0.13§
0.93 ± 0.26§ N/A 0.61 ± 0.21§ 1.04 ± 0.35 Cavg4 (μg/mL) [steady state qid] 0.59
± 0.20§ 0.94 ± 0.29§ 1.88 ± 0.59§ N/A 1.09 ± 0.30§ 2.17 ± 0.59 Vβ 5 (L/kg) 0.175
± 0.039 0.210± 0.044 % Dose metabolized = < 50
% Dose excreted in feces = 6
% Dose excreted in urine = 91
% Plasma protein binding = 99
*Derived from PO pharmacokinetic studies in 77 normal fasted volunteers
†Derived from IM pharmacokinetic studies in 54 normal volunteers
‡Derived from IV pharmacokinetic studies in 24 normal volunteers
§Mean value was simulated from observed plasma concentration data and standard
deviation was simulated from percent coefficient of variation for observed Cmax
and Tmax data
|| Not applicable because 60 mg is only recommended as a single dose
1Time-to-peak plasma concentration
2Peak plasma concentration
3Trough plasma concentration
4Average plasma concentration 5Volume of distribution

Table 2 - The Influence of Age, Liver, and Kidney Function on the Clearance and
Terminal Half-life of Ketorolac Tromethamine (IM1 and ORAL2) in Adult
Populations



Type of Subjects Total Clearance [in L/h/kg]3 Terminal Half-life [in hours] IM
ORAL IM ORAL Mean
(range) Mean
(range) Mean
(range) Mean
(range) Normal Subjects
IM (n=54)
mean age=32, range=18-60
Oral (n=77)
mean age=32, range=20-60 0.023
(0.010-0.046) 0.025
(0.013-0.050) 5.3
(3.5-9.2) 5.3m
(2.4-9.0) Healthy Elderly Subjects
IM (n=13),
Oral (n=12)
mean age=72, range=65-78 0.019
(0.013-0.034) 0.024
(0.018-0.034) 7.0
(4.7-8.6) 6.1
(4.3-7.6) Patients with Hepatic Dysfunction
IM and Oral (n=7)
mean age=51, range=43-64 0.029
(0.013-0.066) 0.033
(0.019-0.051) 5.4
(2.2-6.9) 4.5
(1.6-7.6) Patients with Renal Impairment
IM (n=25), Oral (n=9) serum creatinine=1.9-5.0 mg/dL,
mean age (IM)=54, range=35-71
mean age (Oral)=57, range=39-70 0.015
(0.005-0.043) 0.016
(0.007-0.052) 10.3 (5.9-19.2) 10.8 (3.4-18.9) Renal Dialysis Patients
IM and Oral (n=9) mean age=40, range=27-63 0.016
(0.003-0.036) — 13.6
(8.0-39.1) — 1Estimated from 30 mg single IM doses of ketorolac tromethamine
2Estimated from 10 mg single oral doses of ketorolac tromethamine
3Liters/hour/kilogram

IV ADMINISTRATION

In normal adult subjects (n=37), the total clearance of 30 mg IV-administered
ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life
was 5.6 (4.0-7.9) hours. (See Kinetics in Special Populations for use of IV
dosing of ketorolac tromethamine in pediatric patients.)

CLINICAL STUDIES

ADULT PATIENTS

In a postoperative study, where all patients received morphine by a PCA device,
patients treated with ketorolac tromethamineIV as fixed intermittent boluses
(e.g., 30 mg initial dose followed by 15 mg q3h), required significantly less
morphine (26%) than the placebo group. Analgesia was significantly superior, at
various postdosing pain assessment times, in the patients receiving ketorolac
tromethamineIV plus PCA morphine as compared to patients receiving
PCA-administered morphine alone.

PEDIATRIC PATIENTS

There are no data available to support the use of TORADOL (ketorolac
tromethamine) ORAL in pediatric patients.

QUESTION

Medically speaking, the term "myalgia" refers to what type of pain? See Answer
Medication Guide


PATIENT INFORMATION

MEDICATION GUIDE FOR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
(See the end of this Medication Guide for a list of prescription NSAID
medicines.)

What is the most important information I should know about medicines called
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can
lead to death. This chance increases:

 * with longer use of NSAID medicines
 * in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery
called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at
any time during treatment. Ulcers and bleeding:

 * can happen without warning symptoms
 * may cause death

The chance of a person getting an ulcer or bleeding increases with:

 * taking medicines called “corticosteroids” and “anticoagulants”
 * longer use
 * smoking
 * drinking alcohol
 * older age
 * having poor health

NSAID medicines should only be used:

 * exactly as prescribed
 * at the lowest dose possible for your treatment
 * for the shortest time needed

What are Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:

 * different types of arthritis
 * menstrual cramps and other types of short-term pain

Who should not take a Nonsteroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

 * if you had an asthma attack, hives, or other allergic reaction with aspirin
   or any other NSAID medicine
 * for pain right before or after heart bypass surgery

Tell your healthcare provider:

 * about all of your medical conditions.
 * about all of the medicines you take. NSAIDs and some other medicines can
   interact with each other and cause serious side effects. Keep a list of your
   medicines to show to your healthcare provider and pharmacist.
 * if you are pregnant. NSAID medicines should not be used by pregnant women
   late in their pregnancy.
 * if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs)?



Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid
retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and
intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma

Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness



Get emergency help right away if you have any of the following symptoms:

 * shortness of breath or trouble breathing
 * chest pain
 * weakness in one part or side of your body
 * slurred speech
 * swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you
have any of the following symptoms:

 * nausea
 * more tired or weaker than usual
 * itching
 * your skin or eyes look yellow
 * stomach pain
 * flu-like symptoms
 * vomit blood
 * there is blood in your bowel movement or it is black and sticky like tar
 * unusual weight gain
 * skin rash or blisters with fever
 * swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare
provider or pharmacist for more information about NSAID medicines.

Other information about Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):

 * Aspirin is an NSAID medicine but it does not increase the chance of a heart
   attack. Aspirin can cause bleeding in the brain, stomach, and intestines.
   Aspirin can also cause ulcers in the stomach and intestines.
 * Some of these NSAID medicines are sold in lower doses without a prescription
   (over-the-counter). Talk to your healthcare provider before using
   over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription:



Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren,
Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine
XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin,
Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with
oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic
Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam
Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600



*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID
label warns that long term continuous use may increase the risk of heart attack
or stroke.

This Medication Guide has been approved by the U.S. Food and Drug
Administration. Date created: June 15, 2005.Celebrex is a registered trademark
of G.D. Searle LLC. Cataflam, Voltaren are registered trademarks of Novartis
Corporation. Arthrotec (combined with misoprostol) is a registered trademark of
G.D. Searle LLC. Dolobid is a registered trademark of Merck & Co. Inc. Lodine,
Lodine XL are registered trademarks of Wyeth. Nalfon, Nalfon 200 are registered
trademarks of Pedinol Pharmacal Inc. Ansaid is a registered trademark of
Pharmacia & Upjohn Company LLC. Motrin is a registered trademark of Johnson &
Johnson. Tab-Profen is a registered trademark of L. Perrigo Company. Vicoprofen
(combined with hydrocodone) is a registered trademark of BASF K & F Corporation.
Combunox (combined with oxycodone) is a registered trademark of Forest
Laboratories, Inc.Indocin, Indocin SR are registered trademarks of Merck & Co.
Inc. Oruvail is a registered trademark of Imperial Bank, As Agent (formerly
registered to Aventis Pharma S.A.). Toradol (ketorolac tromethamine) is a
registered trademark of Hoffmann-La Roche Inc. Ponstel is a registered trademark
of Lasalle National Bank Association.
Mobic is a registered trademark of Boehringer Ingelheim Pharma GMBG & Co. Kg.
Relafen is a registered trademark of SmithKline Beecham Corporation. Naprosyn,
EC-Naprosyn, Anaprox, Anaprox DS are registered trademarks of Syntex
Pharmaceuticals International Ltd. Naprelan is a registered trademark of Elan
Corporation PLC. Naprapac (copackaged with lansoprazole) is a registered
trademark of Syntex Pharmaceuticals International Ltd. Daypro is a registered
trademark of G.D. Searle LLC. Feldene is a registered trademark of Pfizer.
Clinoril is a registered trademark of Merck & Co. Inc. Tolectin, Tolectin DS,
Tolectin 600 are registered trademarks of Johnson & Johnson Corporation.



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