Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3306
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Toradol (Tablet, Film Coated)
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Carefully consider the
potential benefits and risks of TORADOL and other treatment options
before deciding to use TORADOL. 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 TORADOLis not to exceed 5 days. In adults, the
use of TORADOLis 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: 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 TORADOLis not to exceed 5 days. The following table
summarizes TORADOLdosing instructions in terms of age group:
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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 CHNO. TORADOLis 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 on one side, and the word
ROCHE on the other.
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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
occurs within 2 to 3 hours and is not statistically significantly
different over the recommended dosage range of TORADOL. The greatest
difference between large and small doses of TORADOL is in the duration
of analgesia.<br/>Pharmacokinetics: Ketorolac tromethamine is a racemic mixture of [-]S-
and [+]R-enantiomeric forms, with the S-form having analgesic activity.<br/>Comparison of IV, IM and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine,
following IV and IM doses of ketorolac tromethamine and oral doses
of TORADOL, 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.<br/>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, are linear. At
the higher recommended doses, there is a proportional increase in
the concentrations of free and bound racemate.<br/>Absorption: TORADOL is 100% absorbed after oral administration
(see Table 1 ). Oral administration of TORADOL 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.<br/>Distribution: The mean apparent volume (V��) of ketorolac
tromethamine following complete distribution was approximately 13
liters. This parameter was determined from single-dose data. The ketorolac
tromethamine racemate has been shown to be highly protein bound (99%).
Nevertheless, plasma concentrations as high as 10��g/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 .<br/>Metabolism: Ketorolac tromethamine is largely metabolized in
the liver. The metabolic products are hydroxylated and conjugated
forms of the parent drug. The products of metabolism, and some unchanged
drug, are excreted in the urine.<br/>Excretion: The principal route of elimination of ketorolac
and its metabolites is renal. About 92% of a given dose is found in
the urine, approximately 40% as metabolites and 60% as unchanged ketorolac.
Approximately 6% of a dose is excreted in the feces. A single-dose
study with 10 mg TORADOL (n=9) demonstrated that the S-enantiomer
is cleared approximately two times faster than the R-enantiomer and
that the clearance was independent of the route of administration.
This means that the ratio of S/R plasma concentrations decreases with
time after each dose. There is little or no inversion of the R- to
S- form in humans. The clearance of the racemate in normal subjects,
elderly individuals and in hepatically and renally impaired patients
is outlined in Table 2 . The half-life of the ketorolac
tromethamine S-enantiomer was approximately 2.5 hours (SD��0.4)
compared with 5 hours (SD��1.7) for the R-enantiomer. In other
studies, the half-life for the racemate has been reported to lie within
the range of 5 to 6 hours.<br/>Accumulation: Ketorolac tromethamine administered as an IV bolus
every 6 hours for 5 days to healthy subjects (n=13), showed no significant
difference in Con Day 1 and Day 5. Trough levels averaged
0.29��g/mL (SD��0.13) on Day 1 and 0.55��g/mL (SD��0.23) on Day 6. Steady state was approached after the fourth
dose. Accumulation of ketorolac tromethamine
has not been studied in special populations (geriatric, pediatric,
renal failure or hepatic disease patients).<br/>Kinetics in Special Populations:<br/>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
Cfor the two groups (elderly, 2.52��g/mL��0.77; young, 2.99��g/mL��1.03) .<br/>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 (V) 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.<br/>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
AUCof 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 .<br/>Hepatic Insufficiency: There was no significant difference in estimates
of half-life, AUCand Cin 7 patients
with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic
Effect and Table 2 ).<br/>Race: Pharmacokinetic differences due to race have not
been identified.<br/>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.)
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TORADOL10 mg
tablets are round, white, film-coated, red printed tablets. There
is a large T printed on both sides of the tablet, with TORADOL on
one side, and ROCHE on the other, available in bottles of 100 tablets
(NDC 0004-0273-01).<br/>Storage: Store bottles at 15��to 30��C (59��to 86��F).
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WARNING: TORADOL(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 TORADOLand ketorolac tromethamine
should not exceed 5 days. TORADOLis not indicated for use in pediatric patients and it
is NOT indicated for minor or chronic painful conditions. Increasing
the dose of TORADOLbeyond a daily maximum of 40 mg in adults will not provide
better efficacy but will increase the risk of developing serious adverse
events.<br/>GASTROINTESTINAL RISK:<br/>CARDIOVASCULAR RISK:<br/>RENAL RISK:<br/>RISK OF BLEEDING: TORADOL is CONTRAINDICATED
as prophylactic analgesic before any major surgery.<br/>RISK DURING LABOR AND DELIVERY:<br/>CONCOMITANT USE WITH NSAIDS:<br/>SPECIAL POPULATIONS:
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ketorolac tromethamine
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Toradol (Tablet, Film Coated)
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Adverse reaction rates increase with higher doses
of TORADOL. Practitioners should be alert for the severe complications
of treatment with TORADOL, such as GI ulceration, bleeding and perforation,
postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid
reactions and liver failure . These NSAID-related
complications can be serious in certain patients for whom TORADOL
is indicated, especially when the drug is used inappropriately. In patients taking TORADOL 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 TORADOL 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 or other NSAIDs) are: Body as a Whole: angioedema,
death, hypersensitivity reactions such as anaphylaxis, anaphylactoid
reaction, laryngeal edema, tongue edema , 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<br/>Postmarketing Surveillance Study: A large postmarketing observational, nonrandomized
study, involving approximately 10,000 patients receiving ketorolac
tromethamine, demonstrated that the risk of clinically serious gastrointestinal
(GI) bleeding was dose-dependent (see Tables
3A and 3B). This was
particularly true in elderly patients who received an average daily
dose greater than 60 mg/day of ketorolac tromethamine(see Table 3A).
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Carefully consider the potential benefits and risks
of TORADOL and other treatment options before deciding to use TORADOL.
Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals.<br/>Acute Pain in Adult Patients: TORADOLis 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 TORADOLis to be used only
as continuation treatment, if necessary. The
total combined duration of use of TORADOLand 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 . Patients should be switched to alternative analgesics
as soon as possible, but TORADOLtherapy is not to exceed 5 days.
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Toradol
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