Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1602
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Ketorlac Tromethamine (Tablet, Film Coated)
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Ketorlac Tromethamine Tablets:
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Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (��)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol. The structural formula is: CHNOM.W. 376.41 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. Each tablet, for oral administration, contains 10 mg ketorolac tromethamine. In addition, each tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
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Pharmacodynamics: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID). Ketorolac tromethamine inhibits synthesis of prostaglandins and may be considered a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties. Pain relief was statistically different after ketorolac tromethamine dosing from that of placebo at 1/2 hour (the first time point at which it was measured) following the largest recommended doses of ketorolac tromethamine, and by 1 hour following the smallest recommended doses. The peak analgesic effect occurred within 2 to 3 hoursand was not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine by either route was in the duration of analgesia.<br/>Pharmacokinetics: Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.<br/>Comparison of I.V., I.M., and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine following I.V., I.M., and oral doses of ketorolac tromethamine, are compared in TABLE 1. The extent of bioavailability following administration of the oral and I.M. forms of ketorolac tromethamine was equal to that following an I.V. bolus.<br/>Linear Kinetics: Following administration of single oral, I.M., or I.V. doses of ketorolac tromethamine, in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in humans, following single or multiple I.M., I.V., 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.<br/>Binding and Distribution: The ketorolac tromethamine racemate has been shown to be highly protein-bound (99%). Nevertheless, even plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. The mean apparent volume (V) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single dose data.<br/>Metabolism: Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.<br/>Clearance and Excretion: A single-dose study with 10 mg ketorolac tromethamine (n = 9) demonstrated that the S-enantiomer is cleared approximately two times faster than the R-enantiomer, and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals, and in hepatically and renally impaired patients, is outlined in TABLE 2. The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD��0.4) compared with 5 hours (SD��1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.<br/>Accumulation: Ketorolac tromethamine administered as an I.V. bolus, every 6 hours, for 5 days, to healthy subjects (n = 13), showed no significant difference in Con Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD��0.13) on Day 1 and 0.55 mcg/mL (SD��0.23) on Day 6. Steady-state was approached after the fourth dose. Accumulation of ketorolac tromethamine has not been studied in special populations (elderly patients, renal failure patients, or hepatic disease patients).<br/>Effects of Food: Oral administration of ketorolac tromethamine tablets 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/>Kinetics in Special Populations:<br/>Elderly 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 mcg/mL��0.77; young, 2.99 mcg/mL��1.03) (see PRECAUTIONS, Geriatric Use).<br/>Renally Impaired 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 WARNINGS, Renal Effects).<br/>Hepatic Effects: There was no significant difference in estimates of half-life, AUC, C, in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS, Hepatic Effects). % Dose metabolized���50 % Dose excreted in feces = 6 % Dose excreted in urine = 91 % Plasma protein binding = 99 I.V. Administration: In normal subjects (n = 37), the total clearance of 30 mg I.V. administered ketorolac tromethamine was 0.03 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4 to 7.9) hours.<br/>Clinical Studies: The analgesic efficacy of intramuscularly, intravenously and orally administered ketorolac tromethamine was investigated in two postoperative pain models: general surgery (orthopedic, gynecologic and abdominal) and oral surgery (removal of impacted third molars). The studies were double-blind, single- and multiple-dose, parallel trial designs, in patients with moderate to severe pain at baseline. Ketorolac tromethamine-I.V./I.M. was compared as follows: I.M. to meperidine or morphine administered intramuscularly, and I.V. to morphine administered either directly I.V. or through a PCA (Patient-Controlled Analgesia) pump.<br/>Short-Term Use (up to 5 days) Studies: In the comparisons of intramuscular administration during the first hour, the onset of analgesic action was similar for ketorolac tromethamine and the narcotics, but the duration of analgesia was longer with ketorolac tromethamine than with the opioid comparators meperidine or morphine. In a multi-dose, postoperative (general surgery) double-blind trial of ketorolac tromethamine-I.M.30 mg versus morphine 6 and 12 mg I.M., each drug given on an "as needed" basis for up to 5 days, the overall analgesic effect of ketorolac tromethamine-I.M. 30 mg was between that of morphine 6 and 12 mg. The majority of patients treated with either ketorolac tromethamine or morphine were dosed for up to 3 days; a small percentage of patients received 5 days ofdosing. In clinical settings where perioperative morphine was allowed, ketorolac tromethamine-I.V. 30 mg, given once or twice as needed, provided analgesia comparable to morphine 4 mg I.V. once or twice as needed. There was relatively limited experience with 5 consecutive days of ketorolac tromethamine-I.V. use in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with I.V.-administered ketorolac tromethamine were similar to those observed with I.M.-administered ketorolac tromethamine, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of I.V. and I.M. routes of ketorolac tromethamine administration.<br/>Clinical Studies with Concomitant Use of Opioids: Clinical studies in postoperative pain management have demonstrated that ketorolac tromethamine-I.V./I.M., when used in combination with opioids, significantly reduced opioid consumption. This combination may be useful in the subpopulation of patients especially prone to opioid-related complications. Ketorolac tromethamine and narcotics should not be administered in the same syringe. In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine-I.V. as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg q3h), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving ketorolac tromethamine-I.V. plus PCA morphine as compared to patients receiving PCA-administered morphine alone.<br/>Postmarketing Surveillance Study: A large postmarketing observational, non-randomized study, involving approximately 10,000 patients receiving ketorolac tromethamine, demonstrated that the risk of clinically serious gastrointestinal (G.I.) bleeding was dose-dependent (see TABLE 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine (TABLE 3A).
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Ketorolac tromethamine tablets USP, 10 mg are round, white, unscored, film-coated tablets debossed "93" on one side and "314" on the other side, available in bottles of 100. Store at 20��to 25��C (68��to 77��F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
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WARNING: Ketorolac tromethamine, a non-steroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days) management of moderately severe, acute pain, that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. Ketorolac tromethamine is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events.<br/>Cardiovascular Risk:<br/>Gastrointestinal Risk:<br/>Renal Effects:<br/>Risk of Bleeding:<br/>Hypersensitivity:<br/>Labor, Delivery, and Nursing:<br/>Concomitant Use with NSAIDs:<br/>Dosage and Administration:<br/>Ketorlac Tromethamine Tablets:<br/>Special Populations:
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General: Ketorolac tromethamine tablets 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 tablets in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ketorolac tromethamine tablets. 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 ketorolac tromethamine tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine tablets should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine tablets. 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 tablets, 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 tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>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, ketorolac tromethamine tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.<br/>Information for 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.<br/>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 (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine tablets should be discontinued.<br/>Drug Interactions:<br/>ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.<br/>Aspirin: When ketorolac tromethamine tablets are administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac is not altered. The clinical significance of this interaction is not known, however, as with other NSAIDs, concomitant administration of ketorolac tromethamine tablets and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Furosemide: Clinical studies, as well as post marketing observations, have shown that ketorolac tromethamine tablets 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.<br/>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.<br/>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.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.<br/>Carcinogenesis, Mutagenesis, 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 I.M. or I.V. 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 in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ketorolac tromethamine tablets on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: After a single administration of 10 mg of ketorolac tromethamine tablets to humans, the maximum milk concentration observed was 7.3 ng/mL and the maximum milk-to-plasma ratio was 0.037. After 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.<br/>Pediatric Use: Safety and efficacy in pediatric patients (less than 16 years of age) have not been established.<br/>Geriatric Use: As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
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In controlled overdosage, daily doses of 360 mg of ketorolac tromethamine-I.V./I.M. given for five days (3 times the highest recommended dose), caused abdominal pain and peptic ulcers which healed after discontinuation of dosing. Metabolic acidosis has been reported following intentional overdosage. Dialysis does not significantly clear ketorolac tromethamine from the blood stream.
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Ketorlac Tromethamine
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Ketorlac Tromethamine (Tablet, Film Coated)
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Adverse reaction rates increase with higher doses of ketorolac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure (see Boxed WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. The adverse reactions listed below were reported in clinical trials as probably related to ketorolac tromethamine. ���INCIDENCE GREATER THAN 1% [Percentage of incidence in parentheses for those events reported in 3% or more patients] Body as a Whole: edema (4%). Cardiovascular: hypertension. Dermatologic: pruritus, rash. Gastrointestinal: nausea (12%), dyspepsia (12%), gastrointestinal pain (13%), diarrhea (7%), constipation, flatulence, gastrointestinal fullness, vomiting, stomatitis. Hemic and Lymphatic: purpura. Nervous System: headache (17%), drowsiness (6%), dizziness (7%), sweating. ���INCIDENCE 1% OR LESS Body as a Whole: weight gain, fever, infections, asthenia. Cardiovascular: palpitation, pallor, syncope. Dermatologic: urticaria. Gastrointestinal: gastritis, rectal bleeding, eructation, anorexia, increased appetite. Hemic and Lymphatic: epistaxis, anemia, eosinophilia. Nervous System: tremors, abnormal dreams, hallucinations, euphoria, extrapyramidal symptoms, vertigo, paresthesia, depression, insomnia, nervousness, excessive thirst, dry mouth, abnormal thinking, inability to concentrate, hyperkinesis, stupor. Respiratory: dyspnea, pulmonary edema, rhinitis, cough. Special Senses: abnormal taste, abnormal vision, blurred vision, tinnitus, hearing loss. Urogenital: hematuria, proteinuria, oliguria, urinary retention, polyuria, increased urinary frequency. The following adverse events were reported from postmarketing experience. Body as a Whole: hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see Boxed WARNING, WARNINGS), myalgia. Cardiovascular: hypotension and flushing. Dermatologic: Lyell's syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculo-papular rash, urticaria. Gastrointestinal: peptic ulceration, GI hemorrhage, GI perforation (see Boxed WARNING, WARNINGS), melena, acute pancreatitis. Hemic and Lymphatic: postoperative wound hemorrhage, rarely requiring blood transfusion (see Boxed WARNING, WARNINGS, and PRECAUTIONS), thrombocytopenia, leukopenia. Hepatic: hepatitis, liver failure, cholestatic jaundice. Nervous System: convulsions, psychosis, aseptic meningitis. Respiratory: asthma, bronchospasm. Urogenital: acute renal failure (see Boxed WARNING, WARNINGS), flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome.
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Carefully consider the potential benefits and risks of ketorolac tromethamine tablets and other treatment options before deciding to use ketorolac tromethamine tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Ketorolac tromethamine is indicated for the short-term (���5 days) management of moderately severe, acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with ketorolac tromethamine-I.V./.IM., and ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary. Combined use of ketorolac tromethamine-I.V./I.M. and ketorolac tromethamine tablets is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION,and ADVERSE REACTIONS). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.
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Ketorlac Tromethamine
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