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Ketorolac Tromethamine (Tablet, Film Coated)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2349

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Ketorolac Tromethamine (Tablet, Film Coated)
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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, and the structural formula is: CHNO���CHNO Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41. Each tablet for oral administration contains 10 mg ketorolac tromethamine. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, glyceryl triacetate, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate 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 hours and 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 IV, IM, and Oral Pharmacokinetics: The pharmacokinetics of ketorolac tromethamine, following IV, IM, and oral doses of ketorolac tromethamine, are compared in Table 1. The extent of bioavailability following administration of the oral and IM forms of ketorolac tromethamine was equal to that following an IV bolus.<br/>Linear Kinetics: Following administration of single oral, IM, or IV doses of ketorolac tromethamine, in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in humans, following single or multiple IM, IV, or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.<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 ofthe 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 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/>Effect of Food: Oral administration of ketorolac tromethamine after a high fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of absorption.<br/>Kinetics in Special Populations:<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-IV/IM was compared as follows: IM to meperidine or morphine administered intramuscularly, and IV to morphine administered either directly IV 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-IM 30 mg versus morphine 6 and 12 mg IM, each drug given on an "as needed" basis for up to 5 days, the overall analgesic effect of ketorolac tromethamine-IM 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 patientsreceived 5 days of dosing. In clinical settings where perioperative morphine was allowed, ketorolac tromethamine-IV 30 mg, given once or twice as needed, provided analgesia comparable to morphine 4 mg IV once or twice as needed. There was relatively limited experience with 5 consecutive days of ketorolac tromethamine-IV use in controlled clinical trials, as most patients were given the drug for 3 days or less. The adverse events seen with IV-administered ketorolac tromethamine were similar to those observed with IM-administered ketorolac tromethamine, as would be expected based on the similar pharmacokinetics and bioequivalence (AUC, clearance, plasma half-life) of IV and IM routes of ketorolac tromethamine administration.<br/>Clinical Studies with Concomitant Use of Opioids: Clinical studies in postoperative pain management have demonstrated that ketorolac tromethamine-IV/IM, 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-IV 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-IV plus PCA morphine as compared to patients receiving PCA-administeredmorphine 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 is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Ketorolac tromethamine 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). Ketorolac tromethamine is CONTRAINDICATED in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage. The use of ketorolac tromethamine is CONTRAINDICATED in nursing mothers because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates. Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine, or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery, and is CONTRAINDICATED intra-operatively when hemostasis is critical because of the increased risk of bleeding. Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis, and those at high risk of bleeding . Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID related adverse events. The concomitant use of ketorolac tromethamine and probenecid is CONTRAINDICATED.
dailymed-instance:supply
Ketorolac Tromethamine Tablets, USP are available containing 10 mg of ketorolac tromethamine. The tablets are film-coated, white, unscored round tablets debossed with M over 134 on one side and blank on the other side. They are available as follows: NDC 0378-1134-01bottles of 100 tablets STORE AT CONTROLLED ROOM TEMPERATURE 20�����25��C (68�����77��F). [See USP] Dispense in a tight container as defined in the USP using a child-resistant closure.
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WARNING: Ketorolac tromethamine, a nonsteroidal 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. Theresulting 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. GASTROINTESTINAL EFFECTS RENAL EFFECTS RISK OF BLEEDING HYPERSENSITIVITY LABOR, DELIVERY, AND NURSING CONCOMITANT USE WITH NSAIDs DOSAGE AND ADMINISTRATION KETOROLAC TROMETHAMINE TABLETS SPECIAL POPULATIONS
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In controlled overdosage, daily doses of 360 mg of ketorolac tromethamine-IV/IM 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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Ketorolac Tromethamine
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Ketorolac 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 . 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.<br/>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.<br/>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 , 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 , melena, acute pancreatitis. Hemic and Lymphatic: postoperative wound hemorrhage, rarely requiring blood transfusion , thrombocytopenia, leukopenia. Hepatic: hepatitis, liver failure, cholestatic jaundice. Nervous System: convulsions, psychosis, aseptic meningitis. Respiratory: asthma, bronchospasm. Urogenital: acute renal failure , flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome.
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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-IV/IM, and ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary. Combined use of ketorolac tromethamine-IV/IM and ketorolac tromethamine tablets is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses . 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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Ketorolac Tromethamine