Ketorolac Tromethamine Injection - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Class:||Nonsteroidal anti-inflammatory agents|
|Form:||Liquid solution, Intramuscular (IM)|
Actions and Clinical Pharmacology
Ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity mediated by peripheral effects. Ketorolac inhibits the synthesis of prostaglandins through inhibition of the cyclooxygenase enzyme system. At analgesic doses, it has minimal anti-inflammatory and antipyretic activity.
Pain relief is comparable following the administration of ketorolac by intramuscular or oral routes. The peak analgesic effect occurs at 2 - 3 hours post-dosing with no evidence of a statistically significant difference over the recommended dosage range. The greatest difference between large and small doses of ketorolac tromethamine administered by either route is in the duration of analgesia.
Ketorolac tromethamine is rapidly and completely absorbed when administered by either the oral or the intramuscular route. The pharmacokinetics are linear following single and multiple dosing. Steady state plasma levels are attained after one day of q.i.d. dosing.
Following intramuscular administration, peak plasma concentrations of 2.2 to 3.0 μg/mL occur at an average of 50 minutes after a single 30 mg dose. The terminal plasma half-life ranges between 3.5 and 9.2 hours in young adults and between 4.7 and 8.6 hours in elderly subjects (mean age = 72 years).
In renally impaired patients, there is a reduction in clearance and an increase in the terminal half-life of ketorolac tromethamine (see Table 1).
The primary route of excretion of ketorolac tromethamine and its metabolites (conjugates and the p-hydroxy metabolite) is in the urine (91.4%) with the remainder (6.1%) being excreted in the feces.
More than 99% of the ketorolac in plasma is protein bound over a wide concentration range.
The parenteral administration of ketorolac tromethamine has not been demonstrated to affect the hemodynamics of anaesthetized patients.
|TYPES OF SUBJECTS||TOTAL CLEARANCE (in L/h/kg)3||TERMINAL HALF-LIFE (in hours)|
|IM MEAN (range)||ORAL MEAN (range)||IM MEAN (range)||ORAL MEAN (range)|
|Normal Subjects i.m. (n = 54); Oral (n = 77)||0.023 (0.010 - 0.046)||0.025 (0.013 - 0.050)||5.3 (3.5 - 9.2)||5.3 (2.4 - 9.0)|
|Healthy Elderly Subjects i.m. (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 i.m. and Oral (n = 7)||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 i.m. and Oral (n = 9) (serum creatinine 1.9 - 5.0 mg/dL)||0.014 (0.007 - 0.043)||0.016 (0.007 - 0.052)||10.3 (8.1 - 15.7)||10.8 (3.4 - 18.9)|
|Renal Dialisis Patients IM (n = 9)||0.016 (0.003 - 0.036)||13.6 (8.0 - 39.1)|
1 Estimated from 30 mg single IM doses of ketorolac tromethamine
2 Estimated from 10 mg single oral doses of ketorolac tromethamine
Intramuscular injection of Ketorolac Tromethamine Injection, USP is indicated for the short-term management (not to exceed 2 days) of moderate to severe acute pain, including pain following major abdominal, orthopaedic and gynecological operative procedures. The total duration of combined intramuscular and oral treatment should not exceed 5 days.
Like other non-steroidal anti-inflammatory drugs, ketorolac tromethamine has been associated with hypersensitivity reactions. Ketorolac tromethamine should not be used when there is a known or suspected hypersensitivity to the drug and should be discontinued in patients who develop symptoms of hypersensitivity during therapy. Because of the possibility of cross-sensitivity, ketorolac tromethamine should not be used in patients with the complete or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity (e.g., asthma) or other allergic manifestations to acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs. Severe and fatal anaphylactoid reactions have occurred in such individuals.
Ketorolac tromethamine should not be used in patients with suspected or confirmed peptic ulcer disease, gastrointestinal bleeding or perforation, or active inflammatory disease of the gastrointestinal system or in patients who have a history of these disorders. Severe and fatal reactions have occurred in such individuals.
Ketorolac tromethamine is contraindicated in patients with moderate to severe renal impairment or in patients at risk for renal failure due to volume depletion.
Ketorolac tromethamine is contraindicated immediately before any major surgery, and is contraindicated intraoperatively when hemostasis is critical because of the increased risk of bleeding. Ketorolac tromethamine is also contraindicated in patients with coagulation disorders, postoperative patients with high hemorrhagic risk or incomplete haemostasis, and in patients with suspected or confirmed cerebrovascular bleeding.
Ketorolac tromethamine is contraindicated in labour 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.
Ketorolac Tromethamine Injection is contraindicated for neuraxial (epidural or intrathecal) administration due to its alcohol content.
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 also contraindicated.
The long-term administration of ketorolac tromethamine is not recommended as the incidence of side-effects increases with the duration of treatment (see Indications and Dosage and Administration).
The most serious risks associated with NSAIDs including ketorolac tromethamine are:
Gastrointestinal Ulcerations, Bleeding and Perforation
Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, during therapy with non-steroidal anti-inflammatory drugs. The incidence of gastrointestinal complications increases with dosage and duration of treatment. Elderly and debilitated patients are more susceptible to these complications.
To date, studies with NSAIDs have not identified any subset of patients not at risk for developing peptic ulceration and bleeding.
Postmarketing experience with ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding, and perforation in the elderly, and most spontaneous reports of fatal gastrointestinal events are in the aged population.
THE LONG-TERM USE OF KETOROLAC TROMETHAMINE IS NOT RECOMMENDED.
The following renal abnormalities have been associated with ketorolac tromethamine and other drugs that inhibit renal prostaglandin biosynthesis: acute renal failure, nephrotic syndrome, interstitial nephritis, renal papillary necrosis. Elevations of blood urea nitrogen (BUN) and creatinine have been reported in clinical trials with ketorolac tromethamine. Ketorolac tromethamine is contraindicated in patients with moderate to severe renal impairment.
Hypovolemia should be corrected before treatment with ketorolac tromethamine is initiated. Patients who are volume depleted may be dependent on renal prostaglandin production to maintain renal perfusion and, therefore, glomerular filtration rate. In such patients, the use of drugs which inhibit prostaglandin synthesis has been associated with further decreases in renal blood flow and may precipitate acute renal failure. Predisposing factors include dehydration (e.g. as a result of extreme exercise, vomiting or diarrhea associated with the loss of at least 5 to 10% of total body weight, unreplenished blood loss of approximately 500 mL), sepsis, impaired renal function, heart failure, liver dysfunction, diuretic therapy, and advanced age. Caution is advised if ketorolac tromethamine is used in such circumstances. Close monitoring of urine output, serum urea and serum creatinine is recommended until renal function recovers.
Fluid Retention and Edema
Fluid retention, edema, NaCl retention, oliguria, elevations of serum urea nitrogen and creatinine have been observed in patients treated with ketorolac tromethamine. Therefore, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be considered. Ketorolac tromethamine should be used with caution in patients with cardiac decompensation, hypertension or other conditions which cause a predisposition to fluid retention.
Postoperative hematomas and other symptoms of wound bleeding have been reported in association with the perioperative use of intramuscular ketorolac tromethamine. Ketorolac tromethamine is contraindicated in patients who have coagulation disorders. If ketorolac tromethamine is to be administered to patients who are receiving drug therapy that interferes with hemostasis, careful observation is advised.
Use of ketorolac tromethamine in patients who are receiving therapy that affects hemostasis should be undertaken with caution, including close monitoring. The concurrent use of ketorolac tromethamine and prophylactic, low dose heparin (2500 - 5000 units q12h), warfarin and dextrans may also be associated with an increased risk of bleeding (see Drug Interactions).
In patients receiving anticoagulants, the risk of intramuscular hematoma formation from ketorolac tromethamine injections is increased.
The possibility of severe or fatal hypersensitivity reactions should be considered, even for patients with no known history of previous exposure or hypersensitivity to ketorolac tromethamine or other NSAIDs. Counteractive measures must be available when administering the first dose of ketorolac tromethamine. As with other NSAIDs, patients should be questioned for history of allergy to NSAIDs or ASA or for the syndrome consisting of nasal polyps, ASA allergy and asthma before being prescribed ketorolac tromethamine. Asthmatic patients with triad asthma (the syndrome of nasal polyps, asthma and hypersensitivity to ASA or other NSAIDs) may be at particular risk for severe hypersensitivity reactions.
Use in Pregnancy and Lactation
The administration of ketorolac tromethamine is not recommended during pregnancy or lactation. After 1 day at 10 mg q.i.d. oral dosing, ketorolac tromethamine has been detected in the milk of lactating women at a maximum concentration of 7.9 ng/mL
Use in Children
Safety and efficacy in children have not been established. Therefore, ketorolac tromethamine is not recommended for use in children under age 16.
Use in the Elderly
Because ketorolac is cleared somewhat more slowly by the elderly (See Pharmacology, Pharmacokinetics) who are also more sensitive to the gastrointestinal and renal effects of NSAIDs, (See Warnings and Precautions), extra caution and the lowest effective dose (See Dosage and Administration) should be used.
Physicians should be alert to the pharmacologic similarity of ketorolac tromethamine to other non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase.
Close medical supervision is recommended in patients prone to gastrointestinal tract irritation. In these cases, the physician must weigh the benefits of treatment against the possible hazards.
Patients taking any NSAID including ketorolac tromethamine should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur at any time during the treatment. If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, ketorolac tromethamine should be discontinued and appropriate treatment instituted with close patient monitoring.
Caution should be observed if ketorolac tromethamine is to be used in patients with impaired hepatic function, or a history of liver disease. Treatment with ketorolac tromethamine may cause elevations of liver enzymes, and in patients with pre-existing liver dysfunction, it may lead to the development of a more severe hepatic reaction. Meaningful elevations (greater than 3 times normal) of serum transaminases (glutamate pyruvate [SGPT or ALT] and glutamic oxaloacetic [SGOT or AST]), occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued. Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac tromethamine clearance. Studies in patients with active hepatitis or cholestasis have not been performed.
Ketorolac tromethamine inhibits platelet function and may prolong bleeding time. It does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). Unlike the prolonged effects from ASA the inhibition of platelet function by ketorolac tromethamine is normalized within 24 to 48 hours after the drug is discontinued.
Blood dyscrasias associated with the use of NSAIDs are rare, but could occur with severe consequences.
In common with other non-steroidal anti-inflammatory drugs, ketorolac tromethamine may mask the usual signs of infection.
Ketorolac tromethamine is highly bound to human plasma protein (mean 99.2%) and binding is independent of concentration. As ketorolac tromethamine is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein-bound drugs significantly. Therapeutic concentrations of digoxin, warfarin, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac tromethamine protein binding.
Prothrombin time should be carefully monitored in all patients receiving oral anticoagulant therapy concomitantly with ketorolac tromethamine. Ketorolac tromethamine given with two doses of 5000 U of heparin to 11 healthy volunteers, resulted in a mean template bleeding time of 6.4 min (3.2 - 11.4 min) compared to a mean of 6.0 min (3.4 - 7.5 min) for heparin alone and 5.1 min (3.5 - 8.5 min) for placebo.
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) at plasma concentrations of 5 to 10 μg/mL.
Ketorolac tromethamine does not alter digoxin protein binding.
In vitro studies indicated that, at therapeutic concentrations of salicylates (300 μg/mL), the binding of ketorolac tromethamine was reduced from approximately 99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac tromethamine plasma levels.
There is no evidence, in animal or human studies, that ketorolac tromethamine induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence, it would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.
Concomitant administration of ketorolac tromethamine and probenecid results in the decreased clearance of ketorolac and a significant increase in ketorolac plasma levels (approximately three-fold increase) and terminal half-life (approximately two-fold increase). The concomitant use of Ketorolac Tromethamine Injection and probenecid is, therefore, contraindicated.
Ketorolac tromethamine reduces the diuretic response to furosemide by approximately 20% in normovolemic subjects.
Some NSAIDs have been reported to inhibit renal lithium clearance, leading to an increase in plasma lithium concentrations and potential lithium toxicity. The effect of ketorolac tromethamine on lithium plasma levels has not been studied.
The concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, thus enhancing its toxicity. The effect of ketorolac tromethamine on methotrexate clearance has not been studied.
Concomitant use of ACE inhibitors and other NSAIDs may increase the risk of renal impairment, particularly in volume depleted patients.
Intramuscular ketorolac tromethamine has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions.
The adverse reactions listed below were reported in Ketorolac Tromethamine clinical efficacy trials. In these trials, patients (N = 660) received either single 30 mg doses (N = 151) or multiple 30 mg doses (N = 509) over a time period of 5 days or less for pain resulting from surgery. These reactions may or may not be drug related.
Incidence Between 10 and 13%
Nervous System: somnolence
Digestive System: nausea
Incidence Between 4 and 9%
Nervous System: headache
Digestive System: vomiting
Injection Site: injection site pain
Incidence Between 2 and 3%
Nervous System: sweating, dizziness
Cardiovascular System: vasodilatation
Incidence 1% or Less
Nervous system: insomnia, increased dry mouth, abnormal dreams, anxiety, depression, paraesthesia, nervousness, paranoid reaction, speech disorder, euphoria, libido increased, excessive thirst, inability to concentrate, stimulation
Digestive system: flatulence, anorexia, constipation, diarrhea, dyspepsia, gastrointestinal fullness, gastrointestinal hemorrhage, gastrointestinal pain, melena, sore throat, liver function abnormalities, rectal bleeding, stomatitis Cardiovascular system: hypertension, chest pain, tachycardia, hemorrhage, palpitation, pulmonary embolus, syncope, ventricular tachycardia, pallor, flushing
Injection site: injection site reaction
Body as a Whole: asthenia, fever, back pain, chills, pain, neck pain
Special senses: taste perversion, tinnitus, blurred vision, diplopia, retinal hemorrhage
Musculo-skeletal system: myalgia, twitching
Respiratory system: asthma, cough increased, dyspnea, epistaxis, hiccup, rhinitis Skin and appendages: pruritus, rash, subcutaneous hematoma, skin disorder
Urogenital system: dysuria, urinary retention, oliguria, increased urinary frequency, vaginitis
Metabolic/nutritional disorders: edema, hypokalemia, hypovolemia
Hemic and lymphatic system: anemia, coagulation disorder, purpura
The following postmarketing adverse experiences have been reported for patients who have received either the oral or injectable formulation of ketorolac tromethamine:
Renal Events: acute renal failure, flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome, urinary retention.
Hypersensitivity reactions: bronchospasm, laryngeal edema, asthma, hypotension, flushing, rash, anaphylaxis, and anaphylactoid reactions. Such reactions have occurred in patients with no prior history of hypersensitivity.
Gastrointestinal Events: gastrointestinal hemorrhage, peptic ulceration, gastrointestinal perforation, pancreatitis, melena.
Hematologic Events: postoperative wound hemorrhage, rarely requiring blood transfusion (see Precautions), thrombocytopenia, epistaxis, leukopenia
Central Nervous System: convulsions, abnormal dreams, hallucinations, hyperkinesia, hearing loss, aseptic meningitis, extrapyramidal symptoms.
Hepatic Events: hepatitis, liver failure, cholestatic jaundice
Cardiovascular: pulmonary edema, hypotension, flushing
Dermatology: Lyell's syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria.
Body as Whole: infection
In a gastroscopic study of healthy subjects, daily doses of 360 mg given over an 8 hour interval for each of five consecutive days (3 times the highest recommended dose) caused pain and peptic ulcers which resolved after discontinuation of dosing. Metabolic acidosis has been reported following intentional overdosage. Single oral doses of 200 mg have been administered to patients with no apparent serious side effects. Dialysis does not appreciably clear ketorolac from the blood stream.
Dosage and Administration
Dosage should be adjusted according to the severity of the pain and the response of the patient.
Intramuscular: The recommended usual initial dose is 10 - 30 mg, according to pain severity. Subsequent dosing may be 10 mg to 30 mg every 4 - 6 hours as needed to control pain. The lowest effective dose should be administered.
The administration of Ketorolac Tromethamine Injection, USP should be limited to short-term therapy (not over 2 days). The total daily dose should not exceed 120 mg because the risk of toxicity appears to increase with longer use at recommended doses (see Warnings and Precautions). The administration of continuous multiple daily doses of Ketorolac Tromethamine Injection has not been extensively studied. There has been limited experience with intramuscular dosing for more than 3 days since the vast majority of patients have transferred to oral medication or no longer required analgesic therapy after this time. If supplementary analgesia is required, a concomitant low dose of opiate can be used.
Patients Under 50 kg, Over Age 65 years, or With Less Severe Pain at Baseline
Parenteral: The lower end of the dosage range is recommended. The initial dose should be 10 mg. The total daily dose of Ketorolac Tromethamine Injection in the elderly should not exceed 60 mg.
Impaired Renal Function
Ketorolac tromethamine is not recommended for patients with moderate to severe renal impairment.
Conversion from Parenteral to Oral Therapy
Ketorolac tromethamine tablets may be used either as monotherapy or as follow-on therapy to parenteral ketorolac. When ketorolac tromethamine tablets are used as a follow-on therapy to parenteral ketorolac, the total combined daily dose of ketorolac (oral + parenteral) should not exceed 120 mg in younger adult patients or 60 mg in elderly patients on the day the change of formulation is made. On subsequent days, oral dosing should not exceed the recommended daily maximum of 40 mg. Ketorolac Tromethamine Injection should be replaced by an oral analgesic as soon as feasible.
The total duration of combined intramuscular and oral treatment should not exceed 5 days.
As with all parenteral products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discoloration, and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Ketorolac tromethamine is a Prescription drug.