Indications and Usage
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.
Acute Pain in Adult Patients
Ketorolac tromethamine tablets are 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 intravenous or intramuscular dosing of ketorolac tromethamine, and ketorolac tromethamine tablets are to be used only as continuation treatment, if necessary.
The total combined duration of use of ketorolac tromethamine tablets 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 ketorolac tromethamine tablets therapy is not to exceed 5 days.
Dosage and Administration
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. In adults, the combined duration of use of intravenous or intramuscular dosing of ketorolac tromethamine and ketorolac tromethamine tablets is not to exceed 5 days. In adults, the use of ketorolac tromethamine tablets is only indicated as continuation therapy to intravenous or intramuscular dosing of ketorolac tromethamine.
Transition from intravenous or intramuscular dosing of ketorolac tromethamine (single- or multiple-dose) to multiple-dose ketorolac tromethamine tablets:
Patients age 17 to 64: 20 mg PO once followed by 10 mg q4 hours to 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 hours to 6 hours prn not > 40 mg/day
Note:
Oral formulationshould notbe given as an initial dose
Use minimum effective dosefor the individual patient
Do not shorten dosing intervalof 4 hours to 6 hours
Total duration of treatment in adult patients:the combined duration of use of intravenous or intramuscular dosing of ketorolac tromethamine and ketorolac tromethamine tablets is not to exceed 5 days.
The following table summarizes ketorolac tromethamine tablets dosing instructions in terms of age group:
|
Patient Population |
Ketorolac Tromethamine Tablets (Following Intravenous or Intramuscular dosing of ketorolac tromethamine) |
|
Age < 17 years |
Oral not approved |
|
Adult Age 17 years to 64 years |
20 mg once, then 10 mg q4 hours to 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 hours to 6 hours prn not > 40 mg/day |
Contraindications
(See also Boxed WARNING ).
Ketorolac tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine.
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 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 ).
Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.
Ketorolac tromethamine is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
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 contractions, thus increasing the risk of uterine hemorrhage.
Ketorolac tromethamine 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 ).
Ketorolac tromethamine 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 ketorolac tromethamine and probenecid is contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.
Adverse Reactions
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 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 ketorolac tromethamine is indicated, especially when the drug is used inappropriately.
In patients taking 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 Incidence greater than 10% |
| 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 |
Additional adverse experiences reported occasionally (< 1% in patients taking 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 post marketing experience in patients taking 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, and fixed drug eruption (FDE)
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
Post marketing Surveillance Study
A large post marketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamine intravenous/intramuscular, demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3Aand 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine intravenous/intramuscular (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 Tromethamine intravenous/intramuscular
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine intravenous/intramuscular | |||
| ≤ 60 mg | > 60 mg to 90 mg | > 90 mg 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% |
| Age of Patients | Total Daily Dose of Ketorolac Tromethamine intravenous/intramuscular | |||
| ≤ 60 mg | > 60 mg to 90 mg | > 90 mg 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% |
To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.
Warfarin, Digoxin, Salicylate, and Heparin
The in vitrobinding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 mcg/mL to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitrostudies indicate that, at therapeutic concentrations of salicylate (300 mcg/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, ketorolac tromethamine tablets were co-administered with a single dose of 25 mg warfarin , causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed intravenous or intramuscular was given with two doses of 5,000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 min to 11.4 min) compared to a mean of 6 minutes (3.4 min to 7.5 min) for heparin alone and 5.1 minutes (3.5 min to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of 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 ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free 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 post marketing observations, have shown that 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 ketorolac tromethamine tablets 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 mcg/h/mL to 17.8 mcg/h/mL) and terminal half-life increased approximately twofold from 6.6 hours to 15.1 hours. Therefore, concomitant use of 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/Angiotensin II Receptor Antagonists
Concomitant use of ACE inhibitors and/or angiotensin 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 angiotensin II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists.
Antiepileptic Drugs
Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine).
Psychoactive Drugs
Hallucinations have been reported when 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 post marketing experience there have been reports of a possible interaction between ketorolac tromethamine intravenous/intramuscular 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.
Overdosage
Symptoms and Signs
Symptoms following acute NSAIDs 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 times 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 ketorolac tromethamine 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.
Description
Ketorolac tromethamine, USP is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine, USP 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, USP is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine, USP is white to off white, crystalline powder. Freely soluble in water and methanol, slightly soluble in alcohol, dehydrated alcohol and tetrahydrofuran, practically insoluble in acetone, dichloromethane, toluene, ethyl acetate, dioxane, hexane, butyl alcohol and acetonitrile. Ketorolac tromethamine, USP has a pKa of 3.5 and an n‑octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.40 g/mol. Its molecular formula is C 15H 13NO 3•C 4H 11NO 3.
Ketorolac tromethamine tablets, USP are available as round, white, unscored, film-coated tablets. Each film-coated tablet, for oral administration, contains 10 mg ketorolac tromethamine, USP, the active ingredient, with added colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The white film-coating contains hypromellose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, and triacetin.
FDA approved dissolution test specifications differ from USP.
ketorolac tromethamine structural formulaClinical 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 ketorolac tromethamine occurs within 2 hours to 3 hours and is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of 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 Intravenous, Intramuscular and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following intravenous and intramuscular doses of ketorolac tromethamine and oral doses of ketorolac tromethamine, are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL form of ketorolac tromethamine and the intramuscular form of ketorolac tromethamine was equal to that following an intravenous bolus.
Linear Kinetics
In adults, following administration of single ORAL doses of ketorolac tromethamine or intramuscular or intravenous 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 intramuscular or intravenous doses of ketorolac tromethamine 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.
Absorption
Ketorolac tromethamine is 100% absorbed after oral administration (see Table 1). 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.
Distribution
The mean apparent volume (V ꞵ) 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 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.
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 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 hours to 6 hours.
Accumulation
Ketorolac tromethamine administered as an intravenous bolus every 6 hours for 5 days to healthy subjects (n = 13), showed no significant difference in C maxon 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 (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 hours to 7 hours in the elderly (65 years to 78 years) compared with young healthy volunteers (24 years to 35 years) (see Table 2). There was little difference in the C maxfor the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS , Geriatric Use (≥ 65 Years of Age) ).
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 years to 8 years old, the half-life was 5.8 hours ± 1.6 hours, the average clearance was 0.042 L/hr/kg ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (V ꞵ) was 0.34 L/kg ± 0.12 L/kg and the volume of distribution at steady state (V ss) was 0.26 L/kg ± 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 intramuscular 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 hours 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 C maxin 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.
|
Pharmacokinetic Parameters (units) |
Oral Derived from PO pharmacokinetic studies in 77 normal fasted volunteers |
Intramuscular Derived from intramuscular pharmacokinetic studies in 54 normal volunteers |
Intravenous Bolus Derived from intravenous pharmacokinetic studies in 24 normal volunteers |
|||
|
10 mg |
15 mg |
30 mg |
60 mg |
15 mg |
30 mg |
|
|
Bioavailability (extent) |
100% |
|||||
|
T max Time-to-peak plasma concentration (min) |
44 ± 34 |
33 ± 21 Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed C max and T max data |
44 ± 29 |
33 ± 21 ¶ |
1.1 ± 0.7 ¶ |
2.9 ± 1.8 |
|
C max Peak plasma concentration (mcg/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 |
|
C max(mcg/mL) [steady state qid] |
1.05 ± 0.26 ¶ |
1.56 ± 0.44 ¶ |
3.11 ± 0.87 ¶ |
N/A Not applicable because 60 mg is only recommended as a single dose |
3.09 ± 1.17 ¶ |
6.85 ± 2.61 |
|
C min Trough plasma concentration (mcg/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 |
|
C avg Average plasma concentration (mcg/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 |
|
V ꞵ Volume of distribution (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 |
|||||
| Total Clearance [in L/h/kg] Liters/hour/kilogram | Terminal Half-life [in hours] | |||
| Type of Subjects | Intramuscular | ORAL | Intramuscular | ORAL |
| Mean (range) | Mean (range) | Mean (range) | Mean (range) | |
| Normal Subjects | 0.023 | 0.025 | 5.3 | 5.3 |
| Intramuscular (n = 54) | (0.010 to 0.046) | (0.013 to 0.050) | (3.5 to 9.2) | (2.4 to 9.0) |
| mean age = 32, range = 18 to 60 | ||||
| Oral (n = 77) | ||||
| mean age = 32, range = 20 to 60 | ||||
| Healthy Elderly Subjects | 0.019 | 0.024 | 7.0 | 6.1 |
| Intramuscular (n = 13), Oral (n = 12) | (0.013 to 0.034) | (0.018 to 0.034) | (4.7 to 8.6) | (4.3 to 7.6) |
| mean age = 72,
range = 65 to 78 |
||||
| Patients with Hepatic Dysfunction | 0.029 | 0.033 | 5.4 | 4.5 |
| Intramuscular and Oral (n = 7) | (0.013 to 0.066) | (0.019 to 0.051) | (2.2 to 6.9) | (1.6 to 7.6) |
| mean age = 51, range = 43 to 64 | ||||
| Patients with Renal Impairment | 0.015 | 0.016 | 10.3 | 10.8 |
| Intramuscular (n = 25), Oral (n = 9) | (0.005 to 0.043) | (0.007 to 0.052) | (5.9 to 19.2) | (3.4 to 18.9) |
| serum creatinine=1.9 to 5 mg/dL, | ||||
| mean age (Intramuscular) = 54,
range = 35 to 71 |
||||
| mean age (Oral) = 57, range = 39 to 70 | ||||
| Renal Dialysis Patients | 0.016 | - | 13.6 | - |
| Intramuscular and Oral (n = 9) | (0.003 to 0.036) | (8.0 to 39.1) | ||
| mean age = 40, range = 27 to 63 | ||||
Intravenous Administration
In normal adult subjects (n = 37), the total clearance of 30 mg intravenous-administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4 to 7.9) hours (See Kinetics in Special Populations for use of intravenous 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 tromethamine intravenous 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 intravenous plus PCA morphine as compared to patients receiving PCA-administered morphine alone.
Pediatric Patients
There are no data available to support the use of ketorolac tromethamine tablets in pediatric patients.
How Supplied / Storage and Handling
Ketorolac tromethamine tablets, USP 10 mg are round, white, convex, unscored, film-coated tablets, debossed “ KT” on one side and plain on the other side, available in
NDC: 70518-4161-00
NDC: 70518-4161-01
NDC: 70518-4161-02
NDC: 70518-4161-03
PACKAGING: 1 in 1 BOTTLE PLASTIC
PACKAGING: 20 in 1 BOTTLE PLASTIC
PACKAGING: 10 in 1 BOTTLE PLASTIC
PACKAGING: 12 in 1 BOTTLE PLASTIC
Storage
Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°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).
PROTECT FROM LIGHT AND EXCESSIVE HUMIDITY.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
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Repackaged and Distributed By:
Remedy Repack, Inc.
625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762
Patient Counseling Information
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 ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine 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 ketorolac tromethamine tablets to other family members and to discard any unused drug.
Remember that the total combined duration of use of ketorolac tromethamine tablets and intravenous or intramuscular dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine tablets are 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.
- Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (see WARNINGS ).
2. 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. S erious Skin Reactions, including DRESS
Advise patients to stop taking ketorolac tromethamine tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see WARNINGS ).
4. Heart Failure And Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS ).
5. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
6. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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.
7. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS ).
8. Fetal Toxicity
Inform pregnant women to avoid use of ketorolac tromethamine tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ketorolac tromethamine tablets is needed for a pregnant woman between about 20 weeks to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy ).
Repackaged By / Distributed By: RemedyRepack Inc.
625 Kolter Drive, Indiana, PA 15701
(724) 465-8762