Stability: 48 hours RT or REF. Much longer stability intervals have been reported.
WARNINGS
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. 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.
Gastrointestinal Effects
Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation. Therefore, 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.
Renal Effects
Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see package insert for WARNINGS).
Risk of Bleeding
Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see package insert for WARNINGS and PRECAUTIONS). 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.
Hypersensitivity
Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of Ketorolac Tromethamine Injection (see package insert for CONTRAINDICATIONS and WARNINGS). 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).
Intrathecal or Epidural Administration
Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.
Labor, Delivery and Nursing
The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and the uterus.
The use of ketorolac tromethamine is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
Concomitant Use With NSAIDs
Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.
Dosage and Administration
Ketorolac Tromethamine Tablets
Ketorolac tromethamine tablets are indicated only as continuation therapy to Ketorolac Tromethamine Injection, and the combined duration of use of Ketorolac Tromethamine Injection and ketorolac tromethamine tablets is not to exceed five (5) days because of the increased risk of serious adverse events.
The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for Ketorolac Tromethamine Injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION).
Special Populations
Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see package insert for WARNINGS). Doses of Ketorolac Tromethamine Injection are not to exceed 60 mg (total dose per day) in these patients. |
CLINICAL PHARMACOLOGY
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.
Pharmacokinetics
Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.
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.
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.
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 (Vß) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data.
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.
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.
DOSAGE AND ADMINISTRATION
THE COMBINED DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND KETOROLAC TROMETHAMINE TABLETS IS NOT TO EXCEED FIVE (5) DAYS. THE USE OF KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS CONTINUATION THERAPY TO KETOROLAC TROMETHAMINE INJECTION.
Ketorolac Tromethamine Injection
Ketorolac Tromethamine Injection may be used as a single or multiple dose on a regular or “prn” schedule for the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Hypovolemia should be corrected prior to the administration of ketorolac tromethamine (see WARNINGS—Renal Effects). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed five (5) days.
When administering Ketorolac Tromethamine Injection, the IV bolus must be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins in ~30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours.
Single-Dose Treatment: The Following Regimen Should Be Limited to Single Administration Use Only
IM Dosing:
Patients < 65 years of age: One dose of 60 mg.
Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.
IV Dosing:
Patients < 65 years of age: One dose of 30 mg.
Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg.
Multiple-Dose Treatment (IV or IM)
Patients< 65 Years of Age:
The recommended dose is 30 mg Ketorolac Tromethamine Injection every 6 hours. The maximum daily dose should not exceed 120 mg.
For Patients ≥ 65 Years of Age, Renally Impaired Patients (see WARNINGS) and Patients Less Than 50 Kg (110 lbs):
The recommended dose is 15 mg Ketorolac Tromethamine Injection every 6 hours. The maximum daily dose for these populations should not exceed 60 mg.
For breakthrough pain do not increase the dose or the frequency of ketorolac tromethamine. Consideration should be given to supplementing these regimens with low doses of opioids “prn” unless otherwise contraindicated.
Pharmaceutical Information for Ketorolac Tromethamine Injection
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Ketorolac Tromethamine Injection should not be mixed in a small volume (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution.
HOW SUPPLIED
Ketorolac Tromethamine Injection, USP is available in pre-filled syringes as follows:
For IV or IM Single-Dose use:
A syringe containing 1 mL of 15 mg/mL Ketorolac Tromethamine, USP, NDC 10019-021-09, available in boxes of 10.
A syringe containing 1 mL of 30 mg/mL Ketorolac Tromethamine, USP, NDC 10019-022-09, available in boxes of 10.
For IM Single-Dose use only:
A syringe containing 2 mL of 30 mg/mL Ketorolac Tromethamine, USP, (60 mg), NDC 10019-022-32, available in boxes of 10.
Each disposable syringe is supplied with an individually wrapped 22gauge, 1 1/2 inch needle.
Vials:
Ketorolac Tromethamine Injection, USP for intramuscular and intravenous use is available as:
15 mg: 15 mg/mL, 1 mL Vial box of 25, List 3793.
30 mg: 30 mg/mL, 1 mL Vial box of 25, List 3795.
Ketorolac Tromethamine Injection, USP for intramuscular use only is available as:
60 mg: 30 mg/mL, 2 mL Vial box of 25, List 3796.
Store at controlled room temperature 15°-30°C (59°-86°F).
PROTECT FROM LIGHT
Retain in carton until time of use. |
