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.

Kinetics in Special Populations

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 Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS--Use In The Elderly).

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 (seeWARNINGS - Renal Effects).

Hepatic Effects:

There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers (seePRECAUTIONS - Hepatic Effects).

% Dose metabolized = <50

% Dose excreted in feces = 6

% Dose excreted in urine = 91

% Plasma protein binding = 99

* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers

† Derived from IM pharmacokinetic studies in 54 normal volunteers

‡Derived from IV pharmacokinetic studies in 24 normal volunteers

§Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data

|| Not applicable because 60 mg is only recommended as a single dose

1 Time-to-peak plasma concentration

2 Peak plasma concentration

3 Trough plasma concentration

4 Average plasma concentration

5 Volume of distribution

1Estimated from 30 mg single IM doses of ketorolac tromethamine

2Estimated from 10 mg single Oral doses of ketorolac tromethamine

3Liters/Hour/Kilogram

IV Administration: In normal subjects (n=37), the total clearance of 30 mg& IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The Terminal Half-Life was 5.6 (4-7.9) hours.

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 Injection 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.

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 (GI) bleeding was dose-dependent (see Tables 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).

Gastrointestinal Ulcerations, Bleeding and Perforation:

Ketorolac tromethamine is CONTRAINDICATED in patients with previously documented peptic ulcers and/or GI bleeding. Serious gastrointestinal toxicity, such as bleeding, ulceration and perforation, can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. Studies to date with NSAIDs have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Postmarketing experience with parenterally administered ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding and perforation in the elderly.

The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. In a non-randomized, in-hospital postmarketing surveillance study comparing parenteral ketorolac tromethamine to parenteral opioids, higher rates of clinically serious GI bleeding were seen in patients <65 years of age who received an average total daily dose of more than 90 mg of Ketorolac Tromethamine Injection per day (see CLINICAL PHARMACOLOGY - Postmarketing Surveillance Study). The same study showed that elderly (≥65 years of age) and debilitated patients are more susceptible to gastrointestinal complications. A history of peptic ulcer disease was revealed as another risk factor that increases the possibility of developing serious gastrointestinal complications during ketorolac tromethamine therapy (see Tables 3A and 3B).

Impaired Renal Function:

Ketorolac tromethamine should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Renal toxicity with ketorolac tromethamine has been seen in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of ketorolac tromethamine may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac tromethamine therapy is usually followed by recovery to the pretreatment state.

Fluid Retention and Edema:

Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac tromethamine. Therefore, ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.

Hemorrhage:

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of ketorolac tromethamine in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular hematoma formation from administered ketorolac tromethamine IM (see PRECAUTIONS - Drug Interactions). Patients receiving therapy that affects hemostasis should be monitored closely.

In postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of Ketorolac Tromethamine Injection. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGS and PRECAUTIONS).

Anaphylactoid Reactions:

Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, ketorolac tromethamine or other NSAIDs, or in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

General

Information for Patients

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 of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections). Advise patients not to give ketorolac tromethamine tablets to other family members and to discard any unused drug.

Remember that the total duration of ketorolac tromethamine therapy is not to exceed five (5) days.

Drug Interactions

Ketorolac is highly bound to human plasma protein (mean 99.2%).

Thein vitro binding ofwarfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alterdigoxin protein binding. In vitro studies 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 two-fold 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 volunteers, ketorolac tromethamine tablets were coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, Ketorolac Tromethamine Injection was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 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).

Ketorolac Tromethamine Injection reduced the diuretic response to furosemide in normo-volemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).

Concomitant administration of ketorolac tromethamine tablets and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately three-fold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately two-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Inhibition of renal lithiumclearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of ketorolac tromethamine on plasma lithium has not been studied, but cases of increased lithium plasma levels during ketorolac tromethamine therapy have been reported.

Concomitant administration of methotrexateand some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of ketorolac tromethamine on methotrexate clearance has not been studied.

In postmarketing experience there have been reports of a possible interaction between Ketorolac Tromethamine Injection andnondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.

Concomitant use of ACE inhibitorsmay increase the risk of renal impairment, particularly in volume-depleted patients.

Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine).

Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

Ketorolac Tromethamine Injection has been administered concurrently withmorphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix ketorolac tromethamine and morphine in the same syringe.

There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Carcinogenesis, Mutagenesis and 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 IM or IV dose of 30 mg qid, 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.

Pregnancy

Labor and Delivery

The use of 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 (see CONTRAINDICATIONS).

Lactation and Nursing

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 1 day of dosing (qid), 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.

Pediatric Use

Safety and efficacy in pediatric patients (less than 16 years of age) have not been established. Therefore, use of ketorolac tromethamine in pediatric patients is not recommended.

Use In The Elderly (≥ 65 Years Of Age)

Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the adverse effects of NSAIDs (see WARNINGS - Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with Ketorolac Tromethamine Injection. The lower end of the Ketorolac Tromethamine Injection dosage range is recommended for patients over 65 years of age, and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine.

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

Injection-site pain was reported by 2% of patients in multi-dose studies.

• 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, 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

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

Multiple-Dose Treatment (IV or IM)

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.

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.

Directions for use:

Peel back needle wrapping and expose needle hub; avoid touching hub. Aseptically remove rubber protective cap from the syringe. Attach needle to syringe hub with a twist, keeping needle sheath intact. Remove needle sheath and inject medication. To prevent needle-stick injuries, needles should not be recapped, purposely bent, or broken by hand. Dispose of used syringe in accordance with applicable medical waste regulations and guidelines.

Store at controlled room temperature 15°-30°C (59°-86°F).

PROTECT FROM LIGHT

Retain in carton until time of use.

Manufactured for

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

by: Taylor Pharmaceuticals

Decatur, IL 62525

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

400-657-02

MLT-01572/1.0