Ophthalmic Solution: ketorolac tromethamine ophthalmic solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

(See also BOXED WARNING.)

The combined use of ketorolac tromethamine IV/IM and oral ketorolac tromethamine is not to exceed 5 days.

1. Gastrointestinal Ulcerations--Bleeding and Perforation: ketorolac tromethamine is CONTRAINDICATED in patients with previously documented peptic ulcers and/or G.I. 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 compilations increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. In a non-randomized, in-hospital postmarketing surveillance study, comparing parental ketorolac tromethamine to parental opioids, higher rates of clinically serious G.I. bleeding were seen in patients <65 years of age who received an average total daily dose of more than 90 mg of ketorolac tromethamine IV/IM 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 TABLE 3B).

2. 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.

Renal Effects: ketorolac tromethamine and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see CLINICAL PHARMACOLOGY). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION) and such patients should be followed closely. With the use of ketorolac tromethamine, there have been reports of acute renal failure, nephritis, and nephrotic syndrome.

Because patients with underlying renal insufficiency are at increased risk of developing acute renal failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients. Hence, in patients with moderately elevated serum creatinine, it is recommended that the daily dose of ketorolac tromethamine IV/IM be reduced by half, not to exceed 60 mg/day. ketorolac tromethamine IS CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS).

Hypovolemia should be corrected before treatment with ketorolac tromethamine is initiated.

3. Fluid Retention and Edema: Fluid Retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatine 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.

4. 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 (2500-5000 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 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 IV/IM. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGSand PRECAUTIONS).

5. 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.

There is potential for cross sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly aplied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjuction with ocular surgery.

Hepatic Effects: ketorolac tromethamine should be used with caution 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. The administration of ketorolac tromethamine should be discontinued in patients in whom an abnormal liver test has occurred as a result of ketorolac tromethamine therapy.

Hematologic Effects: ketorolac tromethamine inhibits platelet aggregation and may prolong bleeding time; therefore, it is contraindicated as a preoperative medication and caution should be used when hemostasis is critical. Unlike aspirin, the inhibition of platelet function by ketorolac tromethamine disappears within 24 to 48 hours after the drug is discontinued. ketorolac tromethamine does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where ketorolac tromethamine was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for ketorolac tromethamine compared to 0.2% in the control groups receiving narcotic analgesics.

Information for the Patient: 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). Advise patients not to give oral ketorolac tromethamine to other family members and to discard any unused drug. Remember that the total duration of ketorolac tromethamine therapy is not to exceed 5 (five) days.

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 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 Category C: Reproduction studies have been performed during organogenesis, using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation day 17, caused dystocia and higher pup mortality in rats. There are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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).

Nursing Mothers: After a single administration of 10 mg of oral ketorolac tromethamine to humans, the maximum milk concentration observed was 7.3 ng/ml and the maximum milk-to-plasma ratio was 0.037. After one 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 children (less than 16 years of age) have not been established. Therefore, use of ketorolac tromethamine is not recommended for use in children 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 IV/IM. The lower 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.

It is recommended that ketorolac tromethamine) 0.5% sterile ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medication which may prolong bleeding time.

In a study involving 12 volunteers, oral ketorolac tromethamine was 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 IV/IM 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 (3.2-11.4 min) compared to a mean of 6.0 minutes (3.4-7.5 min) for heparin alone and 5.1 minutes (3.5-8.5 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 IV/IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).

Concomitant administration of oral ketorolac tromethamineand probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately 3-fold from 5.4 to 17.8 mcg/h/ml) and terminal half-life increased approximately 2-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Inhibition of renal lithium clearance, 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 methotrexate and 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 three reports of a possible interaction between ketorolac tromethamine IV/IM and non-depolarizing muscle relaxants , that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.

Concomitant use of ACE inhibitors may 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 antiepilectic drugs (Dilantin, Tegretol).

Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (Prozac, Navane, Xanax).

ketorolac tromethamine IV/IM has been administered concurrently with morphine 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.

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 (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.

The adverse reactions listed below were reported in clinical trials as probably related to ketorolac tromethamine.

The following adverse events were reported from postmarketing experience:

In patients with allergic conjunctivitis, the most adverse events reported with the use of Acular (ketorolac tromethamine) ophthalmic solution have been transient stinging and burning on instillation. These events were reported by approximately 40% of the patients treated with Acular ophthalmic solution. In all development studies conducted, other adverse events reported during treatment with Acular include ocular irritation (3%), allergic reactions (3%), superficial ocular infections (0.5%) and superficial keratitis (1%).

Other adverse events reported rarely with the use of ketorolac tromethamine ophthalmic solution include: eye dryness, corneal infiltrates, corneal ulcer, and visual disturbance (blurry vision).

ketorolac tromethamine IV/IM may be used as a single or multiple dose, on a regular or "pm" 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 5 days.

When administering ketorolac tromethamine IV/IM, 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 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours.

The following regimen should be limited to single administration use only.

For breakthrough pain, do not increase the dose or the frequency of ketorolac tromethamine. Consideration should be given to supplementing these regiments with low doses of opioids "pm" unless otherwise contraindicated.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ketorolac tromethamine IV/IM 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.

Oral ketorolac tromethamine is indicated ONLY as continuation therapy to ketorolac tromethamine IV/IM for the management of moderately severe, acute pain that requires analgesia at the opioid level. See also PRECAUTIONS, Information for Patients.

The recommended oral ketorolac tromethamine dose is as follows:

Shortening the recommended dosing intervals may result in increased frequency and severity of adverse reactions.

The maximum combined duration of use (parenteral and oral ketorolac tromethamine) is limited to 5 days.

The recommended dose of Acular is one drop (0.25 mg) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.

Ophthalmic Solution Only: ketorolac tromethamine prevented the development of increased intraocular pressure induced in rabbits with topically applied arachidonic acid. Ketorolac did not inhibit rabbit lens aldose reductase in vivo .

ketorolac tromethamine ophthalmic solution did not enhance the spread of ocular infections induced in rabbits with Candida albicans, Herpes Simplex virus type one, or pseudomonas aeruginosa .