Active ingredient: Ketorolac - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase Inhibitors

Dosage Forms

• Liquid
• Solution
• Tablet

Brands / Synonyms

Acular; Acular LS; Acular Preservative Free; Ketoralac; Ketorlac; Ketorolac Tromethamine; Ketorolaco [Spanish]; Ketorolacum [Latin]; Toradol; Toradol

Indications

For the short-term (~5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting.

Pharmacology

Ketorolac, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. It is a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.

Mechanism of Action

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) chemically related to indomethacin and tolmetin. Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity. Its antiinflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. The resultant reduction in prostaglandin synthesis and activity may be at least partially responsible for many of the adverse, as well as the therapeutic, effects of these medications. Analgesia is probably produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity. However, inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation may also contribute to the analgesic effect. In terms of the ophthalmic applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels in aqueous humor, secondary to inhibition of prostaglandin biosynthesis.

Absorption

Rapidly and completely absorbed after oral administration

Toxicity

LD₅₀ = 189 mg/kg (rat, oral).

Biotrnasformation / Drug Metabolism

Primarily hepatic. Less than 50% of a dose is metabolized. The major metabolites are a glucuronide conjugate, which may also be formed in the kidney, and p-hydroxy ketorolac. Neither metabolite has significant analgesic activity.

Contraindications

1 TORADOL 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.

1 TORADOL is CONTRAINDICATED in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion.

1 TORADOL 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.

1 The use of TORADOL is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.

1 TORADOL is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine, allergic manifestations to aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs).

1 TORADOL is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.

1 TORADOL 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.

1 TORADOL is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.

1 TORADOL^IV/IM is CONTRAINDICATED for neuraxial (epidural or intrathecal) administration due to its alcohol content.

1 The concomitant use of TORADOL and probenecid is CONTRAINDICATED.

Drug Interactions

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

Warfarin, Digoxin, Salicylate, and Heparin

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to10 m g/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 m g/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 andtolbutamide did not alter ketorolac tromethamine protein binding.

In a study involving 12 adult volunteers, TORADOL^ORAL was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, TORADOL^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 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 TORADOL and warfarin or heparin, the administration of TORADOL to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored.

Furosemide

TORADOL^IV/IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).

Probenecid

Concomitant administration of TORADOL^ORAL and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 m g/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of TORADOL and probenecid is contraindicated.

Lithium

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 TORADOL on plasma lithium has not been studied, but cases of increased lithium plasma levels during TORADOL therapy have been reported.

Methotrexate

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

Nondepolarizing Muscle Relaxants

In postmarketing experience there have been reports of a possible interaction between TORADOL^IV/IM and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of TORADOL with muscle relaxants has not been formally studied.

ACE Inhibitors

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

Antiepileptic Drugs

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

Psychoactive Drugs

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

Morphine

TORADOL^IV/IM has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix TORADOL and morphine in the same syringe.

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