Ketocetz

Ketorolac, a pyrrolozine carboxylic acid derivative, is a member of the non-steroidal anti-inflammatory agents (NSAIDs). The drug possesses anti-inflammatory, analgesic, and antipyretic activity by inhibition of prostaglandin synthesis. Both cyclooxygenase (COX) isozymes (COX-1 and COX-2) are target of the drug action. The tromethamine moiety enhances the aqueous solubility of ketorolac. Ketorolac tromethamine is an off-white crystalline powder that has solubilities of 3 mg/mL and more than 500 mg/mL in alcohol and water at 23°C, respectively.

Pharmacology: Pharmacodynamics: Ketorolac tromethamine is a NSAID. The anti-inflammatory potency of systemic ketorolac has been shown to be 2-3 times the indomethacin or naproxen as determined by inhibition of carrageenan-induced paw edema in rats. However, the inhibition potency of cotton pellet-induced granuloma by ketorolac was comparable to that of indomethacin. Ketorolac tromethamine can inhibit platelet aggregation as other non-selective NSAIDs. However, the drug does not inhibit the activity of lipoxygenase enzyme.
Pharmacokinetics: Ketorolac tromethamine injection can be administered intravenously (IV) or intramuscularly (IM). The time to achieve the maximum concentration (Tmax) of the drug are approximately 1.1 to 2.9 minutes or 33 to 44 minutes for IV or IM administration, respectively.
The apparent volume of distribution (Vd) of IV ketorolac tromethamine are 0.21 L/kg in adults and 0.26 L/kg in pediatrics. The Vd of IM ketorolac tromethamine is 0.175 L/kg. 99% of the drug are bound with plasma protein, mainly albumin. 92% of the drug are excreted by renal excretion. However, only 60% of urinary excretion of the drug are unchanged form. Ketorolac tromethamine is metabolized by hepatic hydroxylation and conjugation. Total body clearance (Cl) of the drug is approximately 0.023 to 0.03 L/hr/kg and elimination half-life (t_½) is 5.2 to 5.6 hours in healthy adults.

Ketorolac tromethamine is indicated for the short-term management (5 days or less) of moderately severe acute pain, usually in a postoperative setting.

Recommended dose: The recommended dose of ketorolac tromethamine for short-term management of moderately severe acute pain in healthy adults with normal renal function are as follows: Single-dose treatment: 60 mg IM or 30 mg IV; Multiple-dose treatment: 30 mg IV or IM every 6 hours; Maximum dose: 120 mg/day.
The dosage of ketorolac tromethamine should be reduced by 50% in patients weighing less than 50 kg, elderly patients, and patients with impaired renal function.
Mode of administration: Ketorolac tromethamine should be administered by IV or IM injection. The IV bolus must be given over no less than 15 seconds. The IM dose should be given slowly and deeply into the muscle.

Overdose: Overdose of NSAIDs, including ketorolac, may cause gastrointestinal irritation directly, and by inhibiting cyclooxygenase-1 which is necessary for the formation of the prostaglandins PG12 and PGE2. The acidosis associated with severe NSAIDs overdose is the result of the formation of acidic metabolites and mild hypotension. Overdose of NSAIDs also causes renal arteriolar constriction, reduced renal blood flow and subsequently renal insufficiency. In addition, platelet aggregation is inhibited, predisposing patients to bleeding.
Treatment: Most toxicity associated with NSAIDs overdose resolves with supportive care, decontamination with activated charcoal, and fluid and electrolyte replacement. There is no known specific antidote for NSAIDs overdose. In patients with CNS depression or recurrent seizures, benzodiazepines and airway management by intubation and mechanical ventilation should be considered. Hemodialysis is unlikely to be effective since NSAIDs are highly protein bound. However, renal replacement therapy may be necessary for acid-base and electrolyte correction.

Hypersensitivity reaction to ketorolac, aspirin, other NSAIDs, or any product component.
Patients with increased risk of bleeding includes CABG surgery, cerebrovascular bleeding, peptic ulcer disease and gastrointestinal bleeding, hemostasis disorders, concomitant use with drug affecting hemostasis, and before major surgery.
Patients with renal impairment.
Pregnancy and lactation women.
Neuraxial (epidural or intrathecal) administration.

Dosage and duration of use: Ketolorac tromethamine is indicated for the short-term (not more than 5 days) management of moderately severe acute pain. Initial treatment of ketorolac tromethamine should be IV/IM administration that could be switch to oral administration, if necessary. The total combined duration of use of oral and injection ketorolac tromethamine should not exceed 5 days since increased risk of serious adverse events.
Gastrointestinal risk: Ketorolac tromethamine has known adverse effects on the gastrointestinal tract. Short-term use of the drug can cause peptic ulcers, gastrointestinal bleeding, and/or perforation of the gastrointestinal tract, which can be fatal. These adverse effects can occur at any time during use. Therefore, the drug is contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, and a history of peptic ulcer disease/bleeding. Close monitoring of signs and symptoms of gastrointestinal risk is highly recommended in patients receiving ketorolac tromethamine therapy.
Cardiovascular risk: NSAIDs including ketorolac tromethamine may cause an increased risk of serious thrombotic events, myocardial infarction, or stroke. Patients with preexisting cardiovascular diseases are at greater risk. Therefore, ketorolac tromethamine should not be used in elevated cardiovascular risk patients, particularly for the treatment of perioperative pain in the coronary artery bypass graft (CABG) surgery.
Risk of bleeding: Ketorolac tromethamine can inhibit platelet aggregation, which leads to increased risk of bleeding. The drug should be avoided in patients with bleeding disorders, current or history of serious hemorrhagic events, and those at high risk of bleeding. Ketorolac tromethamine is contraindicated as a prophylactic analgesic before any major surgery.
Use in renal impairment patients and renal risk: Total body clearance of ketorolac tromethamine is reduced in renal impairment patients (0.023-0.03 L/hr/kg in healthy adults and 0.015-0.016 L/hr/kg in renal insufficiency). This leads to two-fold increased elimination half-life of the drug in renal impairment patients. Therefore, ketorolac tromethamine is contraindicated in patients with severe renal impairment.
Intrathecal or epidural administration: Ketorolac tromethamine injection contains alcohol as an excipient. Therefore, the drug is contraindicated for intrathecal or epidural administration.
Special populations: The dosage of ketorolac tromethamine in elderly patients or patients weighing less than 50 kg should be adjusted. The recommended single-dose treatment in these patients is 30 mg IM or 15 mg IV. The multiple-dose treatment is 15 mg IV or IM every 6 hours. The maximum daily dose is 60 mg in these patients.

Pregnancy: Category C: Ketorolac crosses the placenta. The use of ketorolac is contraindicated in labor and delivery. Inhibition of prostaglandin synthesis by ketorolac affects fetal circulation and uterine contraction, resulting in uterine hemorrhage. Safety for use of NSAIDs during pregnancy has not been fully established. NSAIDs exposure during the first trimester is not strongly associated with congenital malformations. Nonteratogenic effects of NSAIDs have been observed during the third trimester, including myocardial degenerative changes, premature closure of ductus arteriosus, fetal tricuspid regurgitation, renal dysfunction, oligohydramnios, bleeding disorder, and gastrointestinal bleeding or perforation.
Lactation: Most NSAIDs, including ketorolac, are excreted into breast milk. Safety of ketorolac in pediatric patients has not been established. Because of the potential risks to breast-feeding infants, ketorolac tromethamine should not be used in lactating women.

See Tables 1 and 2.

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Click on icon to see table/diagram/image

Probenecid: Probenecid may increase the concentrations and toxicity of NSAIDs, including ketorolac tromethamine. Therefore, concomitant use of probenecid and ketorolac tromethamine is contraindicated.
Non-steroidal anti-inflammatory agents (NSAIDs): Concomitant use of ketorolac tromethamine and other NSAIDs, including aspirin, leads to increased risk of serious NSAID-related adverse reactions. Patients receiving any NSAIDs or aspirin should not use ketorolac tromethamine.
Pentoxifylline: Concomitant use of pentoxifylline and ketorolac tromethamine may increase the tendency for bleeding. Concomitant use of pentoxifylline and ketorolac tromethamine is contraindicated.
Drugs with reported adverse interactions with NSAIDs: The adverse interactions with NSAIDs of the following drugs have been observed. These drugs should not be used concomitantly with NSAIDs, including ketorolac tromethamine: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers; Antidepressants (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors); Antiplatelets and anticoagulants; Beta-adrenergic blockers; Cyclosporine; Digoxin; Diuretics (potassium sparing diuretics, thiazide diuretics, and loop diuretics); Fluoroquinolones; Lithium; Methotrexate and derivatives (pemetrexate and pralatrexate); Oral corticosteroids; Tenofovir disoproxil fumarate.
Admixture compatibility: Ketorolac tromethamine injection should not be mixed in a small volume container or syringe with morphine, meperidine, promethazine, or hydroxyzine since precipitation of ketorolac tromethamine may occur.

Store at room temperature, not exceed 30°C. Protect from light.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AB15 - ketorolac ; Belongs to the class of acetic acid derivatives and related substances of non-steroidal antiinflammatory and antirheumatic products.

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