Ketorolac Tromethamine

Pronunciation

Pronunciation: KEE-toe-ROLE-ak troe-METH-a-meen
Class: NSAID

Trade Names

Acular
- Solution, ophthalmic 0.5%

Acular LS
- Solution, ophthalmic 0.4%

Acuvail
- Solution, ophthalmic 0.45%

Ketorolac Tromethamine
- Tablets, oral 10 mg
- Injection, solution 15 mg/mL
- Injection, solution 30 mg/mL
- Spray, intranasal 15.75 mg/spray

Apo-Ketorolac (Canada)
Apo-Ketorolac Ophthalmic Solution (Canada)
ratio-Ketorolac (Canada)
Toradol (Canada)
Toradol IM (Canada)

Pharmacology

Decreases inflammation, pain, and fever through inhibition of prostaglandin synthesis.

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Pharmacokinetics

Absorption

Bioavailability is 100% for oral and injection and 60% for intranasal. T max is approximately 44 min for single oral dose (10 mg), 33 to 44 min for IM, 1.1 min for 15 mg IV, 2.9 min for 30 mg IV, and 45 min for intranasal. C max is dose-dependent and is approximately 0.87 mcg/mL for single oral dose (10 mg), 1.14 to 4.55 mcg/mL for IM, 2.47 to 4.65 mcg/mL for IV, and 1.8 mcg/mL for intranasal.

Distribution

Ketorolac is 99% protein bound. Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. A decrease in serum albumin will lead to an increase in free-drug concentrations. Vd is approximately 13 L.

Metabolism

Largely metabolized in the liver via hydroxylation and conjugation. Ketorolac is a racemic mixture of S- and R-enantiomeric forms, with the S-form having analgesic activity.

Elimination

S-enantiomer is cleared 2 times faster than R-enantiomer. The half-life of S-enantiomer is approximately 2.5 h and the half-life of R-enantiomer is approximately 5 h. 92% of the dose is excreted in the urine (approximately 40% as metabolites and 60% as unchanged drug); 6% is excreted in feces.

Onset

30 min for injection.

Peak

2 to 3 h.

Duration

4 to 6 h for injection.

Special Populations

Renal Function Impairment

Cl is reduced and half-life is increased to 6 to 19 h. AUC is increased by approximately 100% and Vd increases. Ketorolac is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure because of volume depletion. Adjust dose for patients with moderately elevated serum creatinine.

Hepatic Function Impairment

There were no significant differences in patients with liver disease compared with healthy volunteers.

Elderly

Half-life is longer in elderly patients. Exposure is increased by 23% in elderly patients after intranasal administration. Adjust dosage for patients 65 y and older.

Children

The Vd and Cl were higher in children compared with adults.

Race

Pharmacokinetic differences have not been identified.

Patients weighing less than 50 kg

Adjust dosage.

Indications and Usage

Oral, IM, IV, intranasal

Short-term management of moderately severe, acute pain in adults.

Ophthalmic solution 0.4% solution

Reduction of ocular pain and burning/stinging following corneal refractive surgery.

0.45% solution

Treatment of pain and inflammation following cataract surgery.

0.5% solution

Treatment of postoperative inflammation in patients who have undergone cataract extraction; temporary relief of ocular itching due to seasonal allergic conjunctivitis.

Contraindications

Hypersensitivity to ketorolac; patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; hypersensitivity to EDTA (intranasal only); active peptic ulcer disease; recent GI bleeding or perforation; history of peptic ulcer disease or GI bleeding; advanced renal impairment or in patients at risk of renal failure because of volume depletion; suspected or confirmed cerebrovascular bleeding; hemorrhagic diathesis, incomplete hemostasis, and patients at high risk of bleeding; as prophylactic analgesia before any major surgery and intra-operatively when hemostasis is critical; during the perioperative period in the setting of coronary artery bypass graft (CABG); for intrathecal or epidural administration (injection); during labor and delivery; breast-feeding; concomitant use with aspirin or other NSAIDs; concomitant use with probenecid or pentoxifylline.

Ophthalmic

Hypersensitivity to any component of the formulation.

Dosage and Administration

Multiple Dose
Adults 17 to 64 y of age IM / IV

30 mg every 6 h. Do not exceed 120 mg/day.

Intranasal

1 spray in each nostril (total of 31.5 mg) every 6 to 8 h. Do not exceed 4 doses per day (126 mg/day).

65 y and older, renal impairment, or weight less than 50 kg IM / IV

15 mg every 6 h. Do not exceed 60 mg/day.

Intranasal

1 spray in 1 nostril (15.75 mg) every 6 to 8 h. Do not exceed 4 doses per day (63 mg/day).

Single Dose
Adults 17 to 64 y of age IM

60 mg.

IV

30 mg.

65 y and older, renal impairment, or weight less than 50 kg IM

30 mg.

IV

15 mg.

Transition from IV or IM to Oral
Adults 17 to 64 y of age

20 mg as a first oral dose followed by 10 mg every 4 to 6 h as needed. Do not exceed 40 mg per 24 h.

65 y and older, renal impairment, or weight less than 50 kg

10 mg as a first oral dose followed by 10 mg every 4 to 6 h as needed. Do not exceed 40 mg per 24 h.

Ophthalmic
Adults and children 3 y and older 0.4% solution

Instill 1 drop 4 times daily in operated eye as needed for pain and burning/stinging for up to 4 days following corneal refractive surgery.

0.5% solution

Instill 1 drop (0.25 mg) 4 times daily for relief of ocular itching caused by seasonal allergic conjunctivitis. For patients undergoing cataract extraction, instill 1 drop to affected eye(s) 4 times daily beginning 24 h after cataract surgery and continuing through the first 2 wk of the postoperative period.

Adults 0.45% solution

Instill 1 drop to affected eye twice daily beginning 1 day prior to cataract surgery, and continued on the day of surgery and through the first 2 weeks of the postoperative period.

General Advice

  • The combined duration of ketorolac IV/IM, oral, and intranasal is not to exceed 5 days. Oral use is only indicated as continuation therapy to IV/IM.
  • Injection
  • Do not mix IV/IM ketorolac in a small volume (eg, in a syringe) with morphine, meperidine, promethazine, or hydroxyzine; this will result in precipitation of ketorolac from solution.
  • When administering IM/IV, the IV bolus must be given over no less than 15 sec. Give IM administration slowly and deeply into the muscle. Rotate injection sites.
  • Intranasal
  • Discard spray 24 h after the first dose.
  • Ophthalmic solution
  • For ophthalmic use only.
  • Have patient tilt head back and instill prescribed number of drops into affected eye(s) as ordered. Have patient close eye(s) for 2 to 3 min and apply light finger pressure to bridge of nose (nasolacrimal duct) for 1 to 2 min after instillation. Do not touch top of dropper bottle to eye, fingers, or other surface.
  • If using other topical ophthalmic drugs, separate each medication by at least 5 min. Instill ophthalmic ointment last.
  • Advise patient not to administer while wearing contact lenses.
  • Keep the bottle tightly capped in between uses.

Storage/Stability

Store between 59° and 86°F. Store unopened intranasal spray between 36° and 46°F. During use, store intranasal spray between 59° and 86°F. Protect from light.

Drug Interactions

ACE inhibitors (eg, captopril), angiotensin II receptor antagonists (eg, losartan)

The risk of renal impairment, particularly in volume-depleted patients, may be increased. In addition, ketorolac may decrease the antihypertensive effect of these agents. Monitor BP and adjust treatment as needed.

Alcohol, anticoagulants (eg, warfarin), corticosteroids (oral)

May increase risk of gastric erosion and bleeding. Use with caution. Additional clinical and laboratory monitoring may be warranted.

Aminoglycosides (eg, tobramycin)

Coadministration may increase the risk of acute renal insufficiency. If coadministration cannot be avoided, reduce the aminoglycoside dose prior to starting ketorolac. Monitor renal function and aminoglycoside concentrations. Adjust the aminoglycoside dose based on monitored parameters.

Antiepileptic agents (eg, carbamazepine, phenytoin)

Sporadic cases of seizures have been reported with concurrent use of ketorolac and antiepileptic agents.

Aspirin, NSAIDs (eg, ibuprofen)

Risk of inducing serious NSAID-related adverse effects. Concomitant use is contraindicated.

Bisphosphonates (eg, alendronate)

The risk of gastric ulceration may be increased. Use with caution. Closely monitor patients for possible GI adverse reactions, especially gastric ulceration.

Clopidogrel, dextrans, heparin

Risk of bleeding complications may be increased. Use with caution.

Cyclosporine

Risk of nephrotoxicity may be increased. Closely monitor renal function.

Disulfiram, metronidazole

Because ketorolac injection contains alcohol, coadministration may produce an alcohol intolerance reaction. Avoid concurrent use.

Food

Oral administration of ketorolac after a high-fat meal may decrease the C max and delay the T max .

Furosemide, thiazide diuretics (eg, chlorothiazide)

Ketorolac may reduce the diuretic response by approximately 20%.

Lithium

Serum lithium levels may be increased. Closely monitor for signs of lithium toxicity. Adjust the lithium dose as needed.

Methotrexate

May increase methotrexate levels increasing the risk of toxicity. Use with caution. Monitor for renal impairment that could predispose to methotrexate toxicity. Monitor methotrexate concentrations and for signs of methotrexate toxicity.

Nondepolarizing muscle relaxants (eg, vecuronium)

Although concurrent use has not been formally studied, apnea has been reported during postmarketing experience.

Pentoxifylline

The risk of bleeding may be increased. Coadministration is contraindicated.

Probenecid

May increase ketorolac plasma levels. Concomitant use is contraindicated.

Psychoactive agents (eg, alprazolam, fluoxetine, thiothixene)

Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs.

Quinolones (eg, levofloxacin)

Risk of CNS stimulation and seizures from quinolones may be increased. Also, quinolone plasma concentrations may be increased. Use with caution.

Smoking

The risk of GI bleeding may be increased.

SSRIs (eg, fluoxetine, paroxetine)

Risk of GI adverse reactions may be increased. Close clinical monitoring is warranted. Use with caution; consider alternative therapy.

Adverse Reactions

Cardiovascular

Hypertension (1% to 10%); arrhythmia, bradycardia, chest pain, flushing, hypotension, MI, vasculitis (postmarketing).

Intranasal

Bradycardia, hypertension (2%).

CNS

Headache (greater than 10%); dizziness, drowsiness (1% to 10%); aseptic meningitis, coma, convulsions, psychosis (postmarketing).

Dermatologic

Pruritus, rash, sweating (1% to 10%); exfoliative dermatitis, Lyell syndrome, maculopapular rash, Stevens-Johnson syndrome, urticaria (postmarketing).

Intranasal

Rash (3%).

EENT

Tinnitus (1% to 10%); conjunctivitis (postmarketing).

Intranasal

Nasal discomfort (15%); rhinalgia (13%); lacrimation increased (5%); rhinitis (2%).

Ophthalmic

Burning/stinging (40%); corneal edema, iritis, ocular inflammation/irritation, ocular pain, superficial keratitis, superficial ocular infections (1% to 10%); conjunctival hyperemia and/or hemorrhage, increased IOP, tearing/vision blurred (1% to 6%); corneal infiltrates, ocular edema (1% to 5%); corneal ulcer, eye dryness; corneal erosion, corneal perforation, corneal thinning, epithelial breakdown (postmarketing).

GI

Abdominal pain, dyspepsia, nausea (greater than 10%); constipation/diarrhea, flatulence, GI fullness, GI ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, stomatitis, vomiting (1% to 10%); acute pancreatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn disease), ulcerative stomatitis (postmarketing).

Genitourinary

Abnormal renal function (1% to 10%); flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome (postmarketing).

Intranasal

Oliguria (3%), decreased urine output (2%).

Hematologic-Lymphatic

Anemia, increased bleeding time, purpura (1% to 10%); agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (postmarketing).

Hepatic

Elevated liver enzymes (1% to 10%); liver failure (postmarketing).

Intranasal

ALT and/or AST increased (2%).

Hypersensitivity

Hypersensitivity reactions (eg, anaphylactoid reaction, anaphylaxis, laryngeal edema, tongue edema) (postmarketing).

Metabolic

Hyperglycemia, hyperkalemia, hyponatremia (postmarketing).

Respiratory

Bronchospasm, pneumonia, respiratory depression (postmarketing).

Intranasal

Throat irritation (4%).

Miscellaneous

Edema, injection-site pain (1% to 10%); angioedema, myalgia (postmarketing).

Ophthalmic

Allergic reactions (1% to 10%).

Precautions

Warnings

Bleeding risk

Ketorolac 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. Contraindicated as prophylactic preoperative analgesic.

Cardiovascular risk

May cause an increased risk of serious CV thrombotic events, MI, and stroke, which can be fatal. This risk may increase with duration of use. Contraindicated for the treatment of perioperative pain in the setting of CABG surgery.

Concomitant use with NSAIDs

Contraindicated in patients currently receiving aspirin or NSAIDs.

GI risk

Peptic ulcers, GI bleeding, and/or perforation can occur, which can be fatal. Contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, or history of peptic ulcer disease or GI bleeding.

Hypersensitivity

Contraindicated in patients who have previously demonstrated hypersensitivity to ketorolac or allergic manifestations to aspirin or other NSAIDs.

Injection

Intrathecal/epidural administration is contraindicated because of alcohol content.

Labor, delivery, and breast-feeding

Contraindicated in labor and delivery because it may adversely affect fetal circulation and inhibit uterine contractions. Contraindicated in breast-feeding.

Oral, injection, intranasal

Limit therapy to 5 days. Oral therapy is indicated only as continuation therapy to IV/IM, and the combined use is not to exceed 5 days because of the increased risk of serious adverse reactions.

Renal risk

Contraindicated in patients with advanced renal impairment or at risk of renal failure caused by volume depletion.

Special populations

Dosage should be adjusted for patients 65 y and older, patients weighing less than 50 kg, and patients with moderately elevated serum creatine.


Monitor

Monitor for signs/symptoms of GI tract ulcerations and bleeding. In patients on long-term treatment, periodically check CBC and chemistry profile. Closely monitor patients receiving therapy that affects hemostasis.


Pregnancy

Category C ; Category D if used in the third trimester (starting at 30 wk gestation). Avoid use in late pregnancy because it may cause premature closure of the ductus arteriosus. Contraindicated during labor and delivery.

Lactation

Excreted in breast milk. Ketorolac intranasal, oral, and injection is contraindicated in breast-feeding women. Use ketorolac ophthalmic with caution.

Children

IM/IV, Oral, Intranasal

Safety and efficacy not established in patients younger than 17 y.

Ophthalmic

Safety and efficacy not established in patients younger than 3 y (0.4% and 0.5% solution). Safety and efficacy not established in children (0.45% solution).

Elderly

Increased risk of adverse reactions. A lower dose is recommended in elderly patients 65 y and older.

Hypersensitivity

Hypersensitivity may occur; use drug with caution in aspirin-sensitive individuals because of possible cross-sensitivity. There is also a potential for cross-sensitivity to phenylacetic acid derivatives and other NSAIDs.

Renal Function

Assess function before and during therapy because NSAID metabolites are eliminated renally. Dosage adjustments may be necessary.

Hepatic Function

Use with caution in patients with hepatic impairment or a history of liver disease.

Anaphylactoid reactions

May occur without known hypersensitivity to ketorolac. Do not give to patients with the aspirin triad.

Asthma

Patients with asthma may have aspirin-sensitive asthma, which may be associated with severe and sometimes fatal bronchospasm. Do not administer ketorolac to patients with this type of aspirin sensitivity because of possible cross-reactivity.

Cardiac effects

Fluid retention and edema have been reported with ketorolac. Use with caution in patients with cardiac decompensation, hypertension, or other similar conditions.

Hematologic effects

Anemia may occur, possibly caused by fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.

Hemorrhage

Use cautiously in patients with coagulation disorders. Postoperative hematomas and other signs of wound bleeding have been reported postmarketing in association with the perioperative use of ketorolac IV or IM. Ocularly applied NSAIDs may increase bleeding of ocular tissues in conjunction with ocular surgery.

Hepatic effects

May lead to liver enzyme elevations. Discontinue if signs/symptoms of liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash).

Hypertension

New hypertension or worsening of preexisting hypertension, either of which may contribute to increased risk of CV events, may occur.

Infection

May mask the usual signs and symptoms of infection.

Ophthalmic use

Use of topical NSAIDs may result in keratitis. Continued use may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation. These reactions may be sight-threatening. Patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases, rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk of corneal adverse reactions. Topical use of NSAIDs more than 24 h prior to surgery or for use beyond 14 days postsurgery may increase risk of occurrence and severity of corneal adverse reactions.

Renal effects

There have been reports of acute renal failure, nephritis, and nephrotic syndrome in association with ketorolac. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Special risk

Use with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn disease) because their condition may be exacerbated.

Skin reactions

Serious and sometimes fatal skin adverse reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and TEN, have occurred.

Wound healing

All topical NSAIDs and corticosteroids may slow or delay healing. Thus, concomitant use of ketorolac and corticosteroids may increase the risk of healing problems.

Overdosage

Symptoms

Abdominal pain, anaphylactoid reaction, drowsiness, epigastric pain, erosive gastritis, GI bleeding, hyperventilation, lethargy, nausea, peptic ulcers, renal dysfunction, vomiting; acute renal failure, coma, hypertension, respiratory depression (rare).

Patient Information

  • Inform patient that this drug is an NSAID and can cause serious adverse effects, such as GI bleeding.
  • Instruct patient to avoid alcohol, aspirin, and other NSAIDs.
  • Advise patient to seek emergency medical assistance if any of the following occur: chest pain, shortness of breath or trouble breathing, slurred speech, swelling of the face or throat, or weakness in one part or on one side of the body.
  • Instruct patient to report the following symptoms to health care provider: black or bloody stools, edema, flu-like symptoms, itching, persistent headache, skin rash, stomach pain, swelling, unexplained tiredness or fatigue, visual disturbances, vomiting blood, weight gain, or yellowing of the skin or eyes.
  • Advise patient that drug may cause drowsiness or dizziness and to use caution while driving or performing other tasks requiring mental alertness.
  • Advise women of childbearing potential that use of ketorolac in late pregnancy should be avoided because of the risk of premature closure of the ductus arteriosus.
  • Ophthalmic solution
  • Remind patient that eye drops are for use in the eye only.
  • Teach patient proper technique for instilling eye drops: wash hands, and do not allow dropper to touch eye. Tilt head back and look up, pull lower eyelid down; instill prescribed number of drops. Close eye for 1 to 2 min and apply gentle pressure to bridge of nose for 1 to 3 min. Do not rub eye.
  • Advise patient not to touch top of dropper bottle to eye, fingers, or other surface.
  • Advise patient that if more than 1 topical ophthalmic drug is being used, administer the drugs at least 5 min apart. Administer ointment last.
  • Inform patient that temporary stinging or burning are the most common adverse effects and to contact health care provider if they occur and are bothersome.
  • Advise patient to contact eye doctor if eye or eyelid inflammation is noted or if eye symptoms do not improve or they worsen.
  • Instruct patient wearing contact lenses to remove them when instilling eye drops.
  • Inform patients that wound healing may be slowed or delayed while using NSAIDs.
  • Instruct patient to use the ophthalmic solution from 1 individual single-use ketorolac 0.45% vial immediately after opening for administration. Inform the patient to discard the remaining contents immediately after administration.

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