Ketorolac (Toradol®)

Updated April 23, 2014
Author: from LexiComp 2014

Description: Dosing information for this COX-1 Cox-2 inhibitor in Adults, Children and Geriatric Populations

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Ketorolac (systemic): Drug information

Pharmacologic Category: Nonsteroidal Anti-inflammatory Drug (NSAID), Oral & Parenteral
Mechanism of Action: Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties

Pharmacodynamics/Kinetics
Onset of action: Analgesic: I.M., I.V.: ~30 minutes
Peak effect: Analgesic: ≤2-3 hours
Duration: Analgesic: 4-6 hours
Absorption: Oral: Well absorbed (100%)
Distribution: ~13 L; poor penetration into CSF
Protein binding: 99%
Metabolism: Hepatic
Half-life elimination: 2-6 hours; prolonged 30% to 50% in elderly; up to 19 hours in renal impairment
Time to peak, serum: I.M.: 30-60 minutes
Excretion: Urine (92%, ~60% as unchanged drug); feces ~6%

Dosing: Adult age 16-64
Pain management (acute; moderately severe) in
patients ≥50 kg: Note: The maximum combined duration of treatment (for parenteral and oral) is 5 days; do not increase dose or frequency; supplement with low-dose opioids if needed for breakthrough pain.
A.  I.M.: 60 mg as a single dose or 30 mg every 6 hours (maximum daily dose: 120 mg)
B.  I.V.: 30 mg as a single dose or 30 mg every 6 hours (maximum daily dose: 120 mg)
C.  I.M., I.V.: Critically-ill patients (unlabeled dose): 30 mg once, followed by 15-30 mg every 6 hours for up to 5 days (maximum daily dose: 120 mg) (Barr, 2013)
D.  Oral: 20 mg, followed by 10 mg every 4-6 hours as needed; do not exceed 40 mg daily; oral dosing is intended to be a continuation of I.M. or I.V. therapy only
Dosage adjustment for low body weight (<50 kg): Refer to geriatric dosing.

Dosing: Pediatric

Note: To reduce the risk of adverse cardiovascular and GI effects, use the lowest effective dose for the shortest period of time.

Infants ≥1 month and Children <2 years: Multiple-dose treatment: I.V.: 0.5 mg/kg every 6-8 hours, not to exceed 48-72 hours of treatment (Burd, 2002; Dawkins, 2009; Gupta, 2004; Moffett, 2006)

Children 2-16 years and Children >16 years who are <50 kg: Do not exceed adult doses
Single-dose treatment: Manufacturer's recommendations:
I.M.: 1 mg/kg as a single dose; maximum dose: 30 mg
I.V.: 0.5 mg/kg as a single dose; maximum dose: 15 mg
Alternative dosing:
I.M., I.V.: 0.4-1 mg/kg as a single dose; Note: Limited information exists. Single I.V. doses of 0.5-1 mg/kg have been studied in children 2-16 years of age for postoperative analgesia. In one study (Maunuksela, 1992), the median required single I.V. dose was 0.4 mg/kg.
Multiple-dose treatment:
I.M., I.V.: 0.5 mg/kg every 6 hours, not to exceed 5 days of treatment (Buck, 1994; Dsida, 2002; Gupta, 2004; Gupta, 2005)
Oral: No pediatric studies exist.
Children >16 years and >50 kg and Adults <65 years:
Single-dose treatment:
I.M.: 60 mg as a single dose
I.V.: 30 mg as a single dose
Multiple-dose treatment:
I.M., I.V.: 30 mg every 6 hours; maximum dose: 120 mg/day
Oral: Initial: 20 mg, then 10 mg every 4-6 hours; maximum dose: 40 mg/day

Adults ≥65 years, renally impaired, or <50 kg:
Single-dose treatment:
I.M.: 30 mg as a single dose
I.V.: 15 mg as a single dose
Multiple-dose treatment:
I.M., I.V.: 15 mg every 6 hours; maximum dose: 60 mg/day
Oral: 10 mg every 4-6 hours; maximum dose: 40 mg/day


Dosing: Geriatric Pain management (acute; moderately severe):
Adults ≥65 years
: Note: May have an increased incidence of GI bleeding, ulceration, and perforation. The maximum combined duration of treatment (for parenteral and oral) is 5 days.
A.  I.M.: 30 mg as a single dose or 15 mg every 6 hours (maximum daily dose: 60 mg)
B.  I.V.: 15 mg as a single dose or 15 mg every 6 hours (maximum daily dose: 60 mg)
C.  Oral: 10 mg, followed by 10 mg every 4-6 hours as needed; do not exceed 40 mg daily; oral dosing is intended to be a continuation of I.M. or I.V. therapy only

Dosing: Renal Impairment: Use is contraindicated in patients with advanced renal impairment or patients at risk for renal failure due to volume depletion.
Mild-to-moderate impairment:
I.M.: 30 mg as a single dose or 15 mg every 6 hours (maximum daily dose: 60 mg)
I.V.: 15 mg as a single dose or 15 mg every 6 hours (maximum daily dose: 60 mg)
Oral: 10 mg, followed by 10 mg every 4-6 hours as needed; do not exceed 40 mg daily; oral dosing is intended to be a continuation of I.M. or I.V. therapy only
Note: The maximum combined duration of treatment (for parenteral and oral) is 5 days.
Advanced impairment or patients at risk for renal failure due to volume depletion: Use is contraindicated.

Dosing: Hepatic Impairment No dosage adjustment provided in manufacturer’s labeling. Use with caution, may cause elevation of liver enzymes; discontinue if clinical signs and symptoms of liver disease develop.

Administration
I.M.: Administer slowly and deeply into the muscle.
I.V.: Administer I.V. bolus over a minimum of 15 seconds.

Compatibility Stable in D5NS, D5W, LR, NS.
Y-site administration: Compatible: Acetaminophen, cisatracurium, dexmedetomidine, fentanyl, hetastarch in lactated electrolyte injection (Hextend®), hydromorphone, methadone, morphine, pantoprazole, remifentanil, sufentanil. Incompatible: Azithromycin, fenoldopam, haloperidol.
Compatibility in syringe: Compatible: Dexamethasone sodium phosphate, dimenhydrinate, metoclopramide, sufentanil. Incompatible: Haloperidol, hydroxyzine, meperidine, morphine, nalbuphine, prochlorperazine edisylate, promethazine. Variable (consult detailed reference): Diazepam, hydromorphone.

Use Short-term (≤5 days) management of moderate-to-severe acute pain requiring analgesia at the opioid level

Adverse Reactions Significant Frequencies noted for parenteral administration:
>10%:
Central nervous system: Headache (17%)
Gastrointestinal: Gastrointestinal pain (13%), dyspepsia (12%), nausea (12%)

>1% to 10%:
Cardiovascular: Edema (4%), hypertension
Central nervous system: Dizziness (7%), drowsiness (6%)
Dermatologic: Diaphoresis, pruritus, skin rash
Gastrointestinal: Diarrhea (7%), constipation, flatulence, gastrointestinal fullness, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer, heartburn, stomatitis, vomiting
Hematologic & oncologic: Anemia, prolonged bleeding time, purpura
Hepatic: Increased liver enzymes
Local: Pain at injection site (2%)
Otic: Tinnitus
Renal: Renal function abnormality

<1% (Limited to important or life-threatening): 
Abnormality in thinking, acute pancreatitis, acute renal failure, agranulocytosis, alopecia, anaphylactoid reaction, anaphylaxis, angioedema, aplastic anemia, aseptic meningitis, asthma, azotemia, bradycardia, bronchospasm, bruise, cardiac arrhythmia, cholestatic jaundice, coma, confusion, congestive heart failure, conjunctivitis, cough, cystitis, depression, dysuria, eosinophilia, epistaxis, eructation, erythema multiforme, euphoria, exacerbation of urinary frequency, exfoliative dermatitis, extrapyramidal reaction, flank pain, gastritis, glossitis, hallucination, hearing loss, hematemesis, hematuria, hemolytic anemia, hemolytic-uremic syndrome, hepatic failure, hepatitis, hyperglycemia, hyperkalemia, hyperkinesis, hypersensitivity reaction, hyponatremia, hypotension, increased susceptibility to infection, increased thirst, infertility, inflammatory bowel disease, insomnia, interstitial nephritis, jaundice, lack of concentration, laryngeal edema, leukopenia, lymphadenopathy, maculopapular rash, melena, myocardial infarction, nephritis, oliguria, palpitations, pancytopenia, paresthesia, pneumonia, polyuria, proteinuria, psychosis, pulmonary edema, rectal hemorrhage, renal failure, respiratory depression, rhinitis, seizure, sepsis, skin photosensitivity, Stevens-Johnson syndrome, stomatitis (ulcerative), stupor, syncope, tachycardia, thrombocytopenia, tongue edema, toxic epidermal necrolysis, urinary retention, urticaria, vasculitis, weight gain, wound hemorrhage (postoperative)

Contraindications Hypersensitivity to ketorolac, aspirin, other NSAIDs, or any component of the formulation; active or history of peptic ulcer disease; recent or history of GI bleeding or perforation; patients with advanced renal disease or risk of renal failure (due to volume depletion); prophylaxis before major surgery; suspected or confirmed cerebrovascular bleeding; hemorrhagic diathesis, incomplete hemostasis, or high risk of bleeding; concurrent use with ASA, other NSAIDs, probenecid or pentoxifylline; epidural or intrathecal administration; perioperative pain in the setting of coronary artery bypass graft (CABG) surgery; labor and delivery

Warnings/Precautions
Concerns related to adverse effects:
• Bleeding: [U.S. Boxed Warning]: Inhibits platelet function; contraindicated in patients with cerebrovascular bleeding (suspected or confirmed), hemorrhagic diathesis, incomplete hemostasis and patients at high risk for bleeding. Effects on platelet adhesion and aggregation may prolong bleeding time. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).
• Cardiovascular events: [U.S. Boxed Warning]: NSAIDs are associated with an increased risk of adverse cardiovascular thrombotic events, including MI and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Carefully evaluate individual cardiovascular risk profiles prior to prescribing. Use caution with fluid retention. Avoid use in heart failure (ACCF/AHA [Yancy, 2013]). Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk. Concurrent use of aspirin has not been shown to consistently reduce thromboembolic events. Use of ketorolac with aspirin or other NSAIDs is contraindicated.
• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Discontinue use with blurred or diminished vision and perform ophthalmologic exam.
• Gastrointestinal events: [U.S. Boxed Warning]: NSAIDs may increase risk of gastrointestinal irritation, inflammation, ulceration, bleeding, and perforation. These events may occur at any time during therapy and without warning. Use is contraindicated in patients with active/history of peptic ulcer disease and recent/history of GI bleeding or perforation. Use caution with a history of inflammatory bowel disease, concurrent therapy with anticoagulants and/or corticosteroids, smoking, use of alcohol, the elderly, or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. Concurrent use of ketorolac with aspirin or other NSAIDs is contraindicated.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.
• Hypersensitivity reactions: [U.S. Boxed Warning]: Ketorolac injection is contraindicated in patients with prior hypersensitivity reaction to aspirin or NSAIDs. Even in patients without prior exposure, hypersensitivity including bronchospasm and anaphylactic shock, may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Do not use in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.
• Skin reactions: NSAIDs may cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); discontinue use at first sign of skin rash or hypersensitivity.
Disease-related concerns:
• Asthma: Do not administer to patients with aspirin-sensitive asthma; severe bronchospasm may occur. Use caution in patients with other forms of asthma.
• Coronary artery bypass graft surgery/major surgery: [U.S. Boxed Warning]: Use is contraindicated as prophylactic analgesic before any major surgery and is contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery. Wound bleeding and postoperative hematomas have been associated with ketorolac use in the perioperative setting.
• Hepatic impairment: Use with caution in patients with hepatic impairment or a history of liver disease. Closely monitor patients with any abnormal LFT. Rarely, severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, liver failure) have occurred with NSAID use; discontinue if signs or symptoms of liver disease develop, or if systemic manifestations occur.
• Hypertension: Use with caution; may cause new-onset hypertension or worsening of existing hypertension.
• Renal impairment: [U.S. Boxed Warning]: Ketorolac is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion. NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation. Patients with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Use with caution in patients with impaired renal function or history of kidney disease. Dosage adjustment is required in patients with moderate elevation in serum creatinine. Acute renal failure, interstitial nephritis, and nephrotic syndrome have been reported with ketorolac use; papillary necrosis and renal injury have been reported with the use of NSAIDs.
Concurrent drug therapy issues:
• Aspirin/other NSAIDs: [U.S. Boxed Warning]: Concurrent use of ketorolac with aspirin or other NSAIDs is contraindicated due to the increased risk of adverse reactions.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
• Elderly: [U.S. Boxed Warning]: Dosage adjustment is required for patients ≥65 years of age. Avoid use in older adults; use is associated with an increased risk of GI bleeding and peptic ulcer disease in older adults in high risk category (eg, >75 years or age or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents) (Beers Criteria).
• Labor and delivery: [U.S. Boxed Warning]: Ketorolac is contraindicated during labor and delivery (may inhibit uterine contractions and adversely affect fetal circulation).
• Low body weight: [U.S. Boxed Warning]: Dosage adjustment is required for patients weighing <50 kg (<110 pounds).
• Pediatrics: [U.S. Boxed Warning]: Ketorolac is not indicated for use in children.

Pregnancy Implications Adverse events were observed in some animal reproduction studies. Ketorolac crosses the placenta (Walker, 1988). NSAID exposure during the first trimester is not strongly associated with congenital malformations; however, cardiovascular anomalies and cleft palate have been observed following NSAID exposure in some studies (Ericson, 2001). The use of an NSAID close to conception may be associated with an increased risk of miscarriage (Li, 2003; Nielsen, 2001). Nonteratogenic effects have been observed following NSAID administration during the third trimester, including myocardial degenerative changes, prenatal constriction of the ductus arteriosus, fetal tricuspid regurgitation, failure of the ductus arteriosus to close postnatally; renal dysfunction or failure, oligohydramnios; gastrointestinal bleeding or perforation, increased risk of necrotizing enterocolitis; intracranial bleeding (including intraventricular hemorrhage), platelet dysfunction with resultant bleeding; pulmonary hypertension (Van den Veyver, 1993). Because they may cause premature closure of the ductus arteriosus, use of NSAIDs late in pregnancy should be avoided (use after 31 or 32 weeks gestation is not recommended by some clinicians) (Moise, 1993). [U.S. Boxed Warning]: Ketorolac is contraindicated during labor and delivery (may inhibit uterine contractions and adversely affect fetal circulation). The chronic use of NSAIDs in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication.

Pricing: U.S.
Solution (Ketorolac Tromethamine Injection)
15 mg/mL (1 mL): $0.92
30 mg/mL (1 mL): $1.00
60 mg/2 mL (2 mL): $1.50
300 mg/10 mL (10 mL): $10.14
Solution (Ketorolac Tromethamine Intramuscular)
30 mg/mL (1 mL): $2.52
60 mg/2 mL (2 mL): $1.04
Tablets (Ketorolac Tromethamine Oral)
10 mg (100): $113.53


Pharmacodynamics/Kinetics
Onset of action: Analgesic: I.M., I.V.: ~30 minutes
Peak effect: Analgesic: ≤2-3 hours
Duration: Analgesic: 4-6 hours
Absorption: Oral: Well absorbed (100%)
Distribution: ~13 L; poor penetration into CSF
Protein binding: 99%
Metabolism: Hepatic
Half-life elimination: 2-6 hours; prolonged 30% to 50% in elderly; up to 19 hours in renal impairment
Time to peak, serum: I.M.: 30-60 minutes
Excretion: Urine (92%, ~60% as unchanged drug); feces ~6%