Ketorolac is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac is only indicated as continuation treatment following IV or IM dosing of ketorolac, if necessary. The total combined duration of use of ketorolac tablets and injection should not exceed 5 days. The recommended total daily dose of ketorolac tablets (maximum 40 mg) is significantly lower than for ketorolac injection (maximum 120 mg).
Ketorolac is not indicated for use in pediatric patients and is not indicated for minor or chronic painful conditions. Increasing the dose of ketorolac beyond labeled recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
Ketorolac is contraindicated in the setting of coronary artery bypass graft surgery.
Ketorolac can cause peptic ulcers, GI bleeding, and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac is contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, and a history of peptic ulcer disease or GI bleeding. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.
Ketorolac is contraindicated for intrathecal or epidural administration due to its alcohol content.
Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac injection. Ketorolac is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac or allergic manifestations to aspirin or other NSAIDs.
Ketorolac is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion.
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.
Ketorolac is contraindicated as a prophylactic analgesic before any major surgery.
The use of ketorolac in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions.
Ketorolac is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
Dosage should be adjusted for patients ≥65 years of age, for patients <50 kg (110 lbs) of body weight, and for patients with moderately elevated serum creatinine. Doses of ketorolac injection are not to exceed 60 mg (total dose per day) in these patients.
Note: Safety: Use the lowest effective dose for the shortest duration of time; do not shorten dosing interval of 4 to 6 hours. Contraindications include peptic ulcer disease, history of GI bleed, advanced renal impairment, or risk of renal failure (eg, volume depletion). Consider administering in combination with a proton pump inhibitor in patients at risk for GI bleeding (eg, taking dual antiplatelet therapy or an anticoagulant, ≥60 years of age) (Ref). May increase cardiovascular risk (eg, thrombotic events), particularly in patients with established cardiovascular disease. Patients weighing <50 kg or ≥65 years of age may be at increased risk for adverse effects; lower doses are recommended.
Pain management, acute:
Note: Do not exceed recommended doses or administer with another nonsteroidal anti-inflammatory drug (NSAID). May supplement with analgesic(s) from another therapeutic class for breakthrough pain. Oral formulation should not be given as initial therapy; other better tolerated oral NSAIDs are generally preferred.
Weight ≥50 kg and <65 years of age:
IV: 30 mg as a single dose or 15 to 30 mg every 6 hours as needed; maximum daily dose: 120 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
IM: 30 to 60 mg as a single dose or 15 to 30 mg every 6 hours as needed; alternatively, may administer 10 to 30 mg every 4 to 6 hours as needed; maximum daily dose: 120 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
Oral (only as continuation of IM or IV therapy, not for initial therapy): 20 mg once, followed by 10 mg every 4 to 6 hours as needed; maximum daily dose: 40 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
Weight <50 kg or ≥65 years of age:
IV: 15 mg as a single dose or 15 mg every 6 hours as needed; maximum daily dose: 60 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
IM: 30 mg as a single dose or 15 mg every 6 hours as needed; alternatively, may administer 10 mg every 4 to 6 hours as needed; maximum daily dose: 60 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
Oral (only as continuation of IM or IV therapy, not for initial therapy): 10 mg every 4 to 6 hours as needed; maximum daily dose: 40 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
eGFR ≥60 mL/minute/1.73 m2: IM, IV, Oral: No dosage adjustment necessary (Ref).
eGFR >30 to <60 mL/minute/1.73 m2:
IM, IV: Use of analgesics other than nonsteroidal anti-inflammatory drugs may be preferred. If necessary, consider 7.5 to 15 mg every 6 hours (Ref); use the lowest effective dose for the shortest duration possible. Avoid use in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, elderly, or taking concurrent nephrotoxic medications) (Ref).
Oral: 10 mg every 4 to 6 hours as needed; maximum: 40 mg/day; oral dosing is intended to be a continuation of IM or IV therapy (Ref).
eGFR ≤30 mL/minute/1.73 m2: IM, IV, Oral: Avoid use due to increased risk of acute kidney injury (Ref). The manufacturer’s labeling states use is contraindicated in advanced kidney impairment.
Hemodialysis, intermittent (thrice weekly): Not dialyzable: IM, IV, Oral: Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Ref). The manufacturer’s labeling states use is contraindicated in advanced kidney impairment.
Peritoneal dialysis: Unlikely to be significantly dialyzed given very high protein binding (Ref): IM, IV, Oral: Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Ref). The manufacturer’s labeling states use is contraindicated in advanced kidney impairment.
CRRT: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution to avoid adverse effects and discontinue if hepatic function worsens.
(For additional information see "Ketorolac (systemic): Pediatric drug information")
Note: To reduce the risk of adverse cardiovascular and GI effects, use the lowest effective dose for the shortest period of time. The total duration of ketorolac (combined IV/IM and oral) should not exceed 5 days (Ref).
Pain management (acute; moderately severe):
Infants and Children <2 years: Limited data available: IV: 0.5 mg/kg/dose every 6 to 8 hours, not to exceed 48 to 72 hours of treatment; has been used postoperatively primarily following cardiac and abdominal surgery; maximum dose: 15 mg/dose (Ref). A lower dose of 0.25 mg/kg/dose every 6 to 8 hours has also been recommended (Ref). Note: IM administration has been described in patients ≥6 months of age (Ref).
Children ≥2 years and Adolescents ≤16 years: Limited data available:
IM, IV: 0.5 mg/kg/dose every 6 to 8 hours; maximum dose: 30 mg/dose, usual reported duration: 48 to 72 hours; not to exceed 5 days of treatment (Ref).
Oral: 1 mg/kg/dose every 4 to 6 hours; maximum dose: 10 mg/dose; maximum daily dose: 40 mg/day (Ref). Note: Oral formulation should only be used as continuation of IV or IM therapy; do not use as initial therapy (Ref).
Adolescents ≥17 years: 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.
<50 kg:
IM: 30 mg as a single dose or 15 mg every 6 hours; maximum daily dose: 60 mg/day.
IV: 15 mg as a single dose or 15 mg every 6 hours; maximum daily dose: 60 mg/day.
Oral: Initial: 10 mg, then 10 mg every 4 to 6 hours; maximum daily dose: 40 mg/day.
≥50 kg:
IM: 60 mg as a single dose or 30 mg every 6 hours; maximum daily dose: 120 mg/day.
IV: 30 mg as a single dose or 30 mg every 6 hours; maximum daily dose: 120 mg/day.
Oral: Initial: 20 mg, then 10 mg every 4 to 6 hours; maximum daily dose: 40 mg/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; however, dosage adjustments are recommended for adult patients. The specific degree of renal impairment where use is permitted is not defined in the product labeling; however, use is contraindicated in patients with advanced renal impairment or those at risk for renal failure due to volume depletion; some experts have suggested the following:
Infants, Children, and Adolescents:
Aronoff 2007 recommendations: Note: Renally adjusted dose recommendations are based on doses of IV, IM: 0.25 to 1 mg/kg/dose every 6 hours (Ref).
GFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 10 to 29 mL/minute/1.73 m2: Administer 50% of dose.
GFR <10 mL/minute/1.73 m2: Administer 25% to 50% of dose.
Intermittent hemodialysis: Avoid use.
Peritoneal dialysis: Avoid use.
KDIGO guidelines provide the following recommendations for NSAIDs (Ref):
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.
eGFR <30 mL/minute/1.73 m2: Avoid use.
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution, may cause elevation of liver enzymes; discontinue if clinical signs and symptoms of liver disease develop.
Avoid use (Ref).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Kit, Injection, as tromethamine:
ReadySharp Ketorolac: 15 mg/mL [DSC] [contains alcohol, usp]
Solution, Injection, as tromethamine:
Generic: 15 mg/mL (1 mL); 30 mg/mL (1 mL)
Solution, Injection, as tromethamine [preservative free]:
Generic: 15 mg/mL (1 mL); 30 mg/mL (1 mL)
Solution, Intramuscular, as tromethamine:
Generic: 60 mg/2 mL (2 mL)
Solution, Intramuscular, as tromethamine [preservative free]:
Generic: 60 mg/2 mL (2 mL)
Tablet, Oral, as tromethamine:
Generic: 10 mg
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intramuscular:
Toradol: 10 mg/mL (1 mL) [contains alcohol, usp]
Solution, Intramuscular, as tromethamine:
Generic: 30 mg/mL (1 mL, 10 mL)
Tablet, Oral, as tromethamine:
Toradol: 10 mg
Generic: 10 mg
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM387559.pdf, must be dispensed with this medication.
Oral: May administer with food to reduce GI upset.
IM: Administer slowly and deeply into the muscle.
IV: Administer IV bolus over a minimum of 15 seconds.
Oral: May administer with food or milk to decrease GI upset.
Parenteral:
IM: Administer slowly and deeply into muscle; 60 mg per 2 mL vial is for IM use only.
IV bolus: Administer undiluted over at least 15 seconds; in children, ketorolac has been infused over 1 to 5 minutes (Ref).
Pain management, acute: Short-term (≤5 days) management of acute pain.
Migraine, severe, acute treatment
Ketorolac may be confused with Ketalar, methadone
Toradol may be confused with Foradil, Inderal, TEGretol, traMADol, tromethamine
Beers Criteria: Ketorolac is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to an increased risk of GI bleeding, peptic ulcer disease, and acute kidney injury (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Ketorolac is identified as a high-risk medication in patients 65 years and older on the PQA’s Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).
Toradol [Canada and multiple international markets] may be confused with Theradol brand name for tramadol [Netherlands]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for ketorolac.
>10%:
Gastrointestinal: Abdominal pain, dyspepsia, nausea
Hepatic: Increased liver enzymes (≤15%)
Nervous system: Headache
1% to 10%:
Cardiovascular: Edema, hypertension
Dermatologic: Diaphoresis, pruritus, skin rash
Gastrointestinal: Constipation, diarrhea, flatulence, gastrointestinal fullness, gastrointestinal hemorrhage (dose dependent, increased incidence seen in age ≥65 years, can be severe), gastrointestinal perforation, gastrointestinal ulcer, heartburn, stomatitis, vomiting
Hematologic & oncologic: Anemia, prolonged bleeding time, purpuric disease
Local: Pain at injection site (IM, IV)
Nervous system: Dizziness, drowsiness
Otic: Tinnitus
Renal: Renal function abnormality
<1%:
Cardiovascular: Cardiac failure, palpitations, syncope, tachycardia
Dermatologic: Alopecia, ecchymoses, pallor, skin photosensitivity, urticaria
Endocrine & metabolic: Increased thirst, weight changes
Gastrointestinal: Anorexia, dysgeusia, eructation, esophagitis, gastritis, glossitis, hematemesis, increased appetite, melena, xerostomia
Genitourinary: Cystitis, dysuria, exacerbation of urinary frequency, hematuria, infertility, oliguria, proteinuria, urinary retention
Hematologic & oncologic: Eosinophilia, leukopenia, rectal hemorrhage, thrombocytopenia
Hepatic: Hepatitis, jaundice
Infection: Infection, sepsis
Nervous system: Abnormal dreams, abnormality in thinking, anxiety, confusion, depression, euphoria, extrapyramidal reaction, hallucination, insomnia, lack of concentration, malaise, nervousness, paresthesia, stupor, vertigo
Neuromuscular & skeletal: Asthenia, hyperkinetic muscle activity, tremor
Ophthalmic: Blurred vision, visual disturbance
Otic: Hearing loss
Renal: Interstitial nephritis, polyuria, renal failure syndrome
Respiratory: Asthma, cough, dyspnea, epistaxis, pulmonary edema, rhinitis
Miscellaneous: Fever
Frequency not defined:
Cardiovascular: Cerebrovascular accident, coronary thrombosis
Gastrointestinal: Peptic ulcer
Postmarketing:
Cardiovascular: Acute myocardial infarction, bradycardia, cardiac arrhythmia, chest pain, flushing, hypotension, vasculitis
Dermatologic: Bullous skin disease, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Hyperglycemia, hyperkalemia, hyponatremia
Gastrointestinal: Acute pancreatitis, aphthous stomatitis, exacerbation of Crohn’s disease, exacerbation of ulcerative colitis
Genitourinary: Azotemia, nephrotic syndrome
Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia, hemolytic-uremic syndrome, lymphadenopathy, pancytopenia, postoperative hematoma, postoperative wound bleeding
Hepatic: Hepatic failure, hepatotoxicity (idiosyncratic) (Chalasani 2014)
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction, nonimmune anaphylaxis, tongue edema
Immunologic: Drug rash with eosinophilia and systemic symptoms
Nervous system: Aseptic meningitis, coma, flank pain, psychosis, seizure
Neuromuscular & skeletal: Myalgia
Ophthalmic: Conjunctivitis
Renal: Acute kidney injury
Respiratory: Bronchospasm, laryngeal edema, pneumonia, respiratory depression
Hypersensitivity to ketorolac, aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), or any component of the formulation; active or history of peptic ulcer disease; recent or history of GI bleeding or perforation; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; advanced renal disease or patients at risk for renal failure due to volume depletion; prophylactic analgesic before any major surgery; suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or high risk of bleeding; concurrent use with aspirin, other NSAIDs, probenecid, or pentoxifylline; epidural or intrathecal administration (injection only); use in the setting of coronary artery bypass graft surgery; labor and delivery.
Canadian labeling: Additional contraindications (not in US labeling): Intraoperative use; coagulation disorders; active GI bleeding; postoperative patients with high-bleeding risk; severe uncontrolled heart failure; inflammatory bowel disease; severe hepatic impairment or active hepatic disease; moderate to severe renal impairment (serum creatinine >442 micromol/L and/or creatinine clearance <30 mL/minute) or deteriorating renal disease; known hyperkalemia; third trimester of pregnancy; breast-feeding; use in children and adolescents <18 years of age
Concerns related to adverse effects:
• Bleeding and hematologic effects: [US 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. Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term nonsteroidal anti-inflammatory drug (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:[US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (FDA 2015). Avoid use in patients with a recent MI unless benefits outweigh risk of cardiovascular thrombotic events. 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.
• 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).
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• GI events: [US Boxed Warning]: Ketorolac can cause peptic ulcers, GI bleeding, and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac is contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, and a history of peptic ulcer disease or GI bleeding. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, inflammatory bowel disease, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in 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. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (ACC/ACG/AHA [Bhatt 2008]).
• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, jaundice, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if signs or symptoms of hepatic disease develop or if systemic manifestations occur.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in patients ≥65 years of age, in patients with diabetes or renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.
• Hypersensitivity reactions: [US 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. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.
• Renal effects: 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 (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors, and ≥65 years of age are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Acute renal failure, interstitial nephritis, and nephrotic syndrome have been reported with ketorolac use; papillary necrosis and renal injury have been reported with long-term use of NSAIDs.
• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).
Disease-related concerns:
• Aseptic meningitis: May increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.
• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.
• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur (Bhangu 2014; Mechanick 2013). Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain (Chou 2016; Horsley 2019; Thorell 2016).
• Coronary artery bypass graft surgery/major surgery: [US Boxed Warning]: Use is contraindicated as prophylactic analgesic before any major surgery and is contraindicated 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 hepatic disease; patients with advanced hepatic disease are at an increased risk of GI bleeding and kidney failure with NSAIDs (AASLD [Biggins 2021]; AASLD [Runyon 2013]).
• Renal impairment: [US Boxed Warning]: Ketorolac is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion. Use with caution in patients with renal impairment or history of kidney disease. Dosage adjustment is required in patients with moderate elevation in serum creatinine.
Concurrent drug therapy issues:
• Aspirin/other NSAIDs: [US Boxed Warning]: Concurrent use of ketorolac with aspirin or other NSAIDs is contraindicated due to the increased risk of adverse reactions.
Special populations:
• Older adult: [US Boxed Warning]: Dosage adjustment is required for patients ≥65 years of age. Patients ≥65 years of age are at greater risk for serious GI, cardiovascular, and/or renal adverse events; use with caution. Ketorolac is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients ≥65 years of age (independent of diagnosis or condition) due to an increased risk of GI bleeding, peptic ulcer disease, and acute kidney injury (Beers Criteria [AGS 2019]).
• Labor and delivery: [US Boxed Warning]: The use of ketorolac in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions.
• Low body weight: [US Boxed Warning]: Dosage adjustment is required for patients weighing <50 kg (<110 pounds).
• Pediatric: [US Boxed Warning]: Ketorolac is not indicated for use in pediatric patients.
Dosage form specific issues:
• Oral: [US Boxed Warning]: Oral therapy is only indicated for use as continuation treatment, following parenteral ketorolac and is not indicated for minor or chronic painful conditions.
• Oral/injection: [US Boxed Warning]: Systemic ketorolac is indicated for short-term (≤5 days) use in adults for treatment of moderately severe acute pain requiring opioid-level analgesia. The combined therapy duration (oral and parenteral) should not exceed 5 days due to the increased risk of serious adverse events.The recommended total daily dose of ketorolac tablets (maximum 40 mg) is significantly lower than for ketorolac injection (maximum 120 mg).
• Injection: [US Boxed Warning]: Ketorolac injection is contraindicated for epidural or intrathecal administration (formulation contains alcohol).
Other warnings/precautions:
• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.
In neonates, bleeding events have been reported; in a retrospective analysis of 57 postsurgical neonates and infants (age range: 0 to 3 months), 17.2% of patients experienced a bleeding event, most were PNA <21 days and those with PNA <14 days had a significantly higher risk than older neonates (Aldrink 2011). Acute kidney injury (AKI) has been observed in pediatric patients; with ketorolac use following cardiothoracic surgery, an increased risk of AKI was observed in neonates and infants who underwent a bidirectional Glenn procedure and were receiving concomitant aspirin therapy (Moffett 2013).
Substrate of OAT1/3
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor therapy
Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination
Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Risk C: Monitor therapy
Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Risk C: Monitor therapy
Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Apixaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Aspirin: Ketorolac (Systemic) may enhance the adverse/toxic effect of Aspirin. An increased risk of bleeding may be associated with use of this combination. Ketorolac (Systemic) may diminish the cardioprotective effect of Aspirin. Risk X: Avoid combination
Bemiparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy
CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Risk D: Consider therapy modification
Dabigatran Etexilate: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Edoxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Enoxaparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider therapy modification
Heparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Risk D: Consider therapy modification
Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Risk C: Monitor therapy
HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Leflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider therapy modification
Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider therapy modification
Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider therapy modification
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Ketorolac (Systemic) may enhance the adverse/toxic effect of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, episodes of apnea have been reported in patients using this combination. Risk C: Monitor therapy
Nitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Ketorolac (Systemic). Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Risk C: Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: Ketorolac (Systemic) may enhance the adverse/toxic effect of Pentoxifylline. Specifically, the risk of bleeding may be increased with this combination. Risk X: Avoid combination
Phenylbutazone: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Potassium Salts: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider therapy modification
Pretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Ketorolac (Systemic). Risk X: Avoid combination
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapy
Quinolones: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Risk C: Monitor therapy
Rivaroxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: Nonselective NSAIDs may reduce aspirin's cardioprotective effects. Administer ibuprofen 30-120 minutes after immediate-release aspirin, 2 to 4 hours after extended-release aspirin, or 8 hours before aspirin. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider therapy modification
Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk X: Avoid combination
Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider therapy modification
Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination
Teriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Tolperisone: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Tricyclic Antidepressants may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination
Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider therapy modification
Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
High-fat meals may delay time to peak (by ~1 hour) and decrease peak concentrations. Management: Administer tablet with food or milk to decrease gastrointestinal distress.
Nonsteroidal anti-inflammatory drugs may delay or prevent rupture of ovarian follicles. This may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in patients having difficulty conceiving or those undergoing investigation of fertility.
Ketorolac crosses the placenta (Walker 1988).
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) close to conception may be associated with an increased risk of miscarriage due to cyclooxygenase-2 inhibition interfering with implantation (Bermas 2014; Bloor 2013).
Birth defects have been observed following in utero NSAID exposure in some studies; however, data are conflicting (Bloor 2013). Nonteratogenic effects, including prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage, have been observed in the fetus/neonate following in utero NSAID exposure (Bermas 2014; Bloor 2013). Maternal NSAID use may cause fetal renal dysfunction leading to oligohydramnios. Although rare, this may occur as early as 20 weeks' gestation and is more likely to occur with prolonged maternal use. Oligohydramnios may be reversible following discontinuation of the NSAID (Dathe 2019; FDA 2020). In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013).
Maternal use of NSAIDs should be avoided beginning at 20 weeks' gestation. If NSAID use is necessary between 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible; consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found (FDA 2020). Because NSAIDs may cause premature closure of the ductus arteriosus, prescribing information for ketorolac specifically states use should be avoided starting at 30 weeks' gestation
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of ketorolac may be altered. Ketorolac has S and R enantiomers; pharmacologic activity is associated with S-ketorolac enantiomer. The clearance of S-ketorolac was found to increase at delivery compared to postpartum values; the peak serum concentration was decreased (Kulo 2017; Välitalo 2017).
[US Boxed Warning]: The use of ketorolac in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions. The risk of uterine hemorrhage may be increased. NSAIDs may be used as part of multimodal pain management following cesarean delivery (ACOG 2019).
Ketorolac is present in breast milk (Wischnik 1989).
The relative infant dose (RID) of ketorolac is 0.21% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 40 mg/day.
In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).
The RID of ketorolac was calculated using a milk concentration of 7.9 ng/mL providing an estimated infant dose via breast milk of 1.185 mcg/kg/day. This milk concentration was obtained following maternal administration of oral ketorolac 10 mg 4 times a day for 2 days in 10 women 2 to 6 days postpartum (Wischnik 1989).
Information related to breastfeeding is available from 3 studies that evaluated use of ketorolac as part of a multimodal protocol for pain following cesarean delivery. In 1 study, women were given a single dose of ketorolac. There were no differences observed between neonates exposed to the protocol containing ketorolac compared to routine standard care without ketorolac in relation to breastfeeding, neonatal growth, sedation and respiratory depression (Hadley 2019). In a second study, ketorolac was used as needed or as a scheduled dose every 6 hours for 24 hours. More mothers who received the scheduled doses exclusively breastfed their newborns; the duration of breastfeeding was also increased (Teigen 2020). In a third study, the maternal dose of ketorolac (15 or 30 mg) was not found to influence the incidence of breastfeeding when used for up to 24 hours postpartum (Yurashevich 2020).
Nonopioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are preferred for breastfeeding patients who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]).
The manufacturer recommends that caution be used if administered to patients who are breastfeeding. Maternal use of NSAIDs should be avoided if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; Bloor 2013). Agents other than ketorolac are preferred in breastfeeding patients at risk of hemorrhage (ABM [Reece-Stremtan 2017]),
Administer tablet with food or milk to decrease gastrointestinal distress.
Monitor response (pain, range of motion, grip strength, mobility, ADL function), inflammation; observe for weight gain, edema; monitor renal function (serum creatinine, BUN, urine output); CBC and platelets, liver function tests; chemistry profile; blood pressure; observe for bleeding, bruising; evaluate gastrointestinal effects (abdominal pain, bleeding, dyspepsia); mental confusion, disorientation
Serum concentration: Therapeutic: 0.3 to 5 mcg/mL; Toxic: >5 mcg/mL
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
Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.
Onset of action: Analgesic: ~30 minutes.
Peak effect: Analgesic: ~2 to 3 hours.
Duration: Analgesic: 4 to 6 hours.
Absorption: Oral: Well absorbed (100%), administration after a high-fat meal decreased peak and delayed time to peak concentrations by ~1 hour; IM: Rapid and complete.
Distribution: Poor penetration into cerebrospinal fluid.
Infants: Vdss: ~0.2 L/kg (McLay 2018).
Children and Adolescents <16 years: Vdss: 0.18 L/kg (McLay 2018).
Adults: Vd beta: Oral, IM: 0.17 ± 0.04 L/kg; IV: 0.21 ± 0.04 L/kg.
Protein binding: 99%.
Metabolism: Hepatic; undergoes hydroxylation and glucuronide conjugation.
Bioavailability: Oral, IM: 100%.
Half-life elimination:
Infants ≥6 months: S-enantiomer: 0.83 ± 0.7 hours; R-enantiomer: 4 ± 0.8 hours (Lynn 2007).
Children and Adolescents ≤16 years: 3 ± 1.1 hours (Dsida 2002).
Adults:
Mean: ~5 hours; Range: 2 to 9 hours [S-enantiomer ~2.5 hours (biologically active); R-enantiomer ~5 hours]; Prolonged 30% to 50% in elderly.
With renal impairment: Scr 1.9 to 5 mg/dL: Mean: ~11 hours; Range: 4 to 19 hours.
Renal dialysis patients: Mean: ~14 hours; Range: 8 to 40 hours.
Time to peak, serum: Oral: ~45 minutes; IM: ~30 to 45 minutes; IV: 1 to 3 minutes.
Excretion: Urine (92%, ~60% as unchanged drug); feces ~6%.
Altered kidney function: Clearance is reduced and half-life is increased in renal impairment. AUC is increased by ~100% and volume of distribution increases.
Pediatric: Vd and clearance are higher in pediatric patients compared to adults.
Older adult: Half-life is longer in patients ≥65 years of age.
Solution (Ketorolac Tromethamine Injection)
15 mg/mL (per mL): $0.95 - $4.50
30 mg/mL (per mL): $1.04 - $7.61
Solution (Ketorolac Tromethamine Intramuscular)
60 mg/2 mL (per mL): $0.54 - $3.75
Tablets (Ketorolac Tromethamine Oral)
10 mg (per each): $2.16 - $2.27
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