Ketorolac (Monograph)

Brand name: Sprix
Drug class: Other Nonsteroidal Anti-inflammatory Agents
VA class: CN103
Chemical name: (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid compd. with 2-Amino-2-(hydroxymethyl)-1,3-propanediol (1:1)
Molecular formula: C₁₅H₁₃O₃•C₄H₁₁NO₃
CAS number: 74103-07-4

Medically reviewed by Drugs.com on Oct 9, 2023. Written by ASHP.

Warning

Parenteral and oral ketorolac indicated for short-term (≤5 days) management of moderately severe acute pain that requires analgesia at opiate level.²⁰⁷ ¹²⁰¹ Oral ketorolac indicated only for continuation therapy and only if necessary; do not exceed 5 days of total parenteral and oral therapy.²⁰⁷ ¹²⁰¹ Not indicated for pediatric use or for use in minor or chronic painful conditions.²⁰⁷ ¹²⁰¹
Increasing the dose beyond the recommended dose will not result in improved efficacy and increases the risk of serious adverse effects.¹

Can cause peptic ulcers, GI bleeding, and/or perforation,.¹ Contraindicated in patients with active peptic ulcer disease, recent GI bleeding or perforation, or a history of peptic ulcer disease or GI bleeding.¹
Serious GI events can be fatal and can occur at any time and may not be preceded by warning signs and symptoms.¹⁹⁸ ²⁰⁷ ¹²⁰¹ Geriatric individuals and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.¹⁹⁸ ²⁰⁸ (See GI Effects under Cautions.)

Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).¹⁹⁸ ⁵⁰² ⁵⁰⁸ Risk may occur early in treatment and may increase with duration of use.⁵⁰⁰ ⁵⁰² ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁸ (See Cardiovascular Thrombotic Effects under Cautions.)
Contraindicated in the setting of CABG surgery.⁵⁰⁸

Contraindicated in patients with advanced renal impairment and those at risk of renal failure because of volume depletion.¹

Inhibits platelet function.¹ Contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, or incomplete hemostasis and in patients at a high risk of bleeding.¹
Contraindicated as prophylactic analgesic before major surgery.²⁰⁷ ¹²⁰¹

Hypersensitivity reactions (e.g., bronchospasm, anaphylactic shock) reported; appropriate counteractive measures must be available when administering the first dose.¹²⁰¹ Contraindicated in patients with known hypersensitivity to ketorolac, aspirin, or other NSAIAs.¹²⁰¹

Contraindicated for intrathecal or epidural administration because of alcohol content in parenteral formulation.¹

Contraindicated during labor and delivery.²⁰⁷ ¹²⁰¹ (See Pregnancy under Cautions.)

Contraindicated in patients receiving aspirin or other NSAIAs because of cumulative risk of serious adverse effects.²⁰⁷ ¹²⁰¹

Adjust dosage in patients ≥65 years of age, adults weighing <50 kg, and those with moderately increased S_cr.¹²⁰¹ Daily parenteral dosage should not exceed 60 mg in these patients.¹²⁰¹ (See Dosage and Administration.)

Introduction

Prototypical NSAIA;¹ ² ³ ²¹ ³² ³³ ⁷⁰ ⁹¹ ⁹² ⁹³ ⁹⁶ ¹⁴⁰ pyrrolizine carboxylic acid derivative;² ³ ²¹ ³² ³³ ⁷⁰ ⁹¹ ⁹² ⁹³ ⁹⁶ ¹⁴⁰ structurally related to tolmetin and indomethacin.² ³³ ⁴⁷ ⁷⁰ ⁸³

Uses for Ketorolac

Pain

Consider potential benefits and risks of ketorolac therapy as well as alternative therapies before initiating therapy with the drug.¹⁹⁸ Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹⁹⁸

Parenteral ketorolac or sequential parenteral and oral ketorolac: Short-term (i.e., up to 5 days) management of moderately severe, acute pain that requires analgesia at opiate level; mainly used in the postoperative setting.¹ ⁴⁷ ⁴⁸ ⁴⁹ ⁵⁰ ⁵¹ ⁵² ⁵⁴ ⁵⁵ ⁵⁶ ⁵⁷ ⁵⁸ ⁵⁹ ⁶⁰ ⁶¹ ⁶⁸ ⁷⁰ ⁷¹ ⁷² ⁷³ ⁷⁴ ⁷⁵ ⁷⁶ ⁹¹ ⁹⁹ ¹⁰¹ ¹⁵⁹ ¹⁶¹ ¹⁶² ¹⁶⁵ ¹⁹⁶ ¹⁹⁷ ²⁰⁷ ¹²⁰¹

Intranasal ketorolac: Short-term (i.e., up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opiate level.²⁰⁸

Parenteral ketorolac has been used concomitantly with opiate agonist analgesics (e.g., meperidine, morphine) for the management of moderate to severe postoperative pain without apparent adverse drug interactions.¹ ⁹¹ Combined use can result in reduced opiate analgesic requirements.¹ ⁴⁹ (See Syringe Compatibility under Stability.)

Ketorolac Dosage and Administration

General

Current principles of pain management indicate that analgesics, including ketorolac, should be administered at regularly scheduled intervals, although the drug also has been administered on an as-needed basis (i.e., withholding subsequent doses until pain returns).¹ ⁹¹ ¹⁴⁰
Consider potential benefits and risks of ketorolac therapy as well as alternative therapies before initiating therapy with the drug.¹⁹⁸

Administration

Administer by IM or IV injection,¹ ²³ ⁴⁷ ⁴⁸ ⁴⁹ ⁵⁰ ⁵¹ ⁵² ⁵³ ⁵⁴ ¹⁵⁴ ¹⁵⁶ ¹⁶¹ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁵ orally,¹ ⁵⁵ ⁵⁶ ⁵⁷ ⁵⁸ ⁵⁹ ⁶⁰ ⁶¹ or intranasally.²⁰⁸

Switch patients to alternate analgesic therapy as soon as clinically possible.¹ ¹⁵⁴

Oral Administration

Oral formulation is used as continuation therapy only if required following initial parenteral (IV or IM) ketorolac.¹ ¹⁵⁴

Manufacturer makes no specific recommendations regarding administration with meals; high-fat meal may decrease rate but not extent of absorption and reduce peak plasma concentrations.¹

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Rate of Administration

Administer over ≥15 seconds.¹

IM Administration

Administer IM slowly and deeply into the muscle.¹

For drug compatibility information, see Compatibility under Stability.

Intranasal Administration

Administer nasal solution using a metered-dose spray pump.²⁰⁸ Prime pump prior to initial use.²⁰⁸ Consult manufacturer's instructions for use of the nasal spray pump.²⁰⁸

Not an inhalation product; therefore, patient should not inhale during administration.²⁰⁸

Avoid contact with the eyes; if contact occurs, rinse affected eye(s) with water or saline.²⁰⁸ Patient should consult clinician if ocular irritation persists for >1 hour.²⁰⁸

Use each bottle of nasal solution for only 24 hours and then discard; manufacturer states that spray pump will not deliver the intended dose after 24 hours.²⁰⁸

Dosage

Available as ketorolac tromethamine; dosage expressed in terms of the salt.¹

Nasal spray pump delivers 15.75 mg of ketorolac tromethamine per 100-µL metered spray and 8 sprays per single-day bottle.²⁰⁸

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹⁹⁸ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.¹⁹⁸

For breakthrough pain, supplement with low doses of opiate analgesics (unless contraindicated) as needed rather than higher or more frequent doses of ketorolac.¹ ¹⁴²

Adults

Pain

Oral

Adults 17–64 years of age: When switching from parenteral to oral therapy, the first oral dose is 20 mg, followed by 10 mg every 4–6 hours as needed (maximum 40 mg in a 24-hour period).¹ ²⁰⁷

Weight <50 kg: When switching from parenteral to oral therapy, 10 mg every 4–6 hours as needed (maximum 40 mg in a 24-hour period).¹ ²⁰⁷

IV

30 mg for single-dose therapy.¹²⁰¹ For multiple-dose therapy, 30 mg every 6 hours.¹²⁰¹

Weight <50 kg: 15 mg for single-dose therapy.¹²⁰¹ For multiple-dose therapy, 15 mg every 6 hours.¹²⁰¹

IM

60 mg for single-dose therapy.¹²⁰¹ For multiple-dose therapy, 30 mg every 6 hours.¹²⁰¹

Weight <50 kg: 30 mg for single-dose therapy.¹²⁰¹ For multiple-dose therapy, 15 mg every 6 hours.¹²⁰¹

Intranasal

31.5 mg (one spray in each nostril) every 6–8 hours (maximum 126 mg [4 doses] daily).²⁰⁸

Weight <50 kg: 15.75 mg (one spray in only one nostril) every 6–8 hours (maximum 63 mg [4 doses] daily).²⁰⁸

Prescribing Limits

Adults

Pain

Total duration of ketorolac therapy (including parenteral, oral, and intranasal therapy) should not exceed 5 days.¹ ¹³⁷ ¹⁴² ¹⁴³ ¹⁵⁴ ²⁰⁸

Oral

All adults: Maximum 40 mg in a 24-hour period.¹

Administer doses no more frequently than every 4–6 hours.²⁰⁷

IV or IM

Maximum 120 mg in a 24-hour period.¹

Weight <50 kg: Maximum 60 mg in a 24-hour period.¹

Intranasal

Maximum 126 mg (4 doses) daily.²⁰⁸

Weight <50 kg: Maximum 63 mg (4 doses) daily.²⁰⁸

Special Populations

Hepatic Impairment

Evidence in patients with cirrhosis suggests that dosage adjustment may not be necessary.¹³⁷

Renal Impairment

Pain

Contraindicated in patients with advanced renal disease.²⁰⁷ ²⁰⁸ ¹²⁰¹ Use reduced dosage in those with moderately increased S_cr.²⁰⁷ ²⁰⁸ ¹²⁰¹

Oral

When switching from parenteral to oral therapy, 10 mg every 4–6 hours as needed (maximum 40 mg in a 24-hour period).²⁰⁷

IV

15 mg for single-dose therapy.¹²⁰¹ For multiple-dose therapy, 15 mg every 6 hours (maximum 60 mg in a 24-hour period).¹²⁰¹

IM

30 mg for single-dose therapy.¹ For multiple-dose therapy, 15 mg every 6 hours (maximum 60 mg in a 24-hour period).¹²⁰¹

Intranasal

15.75 mg (one spray in only one nostril) every 6–8 hours (maximum 63 mg [4 doses] daily).²⁰⁸

Geriatric Patients

Adults ≥65 years of age: Use dosage recommended for adults weighing <50 kg and those with moderately increased S_cr.²⁰⁷ ²⁰⁸ ¹²⁰¹

Cautions for Ketorolac

Contraindications

Peptic ulcer disease, recent GI bleeding or perforation, or history of peptic ulcer disease or GI bleeding.¹
Advanced renal impairment or risk of renal failure secondary to volume depletion.¹
Labor and delivery.²⁰⁷ ¹²⁰¹
Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to ketorolac or any ingredient in the formulation.¹⁹⁸ ²⁰⁸ ¹²⁰¹
History of asthma, urticaria, or other sensitivity reactions precipitated by aspirin or other NSAIAs.¹
Use as a prophylactic analgesic before major surgery.¹ ¹²⁰¹
In the setting of CABG surgery.¹²⁰¹
Suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, or incomplete hemostasis; high risk of bleeding.¹
Neuraxial (epidural or intrathecal) administration.¹
Concomitant use with probenecid or pentoxifylline.¹²⁰¹
Manufacturers of oral and parenteral ketorolac also state the drug is contraindicated in patients receiving concomitant aspirin or NSAIA therapy.²⁰⁷ ¹²⁰¹

Warnings/Precautions

Warnings

Duration of Therapy

Total duration of therapy (including parenteral, oral, and intranasal formulations) should not exceed 5 days.¹ ¹³⁷ ¹⁴² ¹⁴³ ¹⁵⁴ ²⁰⁸

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.⁵⁰⁰ ⁵⁰² ⁵⁰⁸

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information⁵⁰⁰ ⁵⁰¹ ⁵⁰² indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.⁵⁰⁰ ⁵⁰² ⁵⁰⁶ ⁵⁰⁸

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.⁵⁰⁰ ⁵⁰² ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁸

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.⁵⁰⁸

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.⁵⁰⁵ ⁵⁰⁸

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;⁵⁰⁰ ⁵⁰⁸ ⁵¹¹ absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.⁵⁰⁸ ⁵¹¹

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.²⁰² ²⁰³ ²⁰⁴ ²⁰⁶ ⁵⁰⁰ ⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁶ FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.¹⁹⁸ ⁵⁰⁰ ⁵⁰⁸

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.⁵⁰⁵ ⁵¹¹ ⁵¹² ⁵¹⁶ Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.⁵⁰⁸ Contraindicated in the setting of CABG surgery.⁵⁰⁸

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.¹⁹⁸ ⁵⁰² ⁵⁰⁸ (See Specific Drugs under Interactions.)

GI Effects

Serious, sometimes fatal, GI toxicity (e.g., bleeding, ulceration, or perforation of esophagus, stomach, or small or large intestine) can occur with or without warning symptoms.¹ ¹²⁴ ¹²⁵ ¹⁴¹ ¹⁹⁸ ²⁰⁸

Risk for GI bleeding increased greater than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.¹⁹² ¹⁹³ ²⁰⁸

Other risk factors for GI bleeding include concomitant use of oral corticosteroids, aspirin, anticoagulants, or SSRIs; longer duration of NSAIA therapy; smoking; alcohol use; older age; poor general health status; and advanced liver disease and/or coagulopathy.¹⁹² ¹⁹³ ¹⁹⁵ ²⁰⁸ (See Contraindications under Cautions.)

Geriatric or debilitated patients appear to tolerate ulceration and bleeding less well than other individuals; most spontaneous reports of fatal GI effects involve such patients.¹ ¹²² ¹²⁵ ¹²⁶ ¹²⁷ ¹⁴¹

Use at lowest effective dosage for the shortest duration necessary.¹⁹⁸ Avoid use of more than one NSAIA at a time.²⁰⁸ (See Specific Drugs under Interactions.)

Avoid use of NSAIAs in patients at higher risk for GI toxicity unless expected benefits outweigh increased risk of bleeding; consider alternate therapies.²⁰⁸

NSAIAs may exacerbate inflammatory bowel disease (ulcerative colitis, Crohn's disease); use with great caution in patients with a history of such disease.²⁰⁸

Hematologic Effects

May inhibit platelet aggregation and prolong bleeding time.¹ ² ²³ ²⁴ ³⁴ ⁶⁵ ⁷⁰ ⁹¹ ¹⁴¹ Use with caution and careful monitoring in patients with coagulation disorders.¹ (See Contraindications under Cautions.)

Hematomas and other signs of wound bleeding reported in patients receiving the drug perioperatively; undertake postoperative administration with caution when hemostasis is critical.¹ (See Contraindications under Cautions.)

Increased risk of intramuscular hematoma following IM administration in patients receiving anticoagulants.¹ ¹⁵⁴

Administer with caution in patients receiving therapeutic doses of anticoagulants (e.g., heparin, warfarin).¹ ¹⁵⁴ Concurrent use with prophylactic low-dose heparin (2500–5000 units every 12 hours), warfarin, or dextrans not studied extensively, but also may be associated with increased risk of bleeding.¹ ¹⁵⁴ Administer with caution when the potential benefits justify the possible risks.¹ ⁹¹ ¹⁴⁵ ¹⁵⁴ (See Specific Drugs under Interactions.)

Increased risk of bleeding following tonsillectomy in pediatric patients.¹ ¹⁷⁴ ¹⁹⁶ ¹⁹⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.¹ ¹⁵⁴ Interstitial nephritis and nephrotic syndrome reported in patients receiving ketorolac.¹

Potential for overt renal decompensation.¹ ¹⁵⁴ Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure; in patients with volume depletion; in geriatric patients; and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.¹ ⁹¹ ¹⁴⁷ ¹⁵⁴ ²⁰¹ ²⁰⁵ (See Renal Impairment and also Contraindications under Cautions, and Renal Impairment under Dosage and Administration.)

Correct hypovolemia before initiating ketorolac therapy.¹

Other Warnings and Precautions

Hypertension

Hypertension and worsening of preexisting hypertension reported;¹ ⁹¹ ¹⁹⁸ either event may contribute to the increased incidence of cardiovascular events.¹⁹⁸ Monitor BP.¹⁹⁸

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.¹⁹⁸ ⁵⁰⁸ ⁵⁰⁹ (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.¹ ⁷⁰ ⁹¹ ¹⁴⁰ ⁵⁰⁸

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.⁵⁰⁰ ⁵⁰¹ ⁵⁰⁴ ⁵⁰⁷ ⁵⁰⁸

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.⁵⁰⁸ (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.⁵⁰⁸

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Hypersensitivity Reactions

Anaphylactoid reactions (e.g., anaphylaxis, angioedema) reported.¹ Immediate medical intervention and discontinuance for anaphylaxis.¹

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.¹ ²

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.¹²⁰¹ Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).¹²⁰¹ Symptoms may resemble those of acute viral infection.¹²⁰¹ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹²⁰¹ If signs or symptoms of DRESS develop, discontinue ketorolac and immediately evaluate the patient.¹²⁰¹

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.¹ ⁹¹ ¹⁹⁸ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).¹⁹⁸

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.¹ ¹⁹⁸

Elevations in ALT or AST reported.¹ ⁹¹

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.¹⁹⁸ Discontinue ketorolac if associated with abnormal liver function test results.¹

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.¹²⁰¹

May mask certain signs of infection or other disease.¹³⁸

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.¹²⁰⁰ ¹²⁰¹

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.¹²⁰²

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.¹²⁰⁰ ¹²⁰¹ (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.¹²⁰⁰ ¹²⁰¹ Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.¹²⁰⁰ ¹²⁰¹ Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.¹²⁰⁰ ¹²⁰¹ In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.¹²⁰⁰ ¹²⁰¹ Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).¹²⁰⁰ ¹²⁰¹ Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.¹²⁰¹ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹²⁰¹

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.¹²⁰¹ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.¹²⁰¹

In animal studies, ketorolac delayed parturition and increased incidence of dystocia.¹ ⁹¹ Animal studies conducted during organogenesis revealed no evidence of fetal harm.¹ ⁹¹ ⁹²

Ketorolac may adversely affect fetal circulation and inhibit uterine contractions during labor and delivery, increasing risk of uterine hemorrhage.¹ (See Contraindications under Cautions.)

Lactation

May be distributed into milk in small amounts.²⁰⁸

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for ketorolac and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.²⁰⁸

Although no specific adverse events reported in nursing infants, exercise caution and advise women to contact their infant's clinician if they observe any adverse events.²⁰⁸

Fertility

NSAIAs may be associated with reversible infertility in some women.²⁰⁸ Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.²⁰⁸

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.²⁰⁸ ¹²⁰¹

Pediatric Use

Safety and efficacy of ketorolac (oral, parenteral, or intranasal) not established in pediatric patients <17 years of age.²⁰⁷ ²⁰⁸ ¹²⁰¹ Manufacturer states ketorolac nasal spray should not be used in pediatric patients <2 years of age.²⁰⁸

Meta-analysis of data from 13 randomized controlled trials that compared postoperative analgesic efficacy of ketorolac (any dosage and any route of administration) with that of placebo or another active treatment following any type of surgery in pediatric patients up to 18 years of age indicated that available data were inadequate to determine efficacy or assess safety in this population.²¹¹

Bleeding reported following tonsillectomy.¹ ¹⁷⁴ ¹⁹⁶ ¹⁹⁷ (See Hematologic Effects under Cautions.)

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects.²⁰⁸ Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.¹ Incidence and severity of GI complications increase with increasing dose and duration of therapy.¹ ¹⁵⁴

Substantially excreted by the kidneys; risk of adverse effects may be greater in patients with impaired renal function; because geriatric patients are more likely to have decreased renal function, consider monitoring renal function.²⁰⁸

Extreme caution and careful clinical monitoring advised.¹⁵⁴ ¹⁷¹ ¹²⁰¹ If anticipated benefits outweigh potential risks, initiate ketorolac at lower end of dosing range;¹⁵⁴ ²⁰⁸ ¹²⁰¹ adjust dose and frequency of administration based on response to initial therapy.²⁰⁸ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Severe hepatic reactions possible.¹ Use with caution in patients with hepatic impairment or a history of liver disease.¹ ⁹¹ ⁹² ¹⁵⁴ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with renal impairment or a history of kidney disease since ketorolac is a potent inhibitor of prostaglandin synthesis and the drug and its metabolites are excreted principally by the kidneys; monitor closely.¹ ⁹¹ ⁹² ¹⁵⁴ ¹²⁰¹ (See Contraindications under Cautions.)

Clearance may be decreased.¹ Dosage adjustment necessary in patients with moderately elevated S_cr.¹ (See Renal Impairment under Dosage and Administration.)

Patients with underlying renal insufficiency are at risk of developing acute renal failure; consider risks and benefits before instituting therapy in these patients.¹ ¹⁵⁴

Common Adverse Effects

Oral or parenteral: Headache,¹ ²³ ⁷⁰ ⁹¹ ³⁴ somnolence or drowsiness,¹ ²³ ⁴⁷ ⁵⁰ ⁵¹ ⁵³ ⁶¹ ⁷⁰ ⁹¹ ¹³⁴ ¹⁴⁰ dizziness,¹ ²³ ⁵⁰ ⁵³ ⁷⁰ ⁹¹ dyspepsia,¹ ⁵⁰ ⁷⁰ ⁹¹ ¹⁴⁰ nausea,¹ ²³ ⁴⁷ ⁵⁰ ⁵¹ ⁵³ ⁷⁰ ⁹¹ ¹³⁴ ¹⁴⁰ GI pain, ¹ ⁵³ ¹⁴⁰ diarrhea,¹ ⁹¹ ¹⁴⁰ edema.¹

Intranasal: Nasal discomfort, rhinalgia, increased lacrimation, throat irritation, oliguria, rash, bradycardia, decreased urine output, increased ALT and/or AST concentration, hypertension, rhinitis.²⁰⁸

Drug Interactions

Does not induce or inhibit hepatic enzymes involved in drug metabolism; unlikely to alter its own metabolism of that or other drugs metabolized by CYP isoenzymes.¹

Protein-bound Drugs

Could be displaced from binding sites by, or could displace from binding sites, some other protein-bound drugs.¹ ⁹¹

Drugs Affecting Hemostasis

Possible increased risk of bleeding complications;¹ carefully monitor patients receiving therapy that affects hemostasis.¹ ⁹¹ ¹⁴⁵ ¹⁵⁴

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Reduced BP response to ACE inhibitor¹⁹⁸ ²⁰⁷ ²⁰⁸ Possible reversible deterioration of renal function, including acute renal failure, in geriatric patients or patients with volume depletion or renal impairment²⁰⁸	Monitor BP¹⁹⁸ ²⁰⁸ Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter²⁰⁸ Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function²⁰⁸
Acetaminophen	No alteration in the protein binding of ketorolac¹ ⁹¹
Angiotensin II receptor antagonists	Reduced BP response to angiotensin II receptor antagonist²⁰⁵ ²⁰⁷ ²⁰⁸ Possible reversible deterioration of renal function, including acute renal failure, in geriatric patients or patients with volume depletion or renal impairment²⁰⁵ ²⁰⁸	Monitor BP²⁰⁵ ²⁰⁸ Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter²⁰⁸ Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function²⁰⁸
Antacids	No effect on the extent of oral ketorolac absorption¹
Anticonvulsants	Seizures reported in patients receiving carbamazepine or phenytoin¹ Phenytoin does not alter the protein binding of ketorolac¹ ⁹¹
β-Adrenergic blocking agents	Reduced BP response to β-blocker²⁰⁷ ²⁰⁸	Monitor BP²⁰⁸
Cyclosporine	Possible increased cyclosporine-associated nephrotoxicity²⁰⁸	Monitor for worsening renal function²⁰⁸
Dextrans	Possible increased risk of bleeding¹	Carefully monitor patients¹ ⁹¹ ¹⁴⁵ ¹⁵⁴
Digoxin	Increased digoxin serum concentrations and prolonged half-life reported²⁰⁸ No alteration in the protein binding of either drug¹ ⁹¹ ¹⁴⁰	Monitor serum digoxin concentrations²⁰⁸
Diuretics (furosemide, thiazides)	Reduced natriuretic effect¹ ¹⁰⁴ ¹⁹⁸ Possible increased risk of renal failure due to decreased renal blood flow resulting from prostaglandin inhibition¹	Monitor for worsening renal function and for adequacy of diuretic and antihypertensive effects²⁰⁸
Fluticasone, intranasal	Intranasal ketorolac: No change in rate or extent of ketorolac absorption in individuals with symptomatic allergic rhinitis²⁰⁸
Heparin	Increased risk of bleeding complications¹ Increased bleeding time when administered with heparin 5000 units; concurrent use with heparin 2500–5000 units sub-Q every 12 hours not studied extensively¹	Extreme caution advised in patients receiving therapeutic doses of heparin;¹ ⁹¹ ¹⁴⁵ ¹⁵⁴ carefully monitor patients¹ ⁹¹ ¹⁴⁵ ¹⁵⁴
Lithium	Increased plasma lithium concentrations¹ ¹⁵⁷ ¹⁵⁸	Monitor for lithium toxicity¹ ¹⁵⁸
Methotrexate	Increased plasma methotrexate concentrations in patients receiving other NSAIAs; studies with ketorolac have not been undertaken¹	Monitor for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction)²⁰⁸
Nondepolarizing skeletal muscle relaxants	May potentiate the effects of the muscle relaxant resulting in apnea¹	Monitor for apnea²⁰⁸
NSAIAs	Concomitant NSAIAs and aspirin (analgesic dosages): Therapeutic effect not greater than that of NSAIAs alone;²⁰⁸ increased risk for bleeding and serious GI events¹⁹⁸ ²⁰⁸ Aspirin: No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs¹⁹⁸ ⁵⁰² ⁵⁰⁸ Therapeutic anti-inflammatory concentrations of salicylates (300 mcg/mL) may displace ketorolac from binding sites; ibuprofen, naproxen, or piroxicam does not alter the protein binding of ketorolac¹ ⁹¹ Protein binding of NSAIAs reduced by aspirin, but clearance of unbound NSAIA not altered; clinical importance unknown²⁰⁸	Concomitant use of ketorolac and analgesic dosages of aspirin generally not recommended;²⁰⁸ manufacturers of oral and parenteral ketorolac state concomitant use with aspirin or other NSAIAs is contraindicated²⁰⁷ ¹²⁰¹ Advise patients receiving ketorolac not to take low-dose aspirin without consulting clinician;¹⁹⁸ ²⁰⁸ closely monitor patients receiving concomitant antiplatelet agents, including aspirin, for bleeding²⁰⁸
Oxymetazoline, intranasal	Intranasal ketorolac: No change in rate or extent of ketorolac absorption in individuals with symptomatic allergic rhinitis²⁰⁸
Pemetrexed	Possible increased risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity²⁰⁸	Short half-life NSAIAs (e. g., diclofenac, indomethacin): Avoid beginning 2 days before and continuing through 2 days after pemetrexed administration²⁰⁸ Longer half-life NSAIAs (e.g., meloxicam, nabumetone): In the absence of data, avoid beginning at least 5 days before and continuing through 2 days after pemetrexed administration²⁰⁸ Patients with Cl_cr 45–79 mL/minute: Monitor for myelosuppression, renal toxicity, and GI toxicity²⁰⁸
Pentoxifylline	Increased risk of bleeding²⁰⁷ ²⁰⁸ ¹²⁰¹	Concomitant use contraindicated²⁰⁷ ²⁰⁸ ¹²⁰¹
Probenecid	Increased plasma concentrations and AUC of ketorolac¹	Concomitant use contraindicated¹ ¹⁵⁴
Psychotherapeutic agents (e.g., fluoxetine, thiothixene, alprazolam)	Hallucinations reported¹	Monitor for hallucinations²⁰⁸
Serotonin-reuptake Inhibitors (e.g., SSRIs, SNRIs)	Possible increased risk of bleeding due to importance of serotonin release by platelets in hemostasis²⁰⁸	Monitor for bleeding²⁰⁸
Thrombolytic agents	Possible increased risk of bleeding¹	Carefully monitor patients¹ ⁹¹ ¹⁴⁵ ¹⁵⁴
Tolbutamide	No alteration in the protein binding of ketorolac¹ ⁹¹
Warfarin	Increased risk of bleeding complications;¹ concurrent use not studied extensively¹ Possible slight displacement of warfarin (but not ketorolac) from binding sites;¹ ⁹¹ other pharmacokinetic interactions unlikely¹	Extreme caution advised in patients receiving therapeutic doses of warfarin;¹ ⁹¹ ¹⁴⁵ ¹⁵⁴ carefully monitor patients¹ ⁹¹ ¹⁴⁵ ¹⁵⁴

Ketorolac Pharmacokinetics

Absorption

Bioavailability

IM: Rapidly and completely absorbed.¹ ² ³⁶ ³⁷ ³⁸ ¹⁴⁰ ¹⁷³

Oral: Rapidly and almost completed absorbed; ¹ ² ³⁶ ³⁷ ³⁸ ⁷⁰ ⁹⁵ ¹⁷³ bioavailability reported to be 80–100%.¹ ² ³⁶ ³⁷ ³⁸ ⁷⁰ ⁹⁵ ¹⁷³

Intranasal: Bioavailability approximately 60% compared with IM injection.²⁰⁸ Peak concentrations achieved at about 45 minutes.²⁰⁸ Presence of allergic rhinitis does not substantially alter pharmacokinetics.²⁰⁸

Onset

IM administration: Onset in 10 minutes, with peak analgesia at 75–150 minutes.¹ ⁴⁷ ⁵⁰ ⁵¹ ⁵³

Oral administration: Onset in 30–60 minutes, with peak analgesia at 1.5–4 hours.⁵⁵ ⁵⁶ ⁵⁷ ⁵⁸ ⁵⁹ ⁶⁰ ⁶¹ ¹³⁷ ¹³⁸

Duration

Oral or IM administration: 6–8 hours.⁴⁷ ⁵⁰ ⁵¹ ⁵³ ⁵⁵ ⁵⁶ ⁵⁷ ⁵⁸ ⁵⁹ ⁶⁰ ⁶¹ ¹³⁷ ¹³⁸

Food

Food decreases rate but not extent of absorption.¹ ² ⁷⁰ ⁸³

Special Populations

Rate of absorption from GI tract may be decreased in patients with hepatic⁴³ ⁷⁰ or renal⁴⁴ ⁷⁰ impairment and in geriatric individuals.⁴³ ⁷⁰

Distribution

Extent

Not distributed widely.¹ ² ³⁷ ⁷⁰ ¹⁴⁰ Crosses the blood-brain barrier poorly.¹ ⁹¹

Crosses the placenta;¹ ² ⁴¹ ⁶⁵ ⁹¹ ¹⁷³ distributed into milk.¹ ⁴⁰ ⁷⁰ ⁹¹ ⁹²

Intranasal: Most of dose is deposited in nasal cavity and pharynx; <20% is deposited in esophagus and stomach, and <0.5% is deposited in lungs.²⁰⁸

Plasma Protein Binding

>99%.¹ ² ³⁷ ³⁸ ⁷⁰

Elimination

Metabolism

Metabolized in the liver by hydroxylation; ¹ ⁹¹ also undergoes conjugation with glucuronic acid.¹ ³⁷ ³⁸ ¹⁷³

Elimination Route

Excreted in urine (92%) as parent drug (60%) or metabolites (40%) and in feces (6%).¹ ³⁸ ⁷⁰ ¹⁷³

Half-life

4–6 hours in adults;¹ ² ³⁶ ³⁷ ³⁸ ⁷⁰ ⁸⁰ ⁹¹ ⁹⁷ ¹⁴⁰ ¹⁷³ ²⁰⁸ 3.8–6.1 hours in pediatric patients.¹ ¹⁷³ ¹⁹⁷

Special Populations

Hepatic impairment (e.g., cirrhosis) does not appear to substantially affect half-life.¹ ² ⁴³ ¹⁷³ In patients with cirrhosis, half-life of about 4.5–5.4 hours reported.¹ ⁴³ ⁹¹ ¹⁷³

Renal impairment: Half-life is about 9–10 hours (range: 3.2–19 hours);¹ ² ⁴⁴ ⁹¹ ¹⁷³ in patients undergoing dialysis, half-life of about 13.6 hours (range: 8–39.1 hours) reported.¹

Geriatric individuals: Half-life is about 5–7 hours (range: 4.3–8.6 hours).¹ ² ⁴² ⁷⁰ ⁸⁰ ⁹¹ ¹⁷³

Stability

Storage

Nasal

Solution

Unopened: 2–8°C; protect from light and freezing.²⁰⁸ During use: 15–20°C out of direct sunlight.²⁰⁸ Discard within 24 hours after priming the spray pump.²⁰⁸

Oral

Tablets

15–30°C.¹

Parenteral

Injection

15–30°C; protect from light.¹

Compatibility

Parenteral

Solution Compatibility212

Compatible
Dextrose 5% in sodium chloride 0.9%
Dextrose 5% in water
Plasma-Lyte A, pH 7.4
Ringer’s injection
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility

Syringe Compatibility1212
Incompatible
Cyclizine lactate
Haloperidol lactate
Hydroxyzine HCl
Meperidine HCl
Morphine Sulfate
Nalbuphine
Prochlorperazine edisylate
Promethazine HCl
Variable
Diazepam
Hydromorphone HCl

Ketorolac tromethamine 1 mg/mL tested.²¹²

Y-Site Compatibility212
Compatible
Acetaminophen
Dexmedetomidine HCl
Fentanyl citrate
Hetastarch in lactated electrolyte injection (Hextend)
Hydromorphone HCl
Methadone HCl
Morphine sulfate
Remifentanil HCl

Incompatible
Azithromycin
Fenoldopam mesylate
Variable
Cisatracurium besylate

Actions

Inhibits cyclooxygenase-1 (COX-1) and COX-2.⁹¹
Pharmacologic actions similar to those of other prototypical NSAIAs; ² ²¹ ³² ³³ ⁹¹ exhibits anti-inflammatory, analgesic, and antipyretic activity.¹ ² ²¹ ³² ³³ ⁷⁰ ⁹¹ ¹⁴⁰

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.¹⁹⁸
Risk of serious cardiovascular events (e.g., MI, stroke).¹⁹⁸ ⁵⁰⁰ ⁵⁰⁸ Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (e.g., chest pain, dyspnea, weakness, slurred speech) occur.¹⁹⁸ ⁵⁰⁰ ⁵⁰⁸
Risk of GI bleeding and ulceration.¹ ¹⁶⁷ ¹⁸¹ Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding develop.¹
Risk of bleeding following tonsillectomy.¹
Risk of serious skin reactions,¹⁹⁸ DRESS,¹²⁰¹ and anaphylactic and other sensitivity reactions.¹ Advise patients to stop taking ketorolac immediately if they develop any type of rash or fever and to promptly contact their clinician.¹²⁰¹ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.¹
Risk of hepatotoxicity.¹ Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.¹⁹⁸
Risk of kidney failure.¹
Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.⁵⁰⁸
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.¹²⁰⁰ ¹²⁰¹
Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.²⁰⁸
Importance of not exceeding recommended duration of therapy.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹
Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ketorolac Tromethamine
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Nasal	Solution	15.75 mg/metered spray	Sprix	Zyla
Oral	Tablets, film-coated	10 mg*	Ketorolac Tromethamine Tablets
Parenteral	Injection, for IM or IV use	15 mg/mL*	Ketorolac Tromethamine Injection
		30 mg/mL*	Ketorolac Tromethamine Injection
	Injection, for IM use	30 mg/mL*	Ketorolac Tromethamine Injection

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