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Ketorolac (Systemic)

Pronunciation

Pronunciation

(KEE toe role ak)

Index Terms

  • Ketorolac Tromethamine
  • Toradol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection, as tromethamine:

Generic: 15 mg/mL (1 mL); 30 mg/mL (1 mL); 60 mg/2 mL (2 mL); 300 mg/10 mL (10 mL [DSC])

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

Pharmacologic Category

  • Analgesic, Nonopioid
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Oral
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Parenteral

Pharmacology

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.

Absorption

Oral: Well absorbed (100%); IM: Rapid and complete

Distribution

Poor penetration into CSF; Vd beta:

Children 4-8 years: 0.19-0.44 L/kg (mean: 0.26 L/kg)

Adults: 0.11-0.33 L/kg (mean: 0.18 L/kg)

Metabolism

Hepatic; undergoes hydroxylation and glucuronide conjugation; in children 4-8 years, Vdss and plasma clearance were twice as high as adults

Excretion

Urine (92%, ~60% as unchanged drug); feces ~6%

Onset of Action

Analgesic: Oral: 30-60 minutes; IM, IV: ~30 minutes; Peak effect: Analgesic: Oral: 2 to 3 hours; IM, IV: ≤2-3 hours

Time to Peak

Serum: Oral: ~45 minutes; IM: 30-60 minutes; IV: 1-3 minutes

Duration of Action

Analgesic: 4-6 hours

Half-Life Elimination

Infants 6-18 months of age (n=25): S-enantiomer: 0.83 ± 0.7 hours; R-enantiomer: 4 ± 0.8 hours (Lynn 2007)

Children:

1-16 years (n=36): Mean: 3 ± 1.1 hours (Dsida 2002)

3-18 years (n=24): Mean: 3.8 ± 2.6 hours

4-8 years (n=10): Mean: ~6 hours; Range: 3.5-10 hours

Adults:

Mean: ~5 hours; Range: 2-9 hours [S-enantiomer ~2.5 hours (biologically active); R-enantiomer ~5 hours]

With renal impairment: Scr 1.9-5 mg/dL: Mean: ~11 hours; Range: 4-19 hours

Renal dialysis patients: Mean: ~14 hours; Range: 8-40 hours

Protein Binding

99%

Special Populations: Renal Function Impairment

Clearance is reduced and half-life is increased in renal impairment. AUC is increased by ~100% and volume of distribution increases.

Special Populations: Elderly

Half-life is longer in elderly patients.

Use: Labeled Indications

Pain management:

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

Canadian labeling:

Oral: Short-term (≤5 days) management of moderate to moderately severe acute pain following surgery (eg, dental, general, or orthopaedic surgery); short-term (≤7 days) management of moderate to moderately severe acute musculoskeletal pain (eg, pain associated with trauma, post-partum uterine cramping)

Injection: Short-term (≤2 days) management of moderate to severe acute pain following major surgery (eg, major abdominal, orthopaedic, or gynecologic procedures)

Contraindications

Hypersensitivity to ketorolac, aspirin, other NSAIDs, or any component of the formulation; active or history of peptic ulcer disease; recent or history of GI bleeding or perforation; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; advanced renal disease or risk of 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 (CABG) 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; known hyperkalemia; third trimester of pregnancy; breast-feeding; use in children and adolescents <18 years of age

Dosing: Adult

Pain management (acute; moderately severe) in patients ≥50 kg: Note: The maximum combined duration of treatment (for parenteral and oral) is 5 days; do not increase dose or frequency; supplement with low-dose opioids if needed for breakthrough pain. Oral formulation should not be given as an initial dose.

US labeling:

IM: 60 mg as a single dose or 30 mg every 6 hours (maximum: 120 mg/day)

IV: 30 mg as a single dose or 30 mg every 6 hours (maximum: 120 mg/day)

IM, IV: Critically-ill patients (off-label dose): 30 mg once, followed by 15 to 30 mg every 6 hours for up to 5 days (maximum: 120 mg/day) (Barr 2013)

Oral: 20 mg, followed by 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 only

Canadian labeling:

IM: Initial: 10 mg to 30 mg as a single dose and then every 4 to 6 hours as needed (maximum: 120 mg/day) for up to 2 days; lowest effective dose should be utilized

Oral: 10 mg every 4 to 6 hours as needed (maximum: 40 mg/day); therapy should not exceed 5 days for postoperative pain and 7 days for musculoskeletal pain

Conversion from IM to oral: Total combined dose (IM and oral) should not exceed 120 mg/day on the day of conversion; oral dose should not exceed 40 mg/day on subsequent days. When used as a continuation of IM therapy, total duration of therapy (IM and oral) should not exceed 5 days.

Dosage adjustment for low body weight (<50 kg): Refer to geriatric dosing.

Dosing: Geriatric

Pain management (acute; moderately severe): Adults ≥65 years: Note: May have an increased incidence of GI bleeding, ulceration, and perforation. The maximum combined duration of treatment (for parenteral and oral) is 5 days. Oral formulation should not be given as an initial dose.

US labeling:

IM: 30 mg as a single dose or 15 mg every 6 hours (maximum: 60 mg/day)

IV: 15 mg as a single dose or 15 mg every 6 hours (maximum: 60 mg/day)

Oral: 10 mg, followed by 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 only

Canadian labeling:

IM: Initial: 10 mg as a single dose and then the lowest effective dose every 4 to 6 hours as needed; maximum: 60 mg/day

Oral: Refer to adult dosing; lowest effective dose is recommended

Dosing: Pediatric

Pain management (acute; moderately severe): Adolescents ≥17 years: Refer to adult dosing.

Dosing: Renal Impairment

US labeling:

Mild to moderate impairment:

IM: 30 mg as a single dose or 15 mg every 6 hours (maximum: 60 mg/day)

IV: 15 mg as a single dose or 15 mg every 6 hours (maximum: 60 mg/day)

Oral: 10 mg, followed by 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 only

Note: The maximum combined duration of treatment (for parenteral and oral) is 5 days.

Advanced impairment or patients at risk for renal failure due to volume depletion: Use is contraindicated.

Dialysis: Not readily dialyzable due to high protein binding

Canadian labeling:

Serum creatinine: 1.9 mg/dL to 5 mg/dL (170 micromol/L to 442 micromol/L): IM: Reduce dose by 50%; maximum: 60 mg/day. Use with caution and monitor closely.

Serum creatinine: >5 mg/dL (>442 micromol/L): Use is contraindicated.

Note: The maximum combined duration of treatment (for parenteral and oral) is 5 days.

Dosing: Hepatic Impairment

US labeling: 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.

Canadian labeling:

Mild or moderate impairment: No dosage adjustment necessary; use with caution

Severe impairment or active hepatic disease: Use is contraindicated

Administration

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.

Dietary Considerations

Administer tablet with food or milk to decrease gastrointestinal distress.

Compatibility

Stable in D5NS, D5W, LR, NS.

Y-site administration: Incompatible: Azithromycin, fenoldopam, haloperidol.

Compatibility in syringe: Incompatible with haloperidol, hydroxyzine, meperidine, morphine, nalbuphine, prochlorperazine edisylate, promethazine.

Storage

Injection: Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light. Injection is clear and has a slight yellow color. Precipitation may occur at relatively low pH values.

Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light and excessive humidity.

Drug Interactions

5-ASA Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-ASA Derivatives. Monitor therapy

ACE 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 ACE Inhibitors. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. 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. 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. Management: Monitor renal function periodically in patients receiving aliskiren and any nonsteroidal anti-inflammatory agent. Patients at elevated risk of renal dysfunction include those who are elderly, are volume depleted, or have pre-existing renal dysfunction. Monitor therapy

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Monitor therapy

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. 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. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Anticoagulants: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Apixaban: NSAID (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. 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. Avoid combination

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Consider therapy modification

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. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. 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. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of NSAID (Nonselective). 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. Specifically, elevated diclofenac concentrations have been reported. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (e.g., hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: NSAID (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. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. 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. 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. Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Monitor therapy

Drospirenone: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

Edoxaban: NSAID (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. 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. Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Haloperidol: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed. Consider therapy modification

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. 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. Consider therapy modification

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Consider therapy modification

Morniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. 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. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Ketorolac (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Management: Avoid concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pelubiprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

PEMEtrexed: NSAID (Nonselective) may increase the serum concentration of PEMEtrexed. Management: Patients with mild-to-moderate renal insufficiency (estimated creatinine clearance 45-79 mL/min) should avoid NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Consider therapy modification

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. Monitor therapy

Pentoxifylline: Ketorolac (Systemic) may enhance the adverse/toxic effect of Pentoxifylline. Specifically, the risk of bleeding may be increased with this combination. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. 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. 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: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation. Monitor therapy

Probenecid: May increase the serum concentration of Ketorolac (Systemic). Avoid combination

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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). Monitor therapy

Quinolone Antibiotics: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolone Antibiotics. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolone Antibiotics. Monitor therapy

Rivaroxaban: NSAID (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. Consider therapy modification

Salicylates: NSAID (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (Nonselective). Exceptions: Choline Magnesium Trisalicylate. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Monitor therapy

Talniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. 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. Consider therapy modification

Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

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. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): NSAID (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

Frequencies noted for parenteral administration:

>10%:

Central nervous system: Headache (17%)

Gastrointestinal: Gastrointestinal pain (13%), dyspepsia (12%), nausea (12%)

>1% to 10%:

Cardiovascular: Edema (4%), hypertension

Central nervous system: Dizziness (7%), drowsiness (6%)

Dermatologic: Diaphoresis, pruritus, skin rash

Gastrointestinal: Diarrhea (7%), constipation, flatulence, gastrointestinal fullness, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer, heartburn, stomatitis, vomiting

Hematologic & oncologic: Anemia, prolonged bleeding time, purpura

Hepatic: Increased liver enzymes

Local: Pain at injection site (2%)

Otic: Tinnitus

Renal: Renal function abnormality

<1% (Limited to important or life-threatening): Abnormality in thinking, acute pancreatitis, acute renal failure, agranulocytosis, alopecia, anaphylactoid reaction, anaphylaxis, angioedema, aplastic anemia, aseptic meningitis, asthma, azotemia, bradycardia, bronchospasm, bruise, cardiac arrhythmia, cholestatic jaundice, coma, confusion, congestive heart failure, conjunctivitis, cough, cystitis, depression, dysuria, eosinophilia, epistaxis, eructation, erythema multiforme, euphoria, exacerbation of urinary frequency, exfoliative dermatitis, extrapyramidal reaction, flank pain, gastritis, glossitis, hallucination, hearing loss, hematemesis, hematuria, hemolytic anemia, hemolytic-uremic syndrome, hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperglycemia, hyperkalemia, hyperkinesis, hypersensitivity reaction, hyponatremia, hypotension, increased susceptibility to infection, increased thirst, infertility, inflammatory bowel disease, insomnia, interstitial nephritis, jaundice, lack of concentration, laryngeal edema, leukopenia, lymphadenopathy, maculopapular rash, melena, myocardial infarction, nephritis, oliguria, palpitations, pancytopenia, paresthesia, pneumonia, polyuria, proteinuria, psychosis, pulmonary edema, rectal hemorrhage, renal failure, respiratory depression, rhinitis, seizure, sepsis, skin photosensitivity, Stevens-Johnson syndrome, stomatitis (ulcerative), stupor, syncope, tachycardia, thrombocytopenia, tongue edema, toxic epidermal necrolysis, urinary retention, urticaria, vasculitis, weight gain, wound hemorrhage (postoperative)

ALERT: U.S. Boxed Warning

Appropriate use:

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 and only as continuation treatment following intravenous (IV) or intramuscular (IM) dosing of ketorolac, if necessary. The total combined duration of use of ketorolac tablets and injection should not exceed 5 days.

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.

Serious cardiovascular thrombotic events:

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) 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 (CABG) surgery.

Serious gastrointestinal bleeding, ulceration, and perforation:

NSAIDs cause an increased risk of serious gastrointestinal (GI) events, including bleeding, ulceration, and 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.

Intrathecal or epidural administration:

Ketorolac is contraindicated for intrathecal or epidural administration due to its alcohol content.

Hypersensitivity:

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.

Renal risk:

Ketorolac is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion.

Risk of bleeding:

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.

Labor and delivery:

Ketorolac is contraindicated in labor and delivery because it may adversely affect fetal circulation and inhibit uterine contractions.

Concomitant use with NSAIDs:

Ketorolac is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.

Special populations:

Adjust dosage for patients 65 years and older, weighing less than 50 kg (110 lbs), and with moderately elevated serum creatinine. Doses of ketorolac injection are not to exceed 60 mg (total dose per day) in these patients.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: [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 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 (ACCF/AHA [Yancy 2013]). 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).

• Gastrointestinal events: [US Boxed Warning]: NSAIDs cause increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk of serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. 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 gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (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 the elderly, diabetics, 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 the elderly 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 (SJS), and toxic epidermal necrolysis (TEN); 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.

• 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 with NSAIDs.

• 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.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: [US Boxed Warning]: Dosage adjustment is required for patients ≥65 years of age. Elderly patients are at greater risk for serious GI, cardiovascular, and/or renal adverse events; use with caution.

• Labor and delivery: [US Boxed Warning]: Ketorolac is contraindicated during labor and delivery (may inhibit uterine contractions and adversely affect fetal circulation).

• 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. Do not exceed maximum daily recommended doses; does not improve efficacy but may increase the risk of serious adverse effects. The combined therapy duration (oral and parenteral) should not exceed 5 days.

• 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.

Monitoring Parameters

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

Pregnancy Risk Factor

C

Pregnancy Considerations

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

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