Ketorolac (Toradol) is a non-selective COX inhibitor that is available as tablets and injections for the treatment of pain, fever, and inflammation.

Ketorolac (Toradol) Uses:

• Acute moderately severe pain:

  • Short-term (≤5 days) management of moderate to severe acute pain

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Ketorolac (Toradol) Dose in Adults:

Ketorolac (Toradol) Dose in acute moderately severe pain in patients ≥50 kg:

Note:

• • The maximum combined duration of treatment (for parenteral & oral) is 5 days
  • Dose or frequency should not be increased.
  • For breakthrough pain supplement with low-dose opioids, if needed.
  • Do not give oral formulation as an initial dose.
• IM:
  • 60 mg as a single dose or 30 mg QID
  • Alternatively, an initial dose of 10 to 30 mg (stat dose) &then every 4 to 6 hours as needed has been recommended.
  • Maximum dose: 120 mg/day
• IV:
  • 30 mg as a single dose or 30 mg QID (maximum: 120 mg/day)

• 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

Patient population-specific Ketorolac dosing:

• Critically ill patients (off-label dose):

  • IM, IV: 30 mg stat dose, followed by 15 to 30 mg QID for up to 5 days (maximum: 120 mg/day).

• Perioperative patients (off-label dose):

  • IV:
  • Note:
    • Employ a multimodal perioperative pain management strategy.
    • Maximum daily dose: 120 mg/day.
    • Perioperative dosing strategies described in the literature have included a bolus dose of 10 to 30 mg, followed by a continuous infusion of 2 to 5 mg/hour for 24 hours.

• Dosage adjustment for low body weight (<50 kg):

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.
• Do not give oral formulation as an initial dose.
  • IM: 30 mg as a stat dose or 15 mg QID (maximum: 60 mg/day)
  • IV: 15 mg as a stat dose or 15 mg QID (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.

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Ketorolac (Toradol) Dose in Childrens:

Note:

• Use the lowest effective dose for the shortest period of time to reduce the risk of adverse cardiovascular and GI effects.

Ketorolac (Toradol) Dose in the treatment of acute moderately severe pain:

• Infants and Children <2 years: Limited data available:

  • Multiple-dose treatment:

    • 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.

• Children ≥2 years and Adolescents ≤16 years: Limited data available:

  • IM, IV:

    • 0.5 mg/kg/dose QID
    • Maximum dose: 30 mg/dose, the usual reported duration: 48 to 72 hours; not to exceed 5 days of treatment.

  • Oral:

    • 1 mg/kg as a stat dose
    • Maximum dose: 10 mg/dose has been reported in children preoperatively (eg, bilateral myringotomy).

• Adolescents ≥17 years:

Note:

• The maximum combined duration of treatment (for parenteral and oral) is 5 days
• Dose or frequency should not be increased
• Supplement with low-dose opioids if needed for breakthrough pain.

  • <50 kg:

    • IM: 30 mg as a stat dose or 15 mg QID with a maximum daily dose of 60 mg/day.
    • IV: 15 mg as a stat dose or 15 mg QID with a maximum daily dose of 60 mg/day.
    • Oral: Initial: 10 mg, then 10 mg every 4 to 6 hours and a  maximum daily dose of 40 mg/day.

  • ≥50 kg:

    • IM: 60 mg as a stat dose or 30 mg QID with a maximum daily dose of 120 mg/day.
    • IV: 30 mg as a stat dose or 30 mg QID with a maximum daily dose of 120 mg/day.
    • Oral: Initial: 20 mg, then 10 mg every 4 to 6 hours, and a maximum daily dose of 40 mg/day.

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Ketorolac (Toradol) Pregnancy Risk Factor C

• [US Boxed Warning]
  • Pregnancy and delivery are not recommended. It may inhibit uterine contractions, and negatively affect fetal circulation.
• Ketorolac crosses over the placenta.
• Some studies have shown that birth defects can be caused by in utero NSAID use. However, the data is inconsistent.
• Following in utero NSAID administration, nonteratogenic effects such as prenatal constriction, persistent pulmonary hypertension, oligohydramnios and necrotizing enterocolitis have been seen in the fetus/neonate.
• Avoid using NSAIDs during pregnancy as they can cause premature closure of ductus arteriosus.
• After cesarean delivery, NSAIDs can be used in multimodal pain management.
• Consider your breastfeeding status before you use a particular agent.
• Women of reproductive age who have been using NSAIDs for a long time may experience infertility. This can be reversed by stopping the medication.
• Women who are having trouble conceiving or who are undergoing fertility treatment should stop using this medication.
• There is a higher chance of miscarriage if you use NSAIDs near your conception.

Ketorolac use during breastfeeding:

• Breast milk contains Ketorolac.
• The relative infant dose (RID), of ketorolac, is 0.2% when it is calculated from the highest breastmilk concentration and compared to a maternal weight-adjusted dose of 40 mg/day.
• When the RID is less than 10%, breastfeeding is considered acceptable.
• The highest possible milk concentration (7.9ng/mL) is used to estimate the daily infant dose via breastmilk at 1.185 mg/kg/day.
• This was achieved by maternal administration of oral ketorolac QID 10 mg for 2 days to women who gave birth between 2 and 6 days after giving birth.
• NSAIDs can be used by postpartum mothers who want to breastfeed. However, if a mother has platelet dysfunction or thrombocytopenia, they should avoid using ketorolac.
• If breastfeeding women are being given the medication, it is important to be cautious.

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Ketorolac (Toradol) Dose in Kidney Disease:

• Dosage adjustment recommendations:

  • Manufacturer’s labeling:

    • Renally impaired patients:

Note:

• The specific degree of renal impairment where use is permitted is not defined in the product labeling.
• However, it is contraindicated in patients with advanced renal impairment or those at risk for renal failure due to volume depletion.
  • • • IM: 30 mg as a stat dose or 15 mg QID (maximum: 60 mg/day)
      • IV: 15 mg as a stat dose or 15 mg QID (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
    • Use is contraindicated in advanced impairment or patients at risk for renal failure due to volume depletion.

  • Alternative recommendations:

    • GFR >50 mL/minute/1.73 m :
      • 15 to 30 mg IM or IV QID
    • GFR 10 to 50 mL/minute/1.73 m :
      • Preferably avoid or administer 7.5 to 15 mg IM or IV QID
    • GFR <10 mL/minute/1.73 m :
      • Preferably avoid
    • Hemodialysis:
      • Preferably avoid
    • CAPD:
      • Preferably avoid
    • CRRT:
      • 5 to 15 mg IM or IV QID

Ketorolac (Toradol) Dose in Liver disease:

• No dosage adjustments provided in the manufacturer's labeling.
• Use cautiously, may cause elevation of liver enzymes.
• Discontinue if clinical signs and symptoms of liver disease develop.

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Frequencies noted for parenteral administration:

Common Side Effects of Ketorolac (Toradol):

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Gastrointestinal pain
  • Dyspepsia
  • Nausea

Less Common Side Effects of Ketorolac (Toradol):

• Cardiovascular:

  • Edema
  • Hypertension

• Central Nervous System:

  • Dizziness
  • Drowsiness

• Dermatologic:

  • Diaphoresis
  • Pruritus
  • Skin Rash

• Gastrointestinal:

  • Diarrhea
  • 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

• Otic:

  • Tinnitus

• Renal:

  • Renal Function Abnormality

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Contraindications to Ketorolac (Toradol):

• Hypersensitivity to aspirin, ketorolac, and other NSAIDs or any component of this formulation
• Peptic ulcer disease: History or active
• Perforation or GI bleeding in the past or recent
• History of asthma, urticaria or allergic-type reactions following aspirin use or any other NSAIDs
• Patients at high risk of developing advanced renal disease or renal failure from volume depletion
• Before any major surgery, prophylactic analgesia
• High risk of bleeding: Suspected or confirmed hemorhagic diathesis or hemorhagic bleeding.
• Use aspirin, NSAIDs, pentoxifylline, and probenecid concurrently
• Injections only, or intramuscular administration
• Use for the placement of coronary bypass graft surgery (CABG).
• Delivery and labor

Canadian labeling: Additional contraindications:

• Intraoperative use
• Coagulation disorders
• Active GI bleeding
• Patients with high-bleeding risks after surgery
• Uncontrolled severe heart failure
• Inflammatory bowel disease
• Active hepatic disease or severe hepatic impairment
• Moderate to severe renal impairment (serum creatinine >442 micromol/L, and/or creatinine clearance = 30 mg/minute) or deteriorating kidney disease
• Hyperkalemia is a well-known condition
• The third trimester is the most important.
• Breastfeeding
• Use in children and adolescents under 18 years old

Warnings and precautions

• Bleeding and hematologic reactions: [US Boxed Warn]

  • Platelet function is inhibited
  • Patients with suspected or confirmed cerebrovascular bleeding, hemorhagic diathesis and patients at high-risk for bleeding are not recommended to use this medication.
  • The possibility of platelet adhesion or aggregation being reduced and bleeding time being prolonged may be possible.
  • Patients with coagulation problems or those who are taking anticoagulants need to be closely monitored.
  • Anemia may occur.
  • Anemia should be checked in patients on long-term nonsteroidal, anti-inflammatory drug (NSAID), therapy.
  • Rarely, NSAIDs have been linked to potentially severe blood disorders (eg, agranulocytosis or thrombocytopenia and anemia).

• Cardiovascular events: [US Boxed Warn]

  • The increased risk of severe (and possibly fatal) adverse cardiovascular events due to NSAIDs, such as stroke and MI, can be caused by NSAIDs.
  • This risk can occur during treatment and may increase as the duration of use is prolonged.
  • The relative risk of developing cardiovascular disease is similar for those with and without known risk factors.
  • Patients with known cardiovascular disease and risk factors were more likely to experience serious cardiovascular thrombotic episodes (which can occur earlier during treatment).
  • Exacerbation or new-onset hypertension can occur. NSAIDs could also affect the response to ACE inhibitors, thiazide or loop diuretics; may cause cardiovascular events. Monitor BP.
  • Patients with edema may experience sodium and fluid retention.
  • Avoid heart failure
  • Patients with a recent MI should not have any treatment unless the benefits are greater than the risk of developing cardiovascular thrombotic complications.
  • For patients at high risk, it is best to reduce the effective dose and use it for the shortest time possible. Alternate therapies should also be considered.

• CNS effects

  • This can cause blurred vision, drowsiness, dizziness and other neurologic effects that may lead to impairment of mental or physical abilities.
  • It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.

• GI events: [US Boxed Warning]

  • NSAIDs can increase the risk of severe GI inflammation, bleeding, ulceration, and perforation (may even be fatal).
  • Patients with a history peptic ulcer disease or GI bleeding, as well as patients over 65 years old, are more at risk for serious GI events.
  • These events can occur without warning and at any time during therapy.
  • Patients with active GI bleeding should be avoided
  • Avoid non-aspirin NSAIDs in patients who have had a history or experience of severe lower GI bleeding.
  • Use cautiously in patients 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.
  • To reduce the risk of GI adverse reactions, use the lowest effective dose for the shortest time. Consider alternative therapies for high-risk patients.
  • When concomitantly used with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended.

• Hepatic effects

  • Use has been associated with transaminase elevations. It is therefore recommended that patients suffering from abnormal LFT be closely monitored.
  • Rare but sometimes fatal hepatic reactions have been linked to the use of NSAIDs.
  • If you notice any signs or symptoms of hepatic diseases, or if there are systemic manifestations, stop taking the medication immediately.

• Hyperkalemia:

  • NSAIDs may increase hyperkalemia risk, especially in elderly patients, those with diabetes and renal disease.
  • Potassium should always be monitored closely

• Hypersensitivity reactions: [US Boxed Warning]

  • Patients with a history of hypersensitivity to aspirin and NSAIDs are not advised to receive Ketorolac injection.
  • Patients may experience hypersensitivity even if they have never been exposed to the drug. Patients with the "aspirin trifecta" (bronchial asthma and aspirin intolerance, rhinitis, or both) could be at greater risk.
  • Patients who have rhinitis or NSAID therapy and bronchospasm are not recommended to use this medication.

• Effects on the renal system:

  • NSAIDs can cause kidney damage. Dose-dependent decreases of prostaglandin synthesis could be caused by NSAIDs, which reduce renal blood flow.
  • This may lead to renal decompensation, usually reversible.
  • Patients with impaired renal function, hypovolemia and heart failure, as well as those who take diuretics or ACE inhibitors, are at greater risk for renal toxicity.
  • Before starting treatment, patients should be properly hydrated.
  • Pay attention to your renal function.
  • The use of ketorolac has been associated with acute renal failure, interstitial and nephritis, as well as nephrotic syndrome.
  • Long-term use of NSAIDs has been associated with renal injury and papillary necrosis.

• Reactions to skin:

  • NSAIDs can cause severe skin adverse reactions that could prove fatal, including exfoliative dermatitis (SJS), Stevens-Johnson syndrome and toxic epidermal necrolysis.
  • It may happen without notice.
  • Stop using it immediately if you notice any skin rash or hypersensitivity.

• Aseptic meningitis

  • Aseptic meningitis can be more common in patients with SLE (systemic lupus, erythematosus) and mixed connective tissue disorders.

• Asthma

  • Patients with asthma that is aspirin-sensitive should not use this product. Bronchospasm can be severe and potentially fatal.
  • Patients with other forms or asthma should be cautious.

• Bariatric surgery

  • Gastric ulceration: Use of oral nonselective NSAIDs after bariatric surgery should be avoided; it may result in the development of anastomotic ulcerations/perforations.
  • As part of a multimodal pain management strategy, short-term celecoxib and IV ketorolac are recommended.

• Coronary artery bypass surgery or major surgery: [US-Boxed Warning]

  • It is not recommended to be used as a prophylactic analgesic prior to major surgery or in the setting up of coronary bypass graft surgery (CABG).
  • After CABG surgery, the risk of stroke and MI may increase.
  • Ketorolac usage in the perioperative setting has been linked to wound bleeding and postoperative hemorhages.

• Hepatic impairment

  • Patients with hepatic impairment and a history of the hepatic condition should be cautious. Patients with advanced hepatic diseases are at greater risk of GI bleeding from NSAIDs.

• Renal impairment: [US-Boxed Warning]

  • Patients with advanced renal impairment or patients at high risk of developing renal failure from volume depletion are contraindicated.
  • Patients with a history or renal impairment should be cautious.
  • Patients with moderately elevated serum creatinine levels will need to adjust their dosage.

Ketorolac (ophthalmic): Drug Interaction

Risk Factor C (Monitor therapy)
Corticosteroids (Ophthalmic)	Nonsteroidal Anti-Inflammatory Agents (Ophthalmic) may enhance the adverse/toxic effect of Corticosteroids (Ophthalmic). Healing of ophthalmic tissue during concomitant administration of ophthalmic products may be delayed. Exceptions: Loteprednol.
Prostaglandins (Ophthalmic)	Nonsteroidal Anti-Inflammatory Agents (Ophthalmic) may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents (Ophthalmic) may enhance the therapeutic effect of Prostaglandins (Ophthalmic).

 

Monitoring parameters:

• Monitor response (pain, range of motion, grip strength, mobility, ADL function), inflammation
• Observe for weight gain
• Edema
• Monitor Kidney function (serum creatinine, BUN, urine output)
• CBC &platelets
• Liver function tests
• Chemistry profile
• Blood pressure
• Observe for bleeding, bruising
• Evaluate gastrointestinal effects (abdominal pain, bleeding, dyspepsia)
• Mental confusion & disorientation

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How to administer Ketorolac (Toradol)?

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.
• The use of a continuous infusion (off-label) has been described in the perioperative setting.

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Mechanism of action of Ketorolac (Toradol):

• Reversible inhibition of cyclooxygenase-1 (COX-1) enzymes results in decreased production of prostaglandin precursors.
• 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, & decreasing proinflammatory cytokine levels.

The onset of action:

• Analgesic:
  • Oral: 30 to 60 minutes
  • IM, IV: ~30 minutes

Peak effect:

• Analgesic:
  • Oral: 2 to 3 hours
  • IM, IV: ≤2 to 3 hours

Duration:

• Analgesic: 4 to 6 hours

Absorption:

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

Distribution:

• Poor penetration into CSF

Protein binding:

• 99%

Metabolism:

• Hepatic; undergoes hydroxylation and glucuronide conjugation; in children 4 to 8 years, V and plasma clearance was twice as high as adults

Bioavailability:

• Oral, IM: 100%

Half-life elimination:

• Infants 6 to 18 months of age (n=25): S-enantiomer: 0.83 ± 0.7 hours; R-enantiomer: 4 ± 0.8 hours (Lynn 2007)
• Children:
  • • 1 to 16 years (n=36): Mean: 3 ± 1.1 hours (Dsida 2002)
    • 3 to 18 years (n=24): Mean: 3.8 ± 2.6 hours
    • 4 to 8 years (n=10): Mean: ~6 hours; Range: 3.5 to 10 hours
• Adults:
  • Mean:
    • ~5 hours
    • Range: 2 to 9 hours [S-enantiomer ~2.5 hours (biologically active)
    • Renantiomer ~5 hours]
    • Prolonged 30% to 50% in elderly
  • With renal impairment: S 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 60 minutes
• IV: 1 to 3 minutes

Excretion:

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

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International Brands of Ketorolac:

• ReadySharp Ketorolac
• ALTI-Ketorolac
• APO-Ketorolac
• Mar-Ketorolac
• MINT-Ketorolac
• Toradol
• Acuvail
• Adolor
• Altrom
• Analac
• Arolak
• Arvolac
• Bedoral
• Dilox
• Dolac
• Dolorex
• Dolorex Gel
• Dolten
• Eleadol
• Erphapain
• Eurolac
• Fam
• Farpain
• Inco
• Kelac
• Kenalgesic
• Keromin
• Ketanov
• Keto
• Ketobet
• Ketogesic
• Ketolac
• Ketolong
• Ketomed
• Ketoracin
• Ketoral
• Ketoro
• Ketorol
• Ketron
• Kine
• Korac
• Kortezor
• Minolac
• Ni Song
• Nomadol
• Notolac
• Ocudol
• Oradol
• Painoff
• Poenkerat
• Remopain
• Rolac
• Rolesen
• Scelto
• Supradol
• Tabel
• Taradyl
• Teromac
• Tora-Dol
• Toradol
• Toramed
• Toramine
• Torpain
• Tral
• Trolac
• Winop
• Xevolac
• Zerodol

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Ketorolac Brand Names in Pakistan:

Ketorolac Injection 10 mg
Ketrodil	Cirin Pharmaceuticals (Pvt) Ltd.

Ketorolac Injection 30 mg
K-Dol	Akson Pharmaceuticals (Pvt) Ltd.
Ketilac	Wns Field Pharmaceuticals
Ketolac	Nimrall Laboratories
Ketomed	Accurate Medical Suppliers
Ketrodil	Cirin Pharmaceuticals (Pvt) Ltd.
Strolac	Wns Field Pharmaceuticals
Torapan	Caraway Pharmaceuticals
Torolac	Schazoo Zaka

Ketorolac Injection 10 mg/ml
Ketopan	Welwrd Pharmaceuticals
Monak	English Pharmaceuticals Industries
Toradol	Roche Pakistan Ltd.
Trometh	Nexus Pharma (Pvt) Ltd

Ketorolac Injection 30 mg/ml
Ketopan	Welwrd Pharmaceuticals
Monak	English Pharmaceuticals Industries
Toradol	Roche Pakistan Ltd.
Torapan	Glaxosmithkline
Trometh	Nexus Pharma (Pvt) Ltd
Tromit	Standpharm Pakistan (Pvt) Ltd.

Ketorolac Injection IV 10 mg/ml
Toradol	Roche Pakistan Ltd.

Ketorolac Injection IV 30 mg/ml
Toradol	Roche Pakistan Ltd.

Ketorolac Injection IM/IV 30 mg
Toralac	Global Pharmaceuticals

Ketorolac Eye Drops 5 Mg
Torolac	Schazoo Zaka

Ketorolac Tromethamine Eye Drops 0.5 %W/V
Dylac	Azron Pharmaceuticals (Pvt) Ltd
Ketrosan	Sante (Pvt) Limited

Ketorolac Tromethamine Tablets 10 mg
Kelac	Rotex Medica Pakistan (Pvt) Ltd

Ketorolac Tromethamine Tablets 20 mg
Kelac	Rotex Medica Pakistan (Pvt) Ltd