Ketorolac

Ketorolac is an Analgesic / Anti-inflammatory belonging to Non-Steroidal anti-inflammatory Drug

Ketorolac is used in the treatment of Pain management. It is also used to treat Migraine, severe, acute treatment

Ketorolac is Well absorbed (oral); rapidly and completely absorbed (IM). Bioavailability: 100% (oral, IM); approx. 60% (nasal; relative to IM route). Decreased peak and delayed time to peak plasma concentrations with high-fat meal (oral). Distributed mainly in the nasal cavity and pharynx following nasal administration, with <2% in the esophagus and stomach and negligible distribution in the lungs (<5%). Crosses the placenta; enters breast milk (small amounts). Volume of distribution: Approx. 13 L (nasal). Plasma protein binding: 99% and get extensively metabolized in the liver via glucuronic acid conjugation and hydroxylation.

and get excreted Via urine (approx 92%; approx 40% as metabolites, approx 60% as unchanged drug); faeces (approx 6%). Elimination half-life: Approx 5 hours; range: 2-9 hours ([-]S-enantiomer: approx 2.5 hours, [+]R-enantiomer: approx 5 hours).The onset of action of Ketorolac was about 2-4.

The Duration of action of Ketorolac was about 4-6 hours.

Ketorolac shows common side effects like Atrial fibrillation, atrial flutter, peripheral edema

Ketorolac is available in Tablet and injection.

Ketorolac is available in India, Germany, Canada, France, USA.

Ketorolac, an NSAID, has analgesic, antipyretic and anti-inflammatory properties. It reduces prostaglandin synthesis by inhibiting cyclooxygenase (COX)-1 and 2. It also stimulates the secretion of β-endorphins by the pituitary hypothalamus, reduces the level of endogenous pyrogens and affects the thermoregulation centre in the hypothalamus.

Synonym: Ketorolac, sulpyrine.

Ketorolac is available in the form of Injection solution, tablets.

Ketorolac is used in the treatment of Pain management. It is also used to treat Migraine, severe, acute treatment.

Indometacin is an indole acetic derivative with analgesic, antipyretic, and anti-inflammatory effects. It reversibly inhibits cyclooxygenase-1 and -2 (COX-1 and -2) isoenzymes, thereby reducing the synthesis of prostaglandins in body tissues.

Synonym: Ketorolac.

Ketorolac is approved for use in the following clinical indications

Pain management, acute: Short-term (≤5 days) management of acute pain.

Although not approved there have been certain off labelled uses documented for Ketorolac which include:

Migraine, severe, acute treatment (off-label use):

Weight ≥50 kg and <65 years of age:

IV: 30 mg once.

IM: 60 mg once .

Weight <50 kg or ≥65 years of age:

IV: 15 mg once .

IM: 30 mg once

Pain management, acute:

Note: Do not exceed recommended doses or administer with another nonsteroidal anti-inflammatory drug (NSAID). May supplement with analgesic(s) from another therapeutic class for breakthrough pain. Oral formulation should not be given as initial therapy; other better tolerated oral NSAIDs are generally preferred.

Weight ≥50 kg and <65 years of age:

IV: 30 mg as a single dose or 15 to 30 mg every 6 hours as needed; maximum daily dose: 120 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal).

IM: 30 to 60 mg as a single dose or 15 to 30 mg every 6 hours as needed; alternatively, may administer 10 to 30 mg every 4 to 6 hours as needed; maximum daily dose: 120 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) .

Oral (only as continuation of IM or IV therapy, not for initial therapy): 20 mg once, followed by 10 mg every 4 to 6 hours as needed; maximum daily dose: 40 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) .

Weight <50 kg or ≥65 years of age:

IV: 15 mg as a single dose or 15 mg every 6 hours as needed; maximum daily dose: 60 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) .

IM: 30 mg as a single dose or 15 mg every 6 hours as needed; alternatively, may administer 10 mg every 4 to 6 hours as needed; maximum daily dose: 60 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal) .

Oral (only as continuation of IM or IV therapy, not for initial therapy): 10 mg every 4 to 6 hours as needed; maximum daily dose: 40 mg/day; maximum duration: 5 days combined (parenteral, oral, and nasal).

• Ketorolac is available in the dosage strength of 15mg/mL, 30mg/mL, 10 mg.

Ketorolac is available in the form of Injection solution, tablets.

Dosage Adjustment in Kidney Patient

• Altered kidney function:

eGFR ≥60 mL/minute/1.73 m²: IM, IV, Oral: No dosage adjustment necessary .

eGFR >30 to <60 mL/minute/1.73 m²:

• IM, IV: Use of analgesics other than nonsteroidal anti-inflammatory drugs may be preferred. If necessary, consider 7.5 to 15 mg every 6 hours ; use the lowest effective dose for the shortest duration possible. Avoid use in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, elderly, or taking concurrent nephrotoxic medications) .
• Oral: 10 mg every 4 to 6 hours as needed; maximum: 40 mg/day; oral dosing is intended to be a continuation of IM or IV therapy .

eGFR ≤30 mL/minute/1.73 m²: IM, IV, Oral: Avoid use due to increased risk of acute kidney injury.

• Hemodialysis, intermittent (thrice weekly): Not dialyzable: IM, IV, Oral: Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function.
• Peritoneal dialysis: Unlikely to be significantly dialyzed given very high protein binding: IM, IV, Oral: Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function . The manufacturer’s labeling states use is contraindicated in advanced kidney impairment.
• CRRT: Avoid use .
• PIRRT (eg, sustained, low-efficiency defiltration): Avoid use.

Dosage Adjustment for Pediatric Patients

• Moderately Severe Acute Pain (Off-label)

<2 years

• Safety and efficacy not established
• Single dose: 0.5 mg/kg IV/IM once; not to exceed 15 mg
• Multiple dose: 0.5 mg/kg IV/IM q6hr; not to exceed 5 days
• IV: 15 mg as single dose or 15 mg q6hr; not to exceed 60 mg/day
• IM: 30 mg as single dose or 15 mg q6hr; not to exceed 60 mg/day
• PO: 10 mg once after IV/IM therapy, THEN 10 mg q4-6hr; not to exceed 40 mg/day
• IV: 30 mg as single dose or 30 mg q6hr; not to exceed 120 mg/day
• IM: 60 mg as single dose or 30 mg q6hr; not to exceed 120 mg/day

2-16 years

>16 years, <50 kg

>16 years, >50 kg

• PO: 20 mg once after IV/IM therapy, THEN 10 mg q4-6hr; not to exceed 40 mg/day.

Take after eating and with a full glass of water to decrease gastric upset.

Ketorolac is contraindicated in patients with:

Hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to Ketorolac or any component of the formulation; use in the setting of coronary artery bypass graft (CABG) surgery; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAID agents; patients with a history of proctitis or recent rectal bleeding (suppositories).

Neonates (IV only): Necrotizing enterocolitis (proven or suspected); significant kidney impairment; active bleeding (including intracranial hemorrhage and gastrointestinal bleeding), thrombocytopenia, coagulation defects; untreated infection (proven or suspected); congenital heart disease where patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (eg, pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions 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 nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (FDA 2015). Avoid use in patients with 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 that require mental alertness (eg, operating machinery, driving). Headache may occur; cessation of therapy required if headache persists after dosage reduction.

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis Use caution with a history of GI ulcers, 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 older or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended

• Hematologic effects: 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).

• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal liver function test (LFT). Rare, sometimes fatal severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of liver disease develop or if systemic manifestations occur.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in older patients, diabetic patients, patients with kidney disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE inhibitors). Monitor potassium closely.

• Kidney effects: NSAID use may compromise existing kidney function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause kidney decompensation (usually reversible). Patients with impaired kidney function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and ACE inhibitors, and older patients are at greater risk of kidney toxicity. Rehydrate patient before starting therapy; monitor kidney function closely. Long-term NSAID use may result in renal papillary necrosis and other kidney injury.

• Ophthalmic effects: Prolonged therapy may cause corneal deposits and retinal disturbances, including those of the macula. Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long-term therapy.

• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events, including drug reaction with eosinophilia and systemic symptoms, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Ketorolac may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Ketorolac is present in breast milk.

The relative infant dose (RID) of ketorolac is 0.21% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 40 mg/day.

In general, breastfeeding is considered acceptable when the RID is <10% .

Food may decrease the rate but not the extent of absorption. Ketorolac peak serum levels may be delayed if taken with food. Management: Administer with food or milk to minimize GI upset.

• Common Adverse effects:

Constipation, diarrhea, flatulence, gastrointestinal fullness, gastrointestinal hemorrhage

• Less Common Adverse effects:

Anemia, prolonged bleeding time, purpuric disease

• Rare Adverse effects

Dizziness, drowsiness, dysgeusia, eructation, esophagitis, gastritis, glossitis, hematemesis, increased appetite, melena, xerostomia

• May increase the risk of bleeding with oral corticosteroids, SSRIs, and other antiplatelet agents.
• May increase the risk of renal impairment with ACE inhibitors, angiotensin II receptor blockers (ARBs), ciclosporin, and diuretics.
• May diminish the effects of ACE inhibitors, ARBs, diuretics, or β-blockers (e.g. propranolol). Increased risk of seizure with antiepileptic drugs (e.g. phenytoin, carbamazepine). Hallucinations may occur when used with psychoactive drugs (e.g. fluoxetine, tiotixene, alprazolam).
• Ketorolac IV/IM may enhance the adverse effect (particularly episodes of apnoea) of nondepolarising muscle relaxants.
• May increase the serum concentration of methotrexate and digoxin.

Potentially Fatal:

Increased risk of serious NSAID-related adverse events with aspirin or other NSAIDs.

Increased plasma levels and reduced clearance with probenecid.

May increase the risk of bleeding with pentoxifylline and anticoagulants (e.g. heparin, warfarin). Reduces clearance and elevates the plasma levels of lithium, which may increase lithium toxicity.

The common side effects of Ketorolac include the following :

Symptoms: Lethargy, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, headache, disorientation, excitation, drowsiness, fainting, tinnitus, and anaphylactoid reactions. Rarely, diarrhoea, occasional convulsions, hypertension, acute renal failure, respiratory depression, and coma.

Management: Symptomatic and supportive treatment. May consider emesis and/or administration of activated charcoal (60-100 g in adults; 1-2 g/kg in children) and/or osmotic cathartic within 4 hours of ingestion in patients with symptoms or after a large oral overdose (5-10 times the normal dose). Administer IV diazepam in case of frequent or prolonged convulsions. Ensure good urine output of the patient. Closely monitor renal and hepatic function.

• Pharmacodynamics

Ketorolac is a prototypical NSAID with antipyretic and analgesic properties, it is a racemic mixture of (-)S- and (+)R-enantiomers, with the S-form as the biologically active form. It reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, resulting in decreased formation of prostaglandin precursors. Administration via the ophthalmic route decreases the levels of prostaglandin E₂ in the aqueous humour.

• Pharmacokinetics

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Ketorolac -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Ketorolac
5. https://europepmc.org/article/med/6988203