Summary for UKPID
KETOROLAC
Phil Young, BSc (Hons) Msc MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
Summary
Name
Proprietary Toradol (R)
Generic Ketorolac tromethamine
Trial No. RS-37 619
Chemical group/family
Non-steroidal anti-inflammatory
BNF 15.1.4.2
Reference number1
CAS 74103-06-3
CAS 74103-07-4
Manufacturer/supplier2
Syntex Pharmaceuticals
PO Box 8
Welwyn Garden City
Hertfordshire
AL7 3AY
Tel: 01707-366000
Fax: 01707-338297
Presentation2
Injection ; single dose 1 ml ampoules Packs of 10 (10 or 30
mg/ml),
Tablets 10 mg; Polypropylene blister packs size 20 and 100.
0.5 % eye drops, 5 ml
Physico-chemical properties 3
(RS)-5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2]pyrrole-1-carboxylic
acid 2-amino-2-hydroxymethyl-1,3-propanediol
Molecular weight (free base) 376.4 (255.3)
pKa 3.54
Solubility
in alcohol 3 mg/ml
in water 500 mg/ml
Hazard / risk classification
None
Uses
Indications2
Ketorolac injection is indicated for the short-term management of
acute postoperative pain.
Oral ketorolac is indicated for short-term management of moderate
postoperative pain.
Eye drops indicated for prophylaxis and reduction of ocular
inflammation.
Therapeutic Dosage
Oral Adult 10 mg every 4-6 hours. (Elderly 10 mg every
6-8 hours). Max. 40 mg daily.
Max. treatment duration 7 days.
Children Not recommended <16 years
IM/IV Adult Initially 10 mg, then 10-30 mg every 4-6 hours
when required. Max. 90 mg daily.
(60 mg in elderly and patients weighing less
than 50 kg). Max. treatment duration 2 days.
Children Not recommended <16 years
Eye Adults 1 drop three times a day for up to 3 weeks,
starting 24 hours before surgery.
Children Not recommended
Contra-indications
Known hypersensitivity to the ketorolac
Asthma
Previous allergic symptoms with aspirin or NSAID
Active peptic ulceration
Severe established renal impairment
Prerenal conditions including renal artery stenosis,
hypovolaemia, or dehydration
Congestive heart failure
Hypertension
Concurrent high-dose therapy with methotrexate
Pregnancy
Disorders of coagulation or platelet function
Concurrent treatment with lithium salts
Pharmacokinetics4
Oral absorption >95%
Presystemic metabolism <10%
Bioavailability (oral) 80-100%
Plasma half-life
range 4.45-5.6 hr
mean 5.4 hr
Cmax
oral 30-40 mins
IM 45-50 mins
Volume of distribution 0.11-0.33 L.kg-1
Protein binding 99.2%
Metabolism approx 40%
Special populations
Avoid if moderate or severe renal function (serum creatinine
greater than 160 µmol.L-1). Reduce dose and monitor renal
function in patients with lesser renal impairment ; total daily
dose not greater than 60 mg.
Caution in patients with conditions leading to reduced blood
volume (e.g. heart failure, hepatic dysfunction, and
dehydration).
Pregnancy
There is little data available. No increase in malformations was
noted in the offspring of rabbits given oral ketorolac up to 3.6
mg/kg/day; or rats given up to 10 mg/kg/day.5 The maximum
recommended human dose is approximately 2.5 mg/kg/day
parenterally. Administration of 1.5 mg/kg/day to rats caused
dystocia, and increased mortality, an effect commonly seen in
rodents administered NSAIDs. No clinical reports of adverse
effects after human gestational use of ketorolac have been found.
Use of NSAIDs during the third trimester may cause premature
closure of the ductus arteriosus, and oligohydramnios, and should
be avoided.
Breast milk
Ketorolac is distributed into breast milk. Following oral
administration of a single 10 mg dose, peak milk concentrations
of 7.3 ng/ml occurred within 2 hours. Following oral
administration of 10 mg four times daily for 2 days, peak milk
concentrations 2 hours after dosing on the first or second days
was 5.2-7.9 ng/ml.
Toxicokinetics
None known
Adverse effects
Gastrointestinal haemorrhage, peptic ulceration or perforation
are the most frequent serious adverse effects.
Hypersensitivity reactions such as anaphylaxis, bronchospasm,
laryngeal oedema, and hypotension may occur.
Impairment of renal function has been reported with long-term
use. The risk of acute tubular necrosis is probably increased if
ketorolac is given to patients with critically reduced renal
blood flow.
The most commonly reported adverse effects are gastrointestinal
symptoms with dyspepsia, gastrointestinal bleeding, nausea, and
vomiting occurring in 3-9%.
Mild injection site pain occurs in 2-6% of patients receiving
single intramuscular doses. Transient mild swelling, and local
ecchymoses may be seen, but serum creatine kinase levels are not
usually elevated.
Somnolence, diarrhoea, dizziness, headache, sweating, dry mouth,
rectal bleeding, asthma, insomnia, paraesthesia can occur.
Interactions
Methotrexate Reduced excretion and possible increased
frequency of methotrexate adverse effects
Lithium Reduced clearance of lithium
Warfarin Possible displacement from protein binding
NSAIDs Do not use in combination with other NSAIDS,
increased risk of adverse effects.
There is currently no information on the effects of acute
overdose in humans.6
Acute overdosage with ketorolac has not been reported. Symptoms
and management are likely to be similar to other NSAIDs.
Features (combination of diclofenac and ibuprofen
monographs)
Most patients who have ingested NSAIDs will not develop more than
nausea, vomiting, epigastric pain, and perhaps drowsiness.
Occasional patients have developed muscular twitching,
convulsions, impairment of consciousness, and hypotension but
these appear to be relatively uncommon.
Common
Nausea, vomiting, headache, tinnitus, ataxia, drowsiness
Rarely
Coma, hypotension, metabolic acidosis, acute renal failure,
hepatic dysfunction, and gastrointestinal bleeding may develop.
Management
1. Dose of activated charcoal within 1-2 hours of ingestion, or
empty the stomach
2. Treatment is symptomatic and supportive
3. Seizures - administer diazepam 5-10 mg IV every 15 minutes PRN up
to 30 mg
4. Monitor vital signs
5. Hypotension - administer IV fluids
6. Monitor for signs of gastrointestinal ulceration and/or
haemorrhage
7. There is no evidence to suggest that enhanced elimination is of
benefit
References
1. Kim J et al. Acute renal insufficiency in ibuprofen overdose.
Pediatr Emerg Care 1995 ; 11 :107-108
2. Halpern et al. Ibuprofen toxicity. A review of adverse reactions
and overdose. Adverse Drug react Toxicol Rev 1993 ; 12 : 107-128
3. Mann JFE et al. Ibuprofen as an over-the-counter drug : is there
a risk of renal injury ? Clin Nephrol 1993 ; 39 : 1-6
4. Hall AH et al. Ibuprofen overdose in adults. Clin Toxicol 1992 ;
30 :23-37
5. Perazella MA & Buller GK. Can ibuprofen cause acute renal failure
in a normal individual ? A case of acute overdose. Am J Kid Dis
1991 ; 18 : 600-602
6. McElwee NE et al. A prospective, population-based study of acute
ibuprofen overdose : complications are rare and routine serum
levels not warranted. Ann Emerg Med 1990 ; 19 : 657-662
7. Menzies DG et al. Fulminant hyperkalaemia an dmultiple
complications following ibuprofen overdose. Med Toxicol Adverse
Drug Exp 1989 ; 4 : 468-471
8. Jenkinson ML et al. The relationship between plasma ibuprofen
concentrations and toxicity in acute ibuprofen overdose. Human
Toxicol 1988 ; 7 : 319-324
9. Perry SJ et al. Ibuprofen overdose : the first two years of over-
the-counter sales. Human Toxicol 1987 ; 6 : 173-8
10. Hall Ah et al. Ibuprofen overdose : 126 cases. Ann Emerg Med
1986; 15 :1308-1313
11. Meredith TJ & Vale JA. Non-narcotic analgesics : problems of
overdosage. Drugs 1986 ; 32 (S4) : 177-205
12. Lee CY. Acute intoxication due to ibuprofen overdose. Arch Pathol
Lab Med 1986 ; 110 :747-9
13. Barry WS et al Ibuprofen overdose and exposure in utero : results
from a post-marketing voluntary reporting system. Am J Med 1984
(Symposium) : 35-39
14. Court H & Volans GN. Poisoning after overdose with non-steroidal
anti-inflammatory drugs. Adv Drug React Pois Rev 1984 ; 3 : 1-21
EPIDEMIOLOGY
NSAIDs are widely prescribed, however despite this overdosage with
these agents appears to be rare.7 NSAIDs account for about 6.5% of
deliberate overdoses.8,9
MECHANISM OF ACTION 8
NSAIDs probably act by inhibiting prostaglandin synthesis.
Prostaglandins (PGs) are believed to cause vasodilation, increased
vascular permeability, and increased sensitivity of nerve endings to
other inflammatory mediators. By reversible inhibition of
cyclooxygenase, NSAIDs block the conversion of the arachidonic acid
found in cell membrane phospholipids into various PGs.
Since PGs appear to maintain the gastric mucosal barrier, NSAID
inhibition of PG synthesis may be the cause of the gastritis, peptic
ulceration, and gastrointestinal bleeding observed with NSAIDs.
NSAIDs cause sodium retention, especially in patients with underlying
sodium-retaining states such as congestive heart failure. Although the
mechanism is not entirely clear, the inhibition of PG synthesis plays
a leading role. These compounds redistribute renal blood flow away
from the superficial cortical glomeruli to the juxtamedullary
glomeruli, which have a greater capacity to absorb sodium.
NSAID nephrotoxicity appears in at least three distinct forms:
1. Acute renal insufficiency resulting from a reduction in renal
blood flow.
2. Acute tubular necrosis which also may result from decreased
prostaglandin-mediated vasodilation.
3. An acute interstitial nephritis with or without proteinuria.
FEATURES OF POISONING
Acute overdose
Most cases of NSAID overdose develop no effects or mild effects
consisting of lethargy and gastrointestinal upset.
Low grade fever, hypotension, and sinus tachycardia have been noted in
both overdose, and therapeutic use of NSAIDs.
Tinnitus is frequently reported following NSAID overdoses.
Metabolic acidosis occurs rarely in overdose, usually in conjunction
with seizures. Severe fluid and electrolyte imbalance has been
described with piroxicam overdose in a child. Hyperkalaemia has been
reported with therapeutic use of ketorolac.
There are reports of agranulocytosis, pancytopenia, coagulopathy and
prolonged prothrombin time with NSAID overdoses. Thrombocytopenia,
aplastic anaemia, neutropenia, and increased bleeding times have
occurred with therapeutic use of NSAIDs.
Photosensitivity, toxic epidermal necrolysis, erythema multiforme, and
phototoxicity have been reported with therapeutic use of NSAIDs.
Respiratory
Although rare, respiratory arrest has been reported after overdoses of
NSAIDs. Eosiniphilc pneumonia has been induced, characterised by
cough, low-grade fever and dyspnoea following NSAID overdoses.10
Neurologic
Drowsiness, delirium, lethargy, seizures, dizziness, disorientation,
loss of conciosness, tinnitus, headache, hallucinations, and
encephalopathy have been associated with therapeutic dosing and/or
overdose of NSAIDs. Coma has been reported following severe NSAID
overdose. Myoclonic twitching has been reported for several days after
an overdose of piroxicam, and another NSAID.
Gastrointestinal
Nausea, vomiting, epigastric pain, erosive oesophagitis, pancreatitis,
and gastrointestinal bleeding have been associated with therapeutic
use and/or overdose of NSAIDs.
Genitourinary
Acute renal failure, uraemia, and nephrotic syndrome have occurred
with both acute overdose and chronic ingestion of most NSAIDs.
Immunologic
Anaphylactoid reactions have been associated with therapeutic
ingestion of tolmetin, sulindac, ketorolac, fenoprofen, naproxen, and
mefenamic acid, but have not been reported following acute NSAID
overdose.
Mangement
1. Administer an oral dose of of activated charcoal within 1-2 hours
of ingestion of a potentially toxic dose. Alternatively gastric
lavage may be used.
2. Treatment is symptomatic and supportive
3. Seizures - administer diazepam 5-10 mg IV every 15 minutes up to
30 mg until seizures are controlled.
4. Monitor vital signs
5. Hypotension - administer IV fluids
6. Monitor for signs of gastrointestinal ulceration and/or
haemorrhage
7. Monitor the patients electrolyte and acid-base balance. Fluid and
electrolyte imbalances have been reported.
8. There is no evidence to suggest that enhanced elimination is of
benefit
Analysis
Plasma NSAID levels are insufficiently studied to be clinically
useful.
Author
Phil Young, BSc (Hons) Msc MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph was produced by the staff of the Newcastle Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National Poisons
Information Service.
Last updated July 1997
References
1. Martindale : The Extra Pharmacopoeia. 30th Edition. Reynolds JEF
(Ed.). Pharmaceutical Press. 1993
2. ABPI Data Sheet Compendium. Datapharm Publications Ltd. 1995-96
3. Therapeutic Drugs. Dollery C. (Ed.). Churchill Livinstone. 1991
4. Brocks-DR; Jamali-F . Clin Pharmacokinetics of ketorolac
tromethamine
5. Clin-Pharmacokinet 1992 ; 23(6) : 415-27
6. Dabney BJ : Ketorolac (Reprotext (R) Document) in Dabney BJ
(Ed.): Reprotext (R) System. Micromedex, Inc., Denver, Colorado
(Edition expires May 31st 1996)
7. AHFS Drug Information. McEvoy GK (Ed.)
8. Court H & Volans GN. Poisoning after overdose with NSAID. Adv
Drug React Ac Pois Rev 1984 ; 3 : 1-21
9. Thomas SHL, Bevan L, Bhattacharyya S et al. Presentation of
poisoned patients to accident and emergency departments in the
North of England. Human & Experimental Toxicology 1996 ; 15 :
466-70
10. Macnamara AF, Riyat MS & Quinton DN. Te changing profile of
poisoning and its management. J Roy Soc Med 1996 ; 89 : 608-10
11. Nonsteroidal Anti-inflammatory Drug Monograph. Medical
Toxicology. Ellenhorn MJ & Barceloux DG (Eds.). Elsevier. 1988