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    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 Ámol.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
    


    See Also:
       Toxicological Abbreviations