Ketorolac

Registered South African indications:

• Post-operative pain

Epidemiological evidence suggests that ketorolac injection may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially when used outside the licensed indications and/or for prolonged periods. Ketorolac injection should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis.

 

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other NSAIDs and patients in whom aspirin or other prostaglandin synthesis inhibitors induce allergic reactions
• Pregnancy (including labour and delivery)  
• Breastfeeding
• Moderate to severe renal impairment
• Severe hepatic impairment
• Children <16 years
• History of asthma
• Active or a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy
• Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
• Severe cardiac failure
• Volume depletion or dehydration
• Prophylactic use as analgesia before surgery
• Intra-operative use
• Suspected or confirmed cerebrovascular bleeding
• Patients who have had operations with a high risk of haemorrhage or incomplete haemostasis
• High risk of bleeding, such as haemorrhagic diatheses, including coagulation disorders
• Neuraxial (epidural or intrathecal) administration
• Complete or partial syndrome of nasal polyps, angioedema or bronchospasm
• Coadministration with anticoagulants, including warfarin and low dose heparin (2500-5000 units, 12hrly)
• Coadministration with aspirin or other NSAIDs (including cyclooxygenase-2 selective inhibitors)
• Coadministration with oxpentifylline
• Coadministration with probenecid
• Coadministration with lithium salts

Cautions

• Female patients of reproductive potential
• Mild renal impairment
• Mild to moderate hepatic impairment
• Elderly
• History of renal disease
• Debilitated patients
• History of peptic ulcer(s), particularly if complicated with haemorrhage or perforation
• History of inflammatory bowel disease, including ulcerative colitis and Crohn's disease
• History of gastrointestinal toxicity
• Surgery where strict haemostasis is critical, such as cosmetic or day-case surgery, resection of the prostate or tonsillectomy
• High dose therapy
• Prolonged duration of therapy
• Systemic lupus erythematosus and mixed connective tissue disorders
• History of hypertension (including uncontrolled hypertension) and/or mild to moderate cardiac failure
• Cardiac decompensation
• Ischaemic heart disease
• Peripheral arterial disease
• Cerebrovascular disease
• Risk factors for cardiovascular disease (such as hypertension, hyperlipidaemia, diabetes mellitus and smoking)
• Conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins support the maintenance of renal perfusion
• Inadequate fluid/ blood replacement during surgery
• Hypovolaemia
• Addictive potential 
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: tab, inj

Acute post-operative pain - moderate to severe

• Oral (tab): 10mg, 4-6hrly if needed; Max: 40mg/24hrs. Max duration: 5 days

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May be provided as a single dose of 10mg, or as a multiple dosing schedule as provided above

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Patients should be converted to oral treatment as soon as possible

See additional prescribing points

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• IV/IM: Initial: 10mg, followed by 10-30mg, 4-6hrly if needed. Max: 90mg/24hrs; Max duration: 2 days
• IV: Initial: 30mg, followed by continuous infusion at a rate of up to 5mg/hr for up to 24hrs; Max: 90mg/24hrs; Max duration: 24hrs

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Bolus intravenous doses should be given over no less than 15 seconds

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In the initial post-operative period, ketorolac may be given as often as every two hours, if needed

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The time to onset of analgesic effect following both IV/IM administration is approximately 30mins, with maximum analgesia occurring within 1-2hrs. The median duration of analgesia is generally 4-6hrs

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Ketorolac should not be used for epidural or spinal administration

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Reduce dosage in patients <50kg; Max: 60mg/24hrs 

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Dosage should be adjusted according to the severity of the pain and the patient response

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Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

Not established for use in children below 16 years

Pregnancy

• Contraindicated
• In view of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the foetal cardiovascular system (risk of closure of the ductus arteriosus), ketorolac is contraindicated during pregnancy, labour or delivery
• The safety of ketorolac during human pregnancy has not been established. There was no evidence of teratogenicity in rats or rabbits studied at maternally-toxic doses of ketorolac. Prolongation of the gestation period and/or delayed parturition were seen in the rat. Congenital abnormalities have been reported in association with NSAID administration in man, however, these are low in frequency and do not follow any discernible pattern
• Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre-and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period
• During pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
  - cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
  - renal dysfunction, which may progress to renal failure with oligo-hydroamniosis
• During pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate, at the end of pregnancy, to:
  - possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses
  - inhibition of uterine contractions resulting in delayed or prolonged labour
• Ketorolac crosses the placenta to the extent of approximately 10%
• Ketorolac is contraindicated in labour and delivery because, through its prostaglandin synthesis inhibitory effect it may adversely affect foetal circulation and inhibit uterine contractions, thus increasing the risk of uterine haemorrhage. There may be an increased bleeding tendency in both mother and child

Breastfeeding

• Contraindicated
• Ketorolac and its metabolites have been shown to pass into the foetus and milk of animals. Ketorolac has been detected in human milk at low concentrations, therefore, ketorolac is contraindicated in mothers who are breastfeeding

Fertility

• The use of ketorolac, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive
• In women who have difficulty conceiving or are undergoing investigation of fertility, withdrawal of ketorolac should be considered

Renal Impairment

• Mild: Caution; dose adjustment recommended
  Oral (tab): Reduce daily dose by 50%. Max: 60mg/24hrs 
  IV/IM: Max: 60mg/24hrs 
  IV Infusion: Use not recommended
• Moderate to severe: Contraindicated

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Elderly

• Caution; dose adjustment recommended
  IV/IM: Max: 60mg/24hrs 
  Oral (tab): The lower end of the dosage range is recommended. Doses above 60mg/24hrs increases risk of clinically serious gastrointestinal bleeding

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Nausea, dyspepsia, gastrointestinal pain and diarrhoea are reported as common side effects of ketorolac that may potentially be porphyrinogenic (or be confused with an acute porphyria attack) if leading to a decrease in carbohydrate intake

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Paraesthesia
• Seizures
• Hyperkinesia
• Abnormal thinking
• Depression
• Euphoria
• Insomnia
• Anxiety
• Nervousness
• Psychotic reactions
• Abnormal dreams
• Hallucinations
• Inability to concentrate
• Drowsiness
• Confusion
• Stimulation
• Aseptic meningitis
  - Stiff neck
  - Headache
  - Nausea and vomiting
  - Fever
  - Disorientation
• Fatigue

Cardiovascular Disorders

• Bradycardia
• Palpitations
• Cardiac failure
• Hypotension
• Hypertension
• Arterial thrombotic events
• Haematoma
• Oedema

Respiratory Disorders

• Dyspnoea
• Asthma
• Pulmonary oedema
• Epistaxis

Gastrointestinal Disorders

• Gastrointestinal ulcers
• Peptic ulcers
• Perforation
• Gastrointestinal bleeding
• Nausea and vomiting
• Dyspepsia
• Abdominal pain/ discomfort
• Haematemesis
• Stomatitis
• Ulcerative stomatitis
• Dry mouth
• Oesophagitis
• Diarrhoea
• Eructation
• Constipation
• Flatulence
• Fullness
• Melaena
• Rectal bleeding
• Exacerbation of colitis or Crohn's disease
• Gastritis

Hepatobiliary Disorders

• Hepatitis
• Cholestatic jaundice
• Liver failure
• Abnormal liver function tests

Genitourinary Disorders

• Increased urinary frequency
• Oliguria
• Acute renal failure
• Haemolytic uraemic syndrome
• Flank pain (with or without haematuria and/or azotemia)
• Interstitial nephritis
• Urinary retention
• Nephrotic syndrome
• Increased creatinine
• Increased potassium
• Increased serum urea
• Female infertility

Endocrine and Metabolic Disorders

• Anorexia
• Hyponatraemia
• Hyperkalaemia
• Excessive thirst
• Weight gain
• Pancreatitis

Musculoskeletal Disorders

• Myalgia
• Functional disorders

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Urticaria
• Purpura
• Angioedema
• Exfoliative dermatitis
• Maculopapular rash
• Sweating
• Bullous reactions 
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema multiforme
• Skin photosensitivity
• Injection site reactions and pain (inj)
• Flushing
• Pallor

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Purpura
• Neutropenia
• Agranulocytosis
• Aplastic anaemia
• Haemolytic anaemia
• Anaphylaxis
• Anaphylactoid reactions
• Hypersensitivity reactions
  - Bronchospasm
  - Flushing
  - Rash
  - Hypotension
  - Laryngeal oedema
• Fever
• Postoperative wound haemorrhage
• Prolonged bleeding time

Sensory Disorders

• Optic neuritis
• Abnormal vision
• Visual disturbances
• Abnormal taste
• Hearing loss
• Tinnitus
• Vertigo

Others

• Chest pain

• Aspirin
• Non-steroidal anti-inflammatory drugs
• Cyclooxygenase-2 selective inhibitors
• Anticoagulants
• Low dose heparin (2500-5000 units 12-hourly)
• Dextrans
• Warfarin
• Lithium
• Probenecid  
• Mifepristone
• Oxpentifylline
• Antihypertensive agents
• Diuretics
• Furosemide
• Angiotensin-converting enzyme inhibitors
• Angiotensin II receptor antagonists
• Cardiac glycosides
• Methotrexate
• Ciclosporin
• Corticosteroids
• Quinolone antibiotics
• Antiplatelet agents
• Selective serotonin reuptake inhibitors
• Tacrolimus
• Zidovudine
• Ibuprofen

None routine. Specific cases may require

• Full blood count and platelets
• Renal function
• Hepatic function
• Blood pressure
• Serum urea
• Serum potassium
• Weight gain
• Mental status

Conversion from parenteral to oral formulations

• The administration of continuous multiple daily doses of IM/IV ketorolac should not exceed two days because adverse events may increase with prolonged usage. There has been limited experience with dosing for longer periods since the vast majority of patients have transferred to oral medication, or no longer require analgesic therapy after this time
• Patients should be converted to oral treatment as soon as possible
• For patients receiving parenteral solution for injection, and who are converted to oral tablets, the total combined daily dose should not exceed 90mg (60mg for the elderly, renally-impaired
  patients and patients <50kg). The oral component should not exceed 40mg on the day the change of formulation is made

Gastrointestinal toxicity

• Epidemiological evidence suggests that ketorolac may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially when used outside the licensed indications and/ or for prolonged periods

Use in the elderly

• Older people are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy

Incompatibilities (IV)

• Ketorolac solution for injection should not be mixed in a small volume (e.g. in a syringe) with morphine sulphate, pethidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride as precipitation of ketorolac will occur
• It is compatible with 0.9% normal saline, 5% dextrose, Ringer's and lactated Ringer's solution

Ketorolac is a non-steroidal anti-inflammatory agent demonstrating analgesic and anti-inflammatory activity. Ketorolac inhibits the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins. It demonstrates a minimal anti-inflammatory effect at its analgesic dose. 

Tablet 10mg

• Tora-dol (Akacia) originator

Injection (per ml) 10mg 

• Tora-dol 1% (Akacia) originator

Injection (per ml) 30mg 

• Bedoral (Ranbaxy)
• Tora-dol 3% (Akacia) originator

Also available in the following form: Eye drop.