Consumer medicine information

Ketoral

Ketorolac trometamol

BRAND INFORMATION

Brand name

Ketoral Injection

Active ingredient

Ketorolac trometamol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ketoral.

SUMMARY CMI

KETORAL

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using KETORAL?

KETORAL contains the active ingredient ketorolac trometamol. KETORAL is used to relieve pain and reduce inflammation (swelling and soreness) that may occur in the initial period following surgery. For more information, see Section 1. Why am I using KETORAL? in the full CMI.

2. What should I know before I use KETORAL?

Do not use KETORAL if you are pregnant or intend to become pregnant, or if you are breastfeeding or intend to breastfeed. Do not use if you have ever had an allergic reaction to any medicine containing ketorolac trometamol, aspirin or any other NSAID medicine, or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use KETORAL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KETORAL and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use KETORAL?

  • Your doctor will decide what dose you will receive depending on your weight, the severity of the pain and your response to the treatment. If you are over 65 years old or have reduced kidney function, your doctor may prescribe a lower dose.

More instructions can be found in Section 4. How do I use KETORAL? in the full CMI.

5. What should I know while using KETORAL?

Things you should do
  • Tell your doctor immediately if you become pregnant while taking this medicine.
  • Remind any doctor, dentist or pharmacist you visit that you have recently been given KETORAL.
  • Tell your doctor if you get an infection soon after getting KETORAL.
Things you should not do
  • Do not receive KETORAL for longer than 5 days. Prolonged use may increase the occurrence of side effects.
Driving or using machines
  • Be careful driving or operating machinery until you know how KETORAL affects you.
  • As with other NSAID medicines, KETORAL may cause dizziness or light-headedness in some people.
Drinking alcohol
  • Tell your doctor if you have ever been a heavy alcohol drinker
  • If you drink alcohol, dizziness or light-headedness may be worse.
Looking after your medicine
  • KETORAL will be stored in the pharmacy or on the ward.
  • It is kept in a cool dry place, protected from light, where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using KETORAL? in the full CMI.

6. Are there any side effects?

If any of the following happen, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital: vomiting blood or material that looks like coffee grounds, bleeding from the back passage (rectum), black sticky bowel motions (stools) or bloody diarrhoea, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, asthma, wheezing, shortness of breath, sudden or severe itching, skin rash, hives, fainting, seizures or fits, pain or tightness in the chest or palpitations or flu-like symptoms with a rash on the face then an extended rash with a high temperature and enlarged lymph nodes. Tell your doctor or nurse immediately if you notice any of the following: severe pain or tenderness in any part of the stomach or back, severe dizziness, spinning sensation, hearing loss or ringing in the ears, severe or persistent headache, abnormal vision, bleeding or bruising more easily than normal, reddish or purplish blotches under the skin, skin rash, severe blisters and bleeding in the lips, eyes, mouth, nose and genitals, unusual weight gain, swelling of ankles or legs.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

KETORAL

Active ingredient(s): ketorolac trometamol

Consumer Medicine Information (CMI)

This leaflet provides important information about using KETORAL. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using KETORAL.

Where to find information in this leaflet:

1. Why am I using KETORAL?
2. What should I know before I use KETORAL?
3. What if I am taking other medicines?
4. How do I use KETORAL?
5. What should I know while using KETORAL?
6. Are there any side effects?
7. Product details

1. Why am I using KETORAL?

KETORAL contains the active ingredient ketorolac trometamol. KETORAL belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs).

KETORAL is used to relieve pain and reduce inflammation (swelling and soreness) that may occur in the initial period following surgery.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use KETORAL?

Warnings

Do not use KETORAL if:

  • you are allergic to ketorolac trometamol, aspirin or any other NSAID medicine, or any of the ingredients listed at the end of this leaflet. Many medicines used to treat headaches, period pain and other aches and pains contain aspirin or are a NSAID medicine. If you are not sure if you are taking any of these medicines, ask your doctor before you are given KETORAL. Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
Always check the ingredients to make sure you can use this medicine.
  • you are pregnant or intend to become pregnant.
  • you are breastfeeding or intend to breastfeed.
  • you have kidney disease
  • you have severe liver disease
  • you have severe heart failure
  • you have recently had or are about to have heart bypass surgery
  • you have a peptic ulcer (i.e. stomach or duodenal ulcer), a recent history of one or have had peptic ulcers before
  • you have or have had any bleeding disorders
  • you have asthma
  • you suffer from dehydration
  • you have nasal polyps syndrome, angioedema or bronchospasm (breathing difficulties)
  • you have a history of Stevens-Johnsons Syndrome (a rare skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals)
  • you are receiving the following medicines:
    - other NSAID medicines
    - probenecid, a medicine used to treat gout
    - lithium, a medicine used to treat some types of depression
    - pentoxifylline (oxpentifylline), a medicine used to treat certain blood disorders

Do not give this medicine to a child under the age of 16 years.

  • Safety and effectiveness in children younger than 16 years have not been established.

Check with your doctor if you:

  • you have allergies to any other medicines, foods, preservatives or dyes.
  • have had any of the following medical conditions:
    - heartburn, indigestion, stomach ulcers or other stomach problems
    - kidney or liver disease
    - blood disorders
    - skin reactions due to another medicine
    - asthma or breathing disorders
    - a reaction to any other NSAID medicine
    - heart failure
    - high blood pressure or heart problems
    - swelling of the ankles or feet
    - inflammatory bowel disease, such as Crohn's disease
  • currently have an infection. KETORAL may hide some of the signs of an infection (e.g. pain, fever) and may make you mistakenly think that the infection is not serious or that you are better.
  • plan to have surgery.
  • you have ever smoked or been a heavy alcohol drinker.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

You must not be given this medicine if you are pregnant or intend to become pregnant.

It may affect your developing baby if you take it during pregnancy.

KETORAL may impair fertility and is not recommended in women attempting to conceive.

You must not be given this medicine if you are breastfeeding or intend to breastfeed.

The active ingredient in KETORAL passes into breast milk and there is a possibility that your baby may be affected

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and KETORAL may interfere with each other. These include:

  • aspirin, salicylates or other NSAID medicines (e.g. ibuprofen, naproxen)
  • medicine used to treat some types of depression (e.g. lithium, fluoxetine, paroxetine, citalopram)
  • thiothixene, a medicine used to treat psychosis
  • alprazolam, a medicine used to treat anxiety
  • probenecid, a medicine used to treat gout
  • diuretics, also called fluid or water tablets
  • medicines used to treat epilepsy (e.g. phenytoin, carbamazepine)
  • methotrexate, a medicine used to treat arthritis and some cancers
  • warfarin, a medicine used to stop blood clots
  • medicines used to treat blood disorders (e.g. pentoxifylline (oxpentifylline), heparin)
  • medicines used to treat high blood pressure including ACE inhibitors, angiotensin receptor antagonists and beta-blockers
  • certain antibiotics called aminoglycosides

You may need different amounts of your medicines, or you may need to take different medicines. Your doctor has more information on medicines to be careful with or avoid while you are receiving this medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect KETORAL.

4. How do I use KETORAL?

How much to be given

  • Your doctor will decide what dose you will receive depending on your weight, the severity of the pain and your response to the treatment.
  • If you are over 65 years old or have reduced kidney function, your doctor may prescribe a lower dose.

How to be given it

  • KETORAL is a sterile, clear, slightly yellow liquid.
  • It is given as an injection into a muscle by a doctor or trained nurse.
  • It must not be injected directly into the veins (intravenously).

How long you will be given it

  • KETORAL should not be given for longer than 5 days.
  • Prolonged use may increase the occurrence of side effects.

If you use too much KETORAL

As KETORAL is given to you under the supervision of your doctor or nurse, it is very unlikely that you will receive too much.

However, if you experience any side effects after being given KETORAL, tell your doctor or nurse immediately.

Symptoms of overdose may include stomach pain, nausea and vomiting.

5. What should I know while using KETORAL?

Things you should do

Call your doctor straight away if you:

  • become pregnant while taking this medicine
  • get an infection soon after getting KETORAL.
This medicine may hide some of the signs of an infection and may make you think that the infection is not serious or that you are better. Signs of an infection may include fever, pain, swelling and redness.

Tell all doctors, dentists and pharmacists who are treating you that you have recently been given KETORAL.

Driving or using machines

Be careful driving or operating machinery until you know how KETORAL affects you.

As with other NSAID medicines, this medicine may cause dizziness or light-headedness in some people. Make sure you know how you react to this medicine before you drive a car, operate machinery or do anything else that could be dangerous.

Drinking alcohol

If you drink alcohol, dizziness or light-headedness may be worse.

Looking after your medicine

  • KETORAL will be stored in the pharmacy or on the ward. It is kept in a cool dry place, protected from light, where the temperature stays below 30°C.

6. Are there any side effects?

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given KETORAL.

This medicine helps most people with pain after surgery, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or nurse to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
  • stomach upset including nausea (feeling sick), heartburn, indigestion
  • pain in the stomach, wind, diarrhoea
  • constipation
  • dizziness, headache
  • drowsiness
  • depression or anxiety
  • insomnia
  • sweating
  • skin rash or hives
  • aching muscles, muscle tenderness or weakness not caused by exercise
  • pain at site of injection
  • dry mouth
  • feeling extremely thirsty
  • passing more or less urine than normal
Speak to your doctor or nurse if you have any of these less serious side effects and they worry you.

This list includes the more common side effects of your medicine. They are usually mild.

Serious side effects

Serious side effectsWhat to do
  • severe pain or tenderness in any part of the stomach or back
  • severe dizziness, spinning sensation
  • hearing loss or ringing in the ears
  • severe or persistent headache
  • abnormal vision
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • skin rash
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • unusual weight gain, swelling of ankles or legs
Tell your doctor or nurse immediately if you notice any of these side effects.

This list includes serious side effects. You may need urgent medical attention. Serious side effects are rare.

Serious side effectsWhat to do
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage (rectum), black sticky bowel motions (stools) or bloody diarrhoea
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing, shortness of breath
  • sudden or severe itching, skin rash, hives
  • fainting, seizures or fits
  • pain or tightness in the chest or palpitations
  • flu-like symptoms with a rash on the face then an extended rash with high temperature, increased levels of enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes
Call your doctor or nurse immediately or do straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

These side effects are rare but may be serious. You may need urgent medical attention or hospitalisation.

Very serious side effects

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is only available with a doctor's prescription.

What KETORAL contains

Active ingredient
(main ingredient)		30 mg/mL of ketorolac trometamo
Other ingredients
(inactive ingredients)
  • ethanol
  • sodium chloride
  • sodium hydroxide or hydrochloric acid
  • water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What KETORAL looks like

KETORAL is a sterile, clear to slightly yellow solution in a glass syringe. (AUST R 144524).

Who distributes KETORAL

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30 – 34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in November 2021.

KETORAL_cmi\Nov21/00

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Ketoral Injection

Active ingredient

Ketorolac trometamol

Schedule

S4

 

1 Name of Medicine

Ketorolac trometamol.

2 Qualitative and Quantitative Composition

Ketoral contains 30 mg/1 mL of ketorolac trometamol as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ketoral is a clear, slightly yellow sterile solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term management of moderately severe, acute pain following surgical procedures. The total duration of ketorolac trometamol use should not exceed five days.
It is recommended that parenteral ketorolac be used in the immediate postoperative period. Patients can then be converted to an oral formulation (dependent on their analgesic needs) (see Section 4.2 Dose and Method of Administration, Conversion from parenteral to oral therapy).
The total period of treatment utilising the oral and/or intramuscular route of administration is not to exceed five days.

General.

Ketorolac trometamol is not recommended for use as an obstetric preoperative medication or for obstetric analgesia because it has not been adequately studied for use in these circumstances and because of the known effects of drugs that inhibit prostaglandin biosynthesis on uterine contraction and fetal circulation. There is no satisfactory evidence for the use of ketorolac trometamol in acute exacerbations of chronic painful inflammatory conditions (e.g. rheumatoid arthritis or osteoarthritis).

4.2 Dose and Method of Administration

Dosage should be adjusted according to the severity of the pain and the response of the patient. The lowest effective dose should be used for the shortest possible time in all patient populations.
Opiate analgesics (e.g. morphine and pethidine) may be used concomitantly and may be required for optimum analgesic effect in the early postoperative period when pain is most severe, or when the anxiolytic effects and/or sedative effects of opiates are desired.
Ketorolac trometamol has been administered with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Ketorolac trometamol does not exacerbate opioid related respiratory depression or sedation. When used in association with ketorolac trometamol administered intramuscularly, the daily dose of opioid is usually less than that which is normally required.
Hypovolaemia should be corrected prior to administration of ketorolac trometamol. The intramuscular injection should be given slowly and deeply into the muscle. The administration of ketorolac trometamol should not exceed five days because adverse events may increase with prolonged usage.
Use in one patient on one occasion only. Discard any residue.

Intramuscular.

Adults (< 65 years).

The usual recommended initial dose is 10 to 30 mg followed by 10 to 30 mg every four to six hours up to a maximum daily dose of 90 mg.

Elderly (greater than or equal to 65 years).

An initial dose of 10 to 15 mg followed by 10 to 15 mg every four to six hours up to a maximum daily dose of 60 mg.

Pregnancy.

See Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation.

Mild renal impairment.

If used in patients with mildly impaired renal function (serum creatinine values in males: 130 to < 180 micromol/L; in females: 120 to < 180 micromol/L) the lower end of the ketorolac trometamol intramuscular dosage range should be used. The total daily dose should not exceed 60 mg.
Ketorolac trometamol is contraindicated in patients with more severe degrees of renal impairment (see Section 4.3 Contraindications).

Cardiovascular.

Patients on long-term treatment should be reviewed regularly with regards to efficacy, risk factors and ongoing need for treatment.

Other.

For patients under 50 kg in bodyweight or for patients with less severe pain, the lower end of the ketorolac trometamol intramuscular dosage range is recommended. The total daily dose should not exceed 60 mg.

Conversion from parenteral to oral therapy.

For patients receiving ketorolac trometamol intramuscularly, and who are converted to ketorolac trometamol tablets, the total combined daily dose should not exceed 90 mg (60 mg for the elderly, patients with mild renal impairment and patients weighing less than 50 kg) and the oral component should not exceed 40 mg (30 to 40 mg for the elderly) on the day the change of formulation is made. Patients should be converted to oral treatment as soon as possible.

4.3 Contraindications

Severe heart failure (see Section 4.4 Special Warnings and Precautions for Use, Heart failure).
Undergoing treatment of perioperative pain in setting of coronary artery surgery (CABG).
Dehydration or hypovolaemia from any other cause.
With severe hepatic impairment.
Moderate or severe renal impairment (serum creatinine > 180 micromol/L) or in patients at risk of renal failure due to volume depletion or dehydration (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
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) (see Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal effects).
A history of haemorrhagic diatheses, including coagulation disorders (see Section 4.4 Special Warnings and Precautions for Use, Haematological effects).
Surgery with a high risk of haemorrhage or incomplete haemostasis; and those at high risk of bleeding (see Section 4.4 Special Warnings and Precautions for Use, Haematological effects).
Suspected or confirmed cerebrovascular (intracranial) bleeding (see Section 4.4 Special Warnings and Precautions for Use, Haematological effects).
Patients on full anticoagulation therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Receiving aspirin, other NSAIDs, pentoxifylline (oxpentifylline), probenecid or lithium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Hypersensitivity to ketorolac trometamol or other NSAIDs, and patients in whom aspirin or other prostaglandin synthetase inhibitors induce allergic reactions. Severe anaphylactic-like reactions have been observed in such patients. If such symptoms occur during therapy, treatment should be discontinued (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions).
Individuals with the complete or partial syndrome of nasal polyps, angioedema or bronchospasm (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions).
A history of asthma (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions).
Prior history of Stevens-Johnson syndrome or vesicular bullous rash (see Section 4.4 Special Warnings and Precautions for Use, Severe skin effects; Section 4.8 Adverse Effects (Undesirable Effects)).
Neuraxial (epidural or intrathecal) administration due to the alcohol content of the solution for injection.
Prophylactic administration before major surgery, due to inhibition of platelet aggregation; and intraoperatively because of the increased risk of bleeding.
Use in pregnancy, labour, delivery or lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Children under 16 years of age.

4.4 Special Warnings and Precautions for Use

Cardiovascular thrombotic events.

Observational studies have indicated that nonselective NSAIDs may be associated with an increased risk of serious cardiovascular events, including myocardial infarction and stroke, which may increase with dose or duration of use. Patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or cardiovascular risk factors may also be at greater risk. To minimise the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration (see Section 4.2 Dose and Method of Administration). Although ketorolac trometamol has not been shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk for ketorolac.
Physicians and patients should remain alert for such CV events even in the absence of previous CV symptoms. Patients should be informed about signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
There is no consistent evidence that the concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.

Hypertension.

NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension and patients taking antihypertensives with NSAIDs may have an impaired antihypertensive response. Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.

Heart failure.

Fluid retention and oedema have been observed in some patients taking NSAIDs; therefore, caution is advised in patients with fluid retention, cardiac decompensation, heart failure, hypertension or similar conditions.

Gastrointestinal effects.

Ketorolac trometamol can cause gastrointestinal irritation, ulcers, perforation or bleeding, which can be fatal, at any time, with or without warning symptoms or a previous history of serious gastrointestinal events.
Upper gastrointestinal ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for three to six months and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious gastrointestinal effect at some time during the course of therapy. However, even short-term therapy is not without risk.
The risk of gastrointestinal bleeding, ulceration or perforation increases with dose and duration of treatment; in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation; in the elderly; and in those with a history of smoking or alcoholism. Caution is advised in these patients and treatment should commence on the lowest dose available. Combination therapy with gastroprotective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients.
Elderly and debilitated individuals are more susceptible to gastrointestinal complications (see Section 4.2 Dose and Method of Administration, Elderly (greater than or equal to 65 years) for dosage reductions in this patient group). Most reports of fatal gastrointestinal effects are in this population. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis; Crohn's disease) as their condition may be exacerbated.
Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrointestinal ulceration or bleeding, such as NSAIDs, oral corticosteroids; anticoagulants such as warfarin; selective serotonin reuptake inhibitors (SSRIs); or antiplatelet agents such as aspirin, as these combinations may increase the risk of serious gastrointestinal adverse effects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Combination therapy with gastroprotective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients.
Prescribers should warn patients about the signs and symptoms of serious gastrointestinal toxicity. Patients administered ketorolac trometamol should be instructed to advise their doctor immediately if they experience any unusual abdominal symptoms (especially gastrointestinal bleeding). Ketorolac trometamol should be discontinued, appropriate treatment instituted and the patient closely monitored.
In a nonrandomised, in hospital postmarketing surveillance study, increased rates of clinically serious gastrointestinal bleeding were seen in patients 65 years of age and under who received an average daily dose of greater than ketorolac trometamol 90 mg administered IM as compared to those patients receiving parenteral opioids.

Haematological effects.

Ketorolac trometamol inhibits platelet aggregation and may prolong bleeding time. Unlike the prolonged effects from aspirin, the inhibition of platelet function by ketorolac trometamol resolves within 24 to 48 hours after the medicine is discontinued. Ketorolac trometamol does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, the incidence of clinically significant postoperative bleeding was 5/1,170 (0.4%) compared to 1/570 (0.2%) in the control groups receiving opiates.
The use of ketorolac trometamol in patients who have coagulation disorders should be undertaken very cautiously, and those patients carefully monitored. Patients on anticoagulation therapy (e.g. heparin or warfarin) may be at increased risk of bleeding if given ketorolac trometamol concurrently (see Section 4.3 Contraindications). The concomitant use of ketorolac trometamol and prophylactic low dose heparin has not been studied extensively and may also be associated with an increased risk of bleeding. Concomitant administration of dextrans may also increase the risk of postoperative bleeding. Patients receiving other medicines that affect haemostasis should be carefully observed if ketorolac trometamol is administered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In postmarketing experience, postoperative wound haemorrhage has been reported in association with the immediate perioperative use of IM ketorolac trometamol. Therefore, ketorolac trometamol should not be used in patients who have had surgery with a high risk of haemorrhage or incomplete haemostasis. Caution should be used where strict haemostasis is critical, e.g. in cosmetic or day care surgery, resection of the prostate or tonsillectomy. Haematomata, other signs of wound haemorrhage and epistaxis have been reported with the use of ketorolac. Doctors should be aware of the pharmacological similarity of ketorolac trometamol to other NSAIDs that inhibit cyclooxygenase and the risk of bleeding, particularly in the elderly.

Severe skin effects.

NSAIDs may very rarely cause serious cutaneous adverse effects such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS) and toxic epidermal necrolysis (TEN), which can be fatal and occur without warning. These serious adverse effects are idiosyncratic and are independent of dose or duration of use.
Patients should be advised of the signs and symptoms of serious skin effects and to consult their doctor at the first appearance of a skin rash or other sign of hypersensitivity.
DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NSAID and evaluate the patient immediately.

Injection site effects.

Ketorolac trometamol injection administered IM has produced pain at the injection site in 2 to 4% of patients. Ecchymosis, bruising, haematoma and tingling at the injection site have rarely been reported. Adverse local effects may be minimised by applying pressure at the injection site for 15 to 30 seconds after administration.
There has been no evidence (e.g. alterations in serum creatine kinase (CK) or creatine phosphokinase (CPK) concentrations) of substantial adverse muscular tissue effects following single or multiple IM injections of ketorolac trometamol.

Anaphylactic reactions.

Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal oedema and angioedema) may occur in individuals with or without a history of hypersensitivity to aspirin, other NSAIDs or ketorolac trometamol. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Therefore, ketorolac trometamol should be used with caution in patients with a history of asthma and in patients with the complete or partial syndrome of nasal polyps, angioedema and bronchospasm.

Special senses.

Adverse ophthalmological effects have been observed with NSAIDs; accordingly, patients who develop visual disturbances during treatment with ketorolac trometamol should have an ophthalmological examination.

Drug abuse and physical dependence.

Ketorolac trometamol is not a narcotic agonist or antagonist. Subjects did not show any subjective symptoms or objective signs of drug withdrawal upon abrupt discontinuation of IM dosing. Ketorolac trometamol did not exhibit activity in classical animal studies which are reasonable predictors of opiate analgesic action (hot plate and tail withdrawal test). In vitro ketorolac trometamol does not bind to opiate receptors. These studies demonstrate that ketorolac trometamol does not have central opiate-like activity.

General.

Undesirable effects may be minimised by using the lowest minimum effective dose for the shortest duration necessary to control symptoms (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Ketorolac trometamol is not an anaesthetic agent and possesses no sedative or anxiolytic properties, therefore, it is not recommended as a preoperative or intraoperative medication for the support of anaesthesia when these effects are required. Ketorolac trometamol IM should not be used for spinal or epidural administration. Ketorolac trometamol IM contains ethanol 10% (see Section 4.3 Contraindications). The total duration of ketorolac trometamol treatment should not exceed five days.

Use in hepatic impairment.

As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged or may be transient with continued therapy. The ALT (SGPT) test is probably the most sensitive indicator of liver injury. Meaningful (three times the upper limit of normal) elevations of ALT or AST (SGOT) have been reported in controlled clinical trials (with the oral formulation of ketorolac trometamol) in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash), ketorolac trometamol should be discontinued.
Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac trometamol clearance. Studies to assess the pharmacokinetics of ketorolac trometamol in patients with active hepatitis or cholestasis have not been done. Physicians and patients should remain alert for hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity.
A patient with symptoms and/or signs suggesting liver dysfunction (e.g. nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant and flu-like symptoms), or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic effects while on therapy with ketorolac trometamol.

Use in renal impairment.

As with other NSAIDs that inhibit prostaglandin biosynthesis, elevations of serum urea, nitrogen, potassium and creatinine have been reported in clinical trials with ketorolac, and can occur after one dose. Ketorolac trometamol and its metabolites are eliminated primarily by the kidneys which, in patients with reduced creatinine clearance, will result in diminished clearance of the medicine. Patients with moderate to severe impairment of renal function should not receive ketorolac trometamol (see Section 4.2 Dose and Method of Administration, Mild renal impairment, for dosage reduction in patients with mild renal impairment, i.e. serum creatinine < 180 micromol/L). Ketorolac trometamol should be used with caution in patients with a history of kidney disease. Renal function should be monitored in patients who have had more than a single intramuscular dose of ketorolac, particularly in elderly patients.
As with other NSAIDs that inhibit prostaglandin biosynthesis, the following renal abnormalities may be associated with the use of ketorolac trometamol: glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, acute renal failure and hyperkalaemia. Other renal conditions/ diseases are possible.
Caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in renal prostaglandin formation and may precipitate overt renal failure. Patients at greatest risk of this effect are those who are volume depleted because of blood loss or severe dehydration, patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state. Inadequate fluid/ blood replacement during surgery, leading to hypovolaemia (see Section 4.3 Contraindications), may lead to renal dysfunction which could be exacerbated when ketorolac trometamol is administered. Therefore, volume depletion should be corrected and close monitoring of serum urea, serum creatinine and urine output is recommended until the patient is normovolaemic. In patients on renal dialysis, ketorolac trometamol clearance is reduced to approximately half the normal rate and terminal half-life increases approximately threefold.

Use in the elderly.

Because ketorolac trometamol is cleared somewhat more slowly by the elderly (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations) who are also more sensitive to the fluid retaining, gastrointestinal toxicity and renal impairment effects (see Section 4.4 Special Warnings and Precautions for Use) of this medicine, extra caution and the lowest effective dose should be used when treating the elderly with ketorolac trometamol (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety and efficacy in children have not been established, therefore, ketorolac trometamol is not recommended for use in children under 16 years of age (see Section 4.3 Contraindications).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Protein binding.

Ketorolac trometamol is highly bound to human plasma protein (mean 99.2%) and binding is independent of concentration. The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac trometamol (99.5% control versus 99.3% binding with ketorolac trometamol concentrations of 5 to 10 microgram/mL). Ketorolac trometamol does not alter digoxin protein binding.
In vitro studies indicated that at therapeutic concentrations of salicylate (300 microgram/mL), the binding of ketorolac trometamol was reduced from approximately 99.2% to 97.5%. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, paracetamol, phenytoin, tolbutamide and piroxicam did not alter ketorolac trometamol protein binding. Because ketorolac trometamol is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein bound drugs significantly.

Enzyme induction/ inhibition.

There is no evidence in animal or human studies that ketorolac trometamol induces or inhibits the hepatic enzymes capable of metabolising it or other drugs. Hence, ketorolac trometamol would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.

Warfarin.

The concurrent use of NSAIDs and warfarin has been associated with severe and sometimes fatal haemorrhage. The exact mechanism of the interaction between NSAIDs and warfarin is unknown, but may involve enhanced bleeding from NSAID induced gastrointestinal ulceration, or an additive effect of anticoagulation by warfarin and inhibition of platelet function by NSAIDs. Ketorolac trometamol should be used in combination with warfarin only if absolutely necessary, and patients taking this combination of drugs should be closely monitored.

Anticoagulant therapy and other drugs affecting haemostasis.

NSAIDs may enhance the effects of anticoagulants, such as warfarin, low molecular weight heparin and dextrans (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Haematological effects). Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued.

Aspirin and other nonsteroidal anti-inflammatory drugs.

In patients concurrently receiving aspirin or other NSAIDs, the risk of inducing serious NSAID related adverse effects may be increased (see Section 4.3 Contraindications).

Pentoxifylline (oxpentifylline).

When ketorolac trometamol is administered concurrently with pentoxifylline (oxpentifylline), there is an increased tendency to bleeding (see Section 4.3 Contraindications).

Methotrexate.

Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of ketorolac on methotrexate clearance has not been studied.

Angiotensin converting enzyme (ACE) inhibitors.

As with other NSAIDs, ketorolac may increase the risk of renal impairment associated with the use of ACE inhibitors, particularly in patients who are actually or effectively volume depleted.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly during initiation of the combination. The combination of drugs from these three classes should be used with caution, particularly in elderly patients or those with pre-existing renal impairment.

Diuretics.

Ketorolac trometamol reduces the diuretic response to frusemide in normovolaemic healthy subjects by approximately 20%.

Nephrotoxic agents.

The use of drugs with nephrotoxic activity (e.g. aminoglycoside antibiotics) should be avoided when using ketorolac trometamol.

Selective serotonin reuptake inhibitors (SSRIs).

There is an increased risk of gastrointestinal bleeding when antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

Probenecid.

Concomitant administration of oral ketorolac trometamol and probenecid resulted in decreased clearance of ketorolac trometamol and significant increases in ketorolac trometamol plasma levels (total area under the curve (AUC) increased approximately threefold from 5.4 to 17.8 microgram.hour/mL). Terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore the concomitant use of ketorolac trometamol and probenecid is contraindicated.

Lithium.

Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis inhibiting drugs. The effect of ketorolac trometamol on plasma lithium has not been studied, but cases of increased plasma levels during ketorolac trometamol therapy have been reported.

Antiepileptic drugs.

Sporadic cases of seizures have been reported during concomitant use of ketorolac trometamol and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive drugs.

Hallucinations have been reported when ketorolac trometamol was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ketorolac trometamol may impair fertility and is not recommended in women attempting to conceive.
(Category C)
Ketorolac trometamol is not recommended for use during pregnancy, labour and delivery (see Section 4.3 Contraindications).
NSAIDs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause premature closure of the fetal ductus arteriosus (see Premature closure of foetal ductus arteriosus), fetal renal impairment leading to oligohydramnios and neonatal renal impairment (see Oligohydramnios and neonatal renal impairment), inhibition of platelet aggregation, and delay labour and birth.
Continuous treatment with NSAIDs during the last trimester of pregnancy should only be given on sound indications. During the last few days before expected birth, agents with an inhibitory effect on prostaglandin synthesis should be avoided.
Reproduction studies with ketorolac trometamol have been performed in rabbits and rats at oral doses of 3.6 and 10 mg/kg/day, respectively. The results from these studies did not reveal any significant evidence of harm to the fetus.
However, studies in rabbits have shown a small increase in the incidence of major vessel anomalies.
Data from epidemiological studies suggest an increased risk of miscarriage after the use of a prostaglandin synthesis inhibitor in early pregnancy.

Premature closure of foetal ductus arteriosus.

NSAIDs may cause premature closure of the foetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at about 30 weeks of gestation (third trimester) and later. NSAIDs increase the risk of premature closure of the foetal ductus arteriosus at approximately this gestational age.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs from about 20 weeks gestation or later in pregnancy may cause foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary from about 20 weeks, limit NSAID use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue NSAID treatment if oligohydramnios occurs and follow up according to clinical practice.
 Ketorolac trometamol is not recommended for treatment of breastfeeding mothers (see Section 4.3 Contraindications).
After a single oral administration of ketorolac trometamol 10 mg to humans, the maximum milk concentration observed was 7.3 nanogram/mL and the maximum milk to plasma ratio was 0.037. After one day of dosing (four doses/day (qid)), the maximum milk concentration was 7.9 nanogram/mL and the maximum milk to plasma ratio was 0.025.

4.7 Effects on Ability to Drive and Use Machines

Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of ketorolac trometamol. If patients experience these or other similar undesirable effects, they should exercise caution in carrying out activities that require alertness.

4.8 Adverse Effects (Undesirable Effects)

Doctors using ketorolac trometamol injection should be alert for the usual complications of nonsteroidal anti-inflammatory treatment.
The adverse effects listed below were reported to be probably related to ketorolac trometamol in clinical trials in which patients received up to 20 doses, in five days, of postoperatively administered ketorolac trometamol 30 mg IM and in clinical trials in which patients received up to eight doses, in two days, of postoperatively administered ketorolac trometamol 30 mg intravenously.

Incidence between 3% and 9%.

Gastrointestinal disorders.

Nausea, dyspepsia, gastrointestinal pain.

Nervous system disorders.

Drowsiness.

Incidence between 1% and 3%.

Gastrointestinal disorders.

Diarrhoea.

General disorders and administration site conditions.

Oedema, injection site pain was reported by 2% of patients in multidose studies (compared with 5% for the morphine control group).

Nervous system disorders.

Dizziness, headache.

Skin and subcutaneous tissue disorders.

Sweating.

Incidence 1% or less.

Ear disorders.

Vertigo.

Eye disorders.

Abnormal vision.

Gastrointestinal disorders.

Constipation, flatulence, gastrointestinal fullness, liver function abnormalities, melaena, peptic ulcer, rectal bleeding, stomatitis, vomiting.

General disorders and administration site conditions.

Asthenia, excessive thirst.

Musculoskeletal and connective tissue disorders.

Myalgia.

Nervous system disorders.

Dry mouth, paraesthesia, stimulation, abnormal taste.

Psychiatric disorders.

Nervousness, abnormal thinking, depression, euphoria, insomnia, inability to concentrate.

Renal and urinary disorders.

Increased urinary frequency, oliguria.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea, asthma.

Skin and subcutaneous tissue disorders.

Pruritus, urticaria, purpura.

Vascular disorders.

Vasodilation, pallor.

Postmarketing adverse effects.

The following international postmarketing adverse effects, although rare, have been reported spontaneously for patients who have received ketorolac trometamol.

Blood and lymphatic system disorders.

Thrombocytopenia, epistaxis, haematoma, angioedema.

Cardiac disorders.

Bradycardia, palpitations, cardiac failure.

Ear disorders.

Hearing loss, tinnitus, vertigo.

Eye disorders.

Abnormal vision.

Gastrointestinal disorders.

Gastrointestinal haemorrhage, peptic ulceration, gastrointestinal perforation, nausea, vomiting, diarrhoea, flatulence, eructation, constipation, dyspepsia, abdominal pain/ discomfort, melaena, haematemesis, stomatitis, ulcerative stomatitis, oesophagitis, rectal bleeding, pancreatitis, dry mouth, fullness, exacerbation of colitis and Crohn's disease, gastritis.

General disorders and administration site conditions.

Weight gain, injection site reactions, pallor, fever, asthenia, oedema, excessive thirst, chest pain.

Hepatobiliary disorders.

Hepatitis, cholestatic jaundice, liver failure.

Immune system disorders.

Anaphylaxis, anaphylactoid reactions, hypersensitivity reactions such as flushing, rash, hypotension, bronchospasm and laryngeal oedema (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions).

Infection.

Infection, aseptic meningitis.

Investigations.

Abnormal liver function tests, increased serum urea, increased creatinine, prolonged bleeding time.

Metabolic and nutrition disorders.

Hyponatraemia, hyperkalaemia, anorexia.

Musculoskeletal and connective tissue disorders.

Myalgia.

Nervous system disorders.

Headache, dizziness, paraesthesia, convulsions, extrapyramidal symptoms, hyperkinesia, taste abnormality, dry mouth, drowsiness.

Psychiatric disorders.

Abnormal dreams, hallucinations, anxiety, psychotic reactions, abnormal thinking, depression, insomnia, nervousness, euphoria, impaired concentration ability.

Renal and urinary disorders.

Acute renal failure, urinary retention, increased urinary frequency, interstitial nephritis, nephritic syndrome, haemolytic uraemic syndrome, oliguria, flank pain with or without haematuria and/or azotaemia (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Pregnancy, puerperium and perinatal conditions.

Oligohydramnios, neonatal renal impairment.

Reproductive system and breast disorders.

Female infertility.

Respiratory, thoracic and mediastinal disorders.

Asthma, dyspnoea, pulmonary oedema.

Skin and subcutaneous tissue disorders.

Rash, Stevens-Johnson syndrome (SJS), exfoliative dermatitis, toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), maculopapular rash, Lyell's syndrome, pruritus, urticaria, purpura, sweating.

Vascular disorders.

Hypotension, hypertension, flushing, pallor, postoperative wound haemorrhage (rarely requiring blood transfusion).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Single overdoses of ketorolac trometamol have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction which have resolved after discontinuation of dosing. Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

Treatment.

Patients should be managed by symptomatic and supportive care following NSAID overdose. There are no specific antidotes. Dialysis does not significantly clear ketorolac from the blood stream.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ketorolac trometamol inhibits the synthesis of prostaglandins and is considered to be a peripherally acting analgesic. It does not have known effects on opiate receptors. No evidence of respiratory depression has been observed after administration of ketorolac trometamol in controlled clinical trials. Ketorolac trometamol possesses no sedative or anxiolytic properties.

Clinical trials.

Controlled clinical trials studying acute severe pain following major surgical procedures, e.g. cholecystectomy, gastric bypass, abdominal hysterectomy, open reduction and fixation of fractures, lumbar laminectomy and extraction of multiple impacted third molar teeth, have established the efficacy of ketorolac trometamol relative to other analgesics.
Given postoperatively, ketorolac trometamol 30 mg intramuscularly has an onset of action and peak analgesic efficacy comparable to intramuscular morphine 12 mg or pethidine 100 mg, and is more effective than intramuscular morphine 6 mg or pethidine 50 mg.
Intramuscular ketorolac trometamol 30 mg has a longer duration of action than intramuscular morphine 12 mg or pethidine 100 mg. Intramuscular ketorolac trometamol 10 mg gives efficacy equal to or greater than intramuscular morphine 6 mg or pethidine 50 mg.

Drug abuse and physical dependence.

Ketorolac trometamol is not a narcotic agonist or antagonist. Subjects did not show any subjective symptoms or objective signs of drug withdrawal upon abrupt discontinuation of intramuscular dosing. Ketorolac trometamol did not exhibit activity in classical animal studies that are reasonable predictors of opiate analgesic action (hotplate and tail withdrawal test). Ketorolac trometamol does not bind to opiate receptors in vitro. These studies demonstrate that ketorolac trometamol does not have central opiate-like activity.

5.2 Pharmacokinetic Properties

The pharmacokinetics of ketorolac in humans following single or multiple intramuscular doses are linear.

Absorption.

The intramuscular form of ketorolac is rapidly and completely absorbed (100% bioavailable). Steady-state plasma levels are achieved after dosing every six hours for one day. A mean peak plasma concentration of 2.2 microgram/mL occurs an average of 50 minutes after a single 30 mg dose.

Binding and distribution.

More than 99% of ketorolac trometamol in plasma is protein bound. Even at high plasma concentrations (10 microgram/mL) only approximately 5% of albumin binding sites will be occupied. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. Plasma protein binding is independent of concentration. As ketorolac trometamol is a highly potent medicine and present in low concentrations in plasma, it would not be expected to displace other protein bound medicines significantly. Nearly all the medicine related material circulating in plasma is ketorolac trometamol (96%) or the pharmacologically inactive p-hydroxyketorolac. The mean apparent volume (Vβ) of ketorolac trometamol following complete distribution was approximately 13 L (this parameter was determined from single dose data). Ketorolac trometamol poorly penetrates the blood brain barrier (levels in the cerebrospinal fluid were found to be 0.002 times or less than those in plasma). Ketorolac crosses the placenta mean umbilical/ maternal vein concentration ratio for ketorolac trometamol was 0.116 and this ratio increased as the time from injection to sampling increased). Ketorolac trometamol has been detected in human milk at low concentrations (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).

Metabolism.

Ketorolac trometamol is largely metabolised in the liver. The major metabolic path of ketorolac in humans is glucuronic acid conjugation. p-Hydroxylation is an additional minor pathway.

Excretion.

The primary route of excretion of ketorolac and its metabolites (conjugates and a para-hydroxy metabolite) is in the urine (mean 91.4%) and the remainder (mean 6.1%) is excreted in the faeces. The terminal plasma half-life of ketorolac is approximately in the range of five to six hours. No changes in clearance occur with chronic dosing.

Pharmacokinetics in special populations.

Use in the elderly.

The mean terminal plasma half-life of ketorolac trometamol increased from five to seven hours in the elderly (aged 65 to 78 years) compared with young healthy volunteers (based on single dose data). There was little difference in the Cmax for the two groups.

Impaired renal function.

The mean half-life of ketorolac trometamol in patients with renal impairment is between 6 and 19 hours, and is dependent on the extent of the impairment (based on single dose data). There is poor correlation between creatinine clearance and total ketorolac trometamol clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the area under the curve (AUC) increased by approximately 100% compared with healthy volunteers. The volume of distribution increases by up to 100%. The increase in volume of distribution of ketorolac trometamol implies an increase in unbound fraction. The AUC ratio of the ketorolac trometamol enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects.

Impaired hepatic function.

Patients with impaired hepatic function do not have any clinically important changes in ketorolac trometamol pharmacokinetics, although there is a statistically significant prolongation of Tmax and terminal phase half-life compared to young healthy volunteers.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are ethanol, sodium chloride, water for injections; sodium hydroxide or hydrochloric acid to adjust pH.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Container type.

Each 1 mL injection is packed in a Type 1 clear glass prefilled syringes which contains 30 mg of ketorolac trometamol.

Pack sizes.

Each carton contains 5 prefilled syringes.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 144524 - Ketoral ketorolac trometamol 30 mg/1 mL injection syringe.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Ketorolac trometamol is a member of the pyrrolo-pyrrole group of NSAIDs and is structurally and pharmacologically related to tolmetin and indometacin. However, unlike these pyrrole acetic acid derivatives, ketorolac is a cyclic propionic derivative. It is commercially available as the racemate; the (-)-(S)- isomer of ketorolac is the active isomer.
Ketorolac trometamol is a white to off white crystalline substance which discolours on exposure to light. It is soluble in water.
Chemical name: (±)-2-benzoyl-1-azabicyclo [3,3,0]octa-2,4-diene-6-carboxylic acid, 2-amino-2-hydroxymethylpropane-1,3-diol salt.
Molecular formula: C15H13NO3.
Molecular weight: 255.27.

CAS number.

74103-07-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes