Consumer medicine information

Ketorolac Juno

Ketorolac trometamol

BRAND INFORMATION

Brand name

Ketorolac Juno

Active ingredient

Ketorolac trometamol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ketorolac Juno.

SUMMARY CMI

KETOROLAC JUNO

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 KETOROLAC JUNO?

Ketorolac Juno contains the active ingredient ketorolac trometamol. Ketorolac is used to relieve pain and reduce inflammation (swelling and soreness) that may occur following surgery.

For more information, see Section 1. Why am I using KETOROLAC JUNO? in the full CMI.

2. What should I know before I use KETOROLAC JUNO?

Do not use 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 ketorolac 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.

For more information, see Section 2. What should I know before I use KETOROLAC JUNO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ketorolac 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 KETOROLAC JUNO?

Ketorolac Juno is given as an injection into a muscle by a doctor or trained nurse. The usual dose for healthy adults is 10 mg to 30 mg every 4 to 6 hours, up to a maximum daily dose of 90 mg.

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

5. What should I know while using KETOROLAC JUNO?

Things you should do
  • Call your doctor straight away if you become pregnant while being treated with ketorolac.
  • Tell your doctor if you get an infection soon after receiving ketorolac.
Things you should not do
  • You should not receive ketorolac for longer than five days. Prolonged use may increase the occurrence of side effects.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ketorolac affects you.
  • As with other NSAID medicines, ketorolac may cause dizziness or light-headedness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • If you drink alcohol, dizziness or light-headedness may be worse.
Looking after your medicine
  • Ketorolac Juno L will be stored in the pharmacy or on the hospital ward. It is kept in a cool dry place where the temperature stays below 25°C. It should be protected from light.

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

6. Are there any side effects?

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects: vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions 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 or hives, fainting, seizures or fits, pain or tightness in the chest, 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 immediately if you notice any of the following serious side effects: severe dizziness, spinning sensation, severe or persistent headache, abnormal vision, bleeding or bruising more easily than normal, reddish or purplish blotches under the skin, severe pain or tenderness in any part of the stomach or back, 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

KETOROLAC JUNO

Active ingredient(s): ketorolac trometamol

Consumer Medicine Information (CMI)

This leaflet provides important information about using ketorolac. 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 this medicine.

Where to find information in this leaflet:

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

1. Why am I using KETOROLAC JUNO?

Ketorolac Juno contains the active ingredient ketorolac trometamol. Ketorolac belongs to a group of medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

Ketorolac is used to relieve pain and reduce inflammation (swelling and soreness) that may occur following surgery. Although ketorolac can relieve the symptoms of pain and inflammation, it will not cure your condition.

Your doctor may have prescribed ketorolac for another purpose.

2. What should I know before I use KETOROLAC JUNO?

Warnings

Do not use Ketorolac Juno if you:

  • are allergic to ketorolac, aspirin or any other NSAID medicine, or any of the ingredients listed at the end of this leaflet. Many medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAID medicines. If you are not sure if you are taking any of these medicines, ask your doctor or pharmacist. If you are allergic to aspirin or NSAID medicines and use ketorolac, these symptoms may be severe. Symptoms of an allergic reaction to these medicines may include:
    - asthma, wheezing or shortness of breath
    - swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
    - hives, itching or skin rash
    - fainting
Always check the ingredients to make sure you can use this medicine.
  • are pregnant
  • are breastfeeding
  • have kidney disease
  • have severe liver disease
  • have severe heart failure
  • have recently had or are about to have heart bypass surgery
  • have a peptic ulcer (stomach or duodenal ulcer), a recent history of one, or have had peptic ulcers before
  • have had any bleeding disorders
  • have asthma
  • suffer dehydration
  • have nasal polyps syndrome, angioedema or bronchospasm (breathing difficulties)
  • have a history of Stevens-Johnsons Syndrome (a rare skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals)
  • 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
    - oxpentifylline, a medicine used to treat certain blood disorders.

Do not give this Ketorolac Juno to a child under 16 years of age. The safety and effectiveness in children under 16 have not been established.

If you are not sure if you should be given this medicine, contact your doctor.

Check with your doctor if you:

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

If you have not told your doctor about any of the above, tell them before you are given ketorolac.

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 use Ketorolac Juno if you are pregnant. Ketorolac may affect your developing baby if you receive it during pregnancy.

Ketorolac may impair fertility and is not recommended in women attempting to conceive. If it is necessary for you to be given Ketorolac Juno, your doctor will discuss the risks and benefits of receiving it.

Your must not use Ketorolac Juno if you are breast-feeding. Ketorolac passes into breast milk. The effect on the baby is not known.

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 may interfere with ketorolac and affect how it works. These include:

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

You may need to use different amounts of your medicine, or you may need to use different medicines. Your doctor will advise you.

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

4. How do I use KETOROLAC JUNO?

How Ketorolac Juno is given

  • Ketorolac Juno is given as an injection, into a muscle by a doctor or trained nurse.
  • The injection should not be injected directly into the veins (intravenously).
  • Your doctor will decide what dose you will receive.
    This depends on your condition.
  • The usual dose for healthy adults is 10 mg to 30 mg every 4 to 6 hours, up to a maximum daily dose of 90 mg.
  • If you are over 65 years old or have reduced kidney function, your doctor may prescribe a lower dose.

When Ketorolac Juno is given

  • Ketorolac Juno is given every 4 to 6 hours as required, up to a maximum daily dose of 90 mg.

How long Ketorolac Juno is given for

  • Ketorolac Juno is not given for longer than five days.
    Prolonged use may increase the occurrence of side effects.

If you receive too much Ketorolac Juno

If you receive too much ketorolac, you may have pain or tenderness in the stomach, stomach upset including nausea (feeling sick), vomiting, heartburn, indigestion or cramps. If you think that you have used too much ketorolac, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you are not sure what to do, contact your doctor or pharmacist.

5. What should I know while using KETOROLAC JUNO?

Things you should do

Call your doctor straight away if you:

  • become pregnant
  • get an infection soon after receiving ketorolac.
    Ketorolac may hide some of the signs of an infection and may make you think, mistakenly, that the infection is not serious or that you are better. Signs of an infection may include fever, pain, swelling and redness.

Remind any doctor, dentist or pharmacist you visit that you are using ketorolac.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ketorolac affects you.

As with other NSAID medicines, ketorolac may cause dizziness or light-headedness in some people. Make sure you know how you react to ketorolac before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

Ketorolac Juno will be stored in the pharmacy or on the hospital ward. It is kept in a cool dry place where the temperature stays below 25°C. It should be protected from light.

Getting rid of any unwanted medicine

If your no longer need this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Other side effects not listed here may occur in some people. Tell your doctor if you notice anything else that is making you feel unwell.

Less serious side effects

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

Serious side effects

Serious side effectsWhat to do
Head related:
  • severe dizziness, spinning sensation
  • severe or persistent headache
  • abnormal vision
Bleeding related:
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
Pain related:
  • severe pain or tenderness in any part of the stomach or back
Other:
  • unusual weight gain, swelling of ankles or legs
Tell your doctor immediately if you notice any of these side effects.
You may need urgent medical attention. These are serious side effects. Serious side effects are rare.

Very serious side effects

Very serious side effectsWhat to do
Gastrointestinal or gut related:
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage (rectum), black sticky bowel motions (stools) or bloody diarrhoea
Allergic reaction related:
  • 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 or hives
  • fainting, seizures or fits
  • pain or tightness in the chest
  • flu-like symptoms with a rash on the face then an extended rash with a high temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.
You may need urgent medical attention or hospitalisation. These side effects are rare.

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.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

Ketorolac Juno is not addictive

What Ketorolac Juno contains

Active ingredient
(main ingredient)		Each 30 mg/mL Ketorolac Juno ampoule contains 30 mg of ketorolac trometamol
Other ingredients
(inactive ingredients)		ethanol
sodium chloride
sodium hydroxide
water for injections
Allergen informationThis medicine does not contain lactose, sucrose, gluten, tartrazine or other azo dyes.

Do not take this medicine if you are allergic to any of the ingredients contained in this product.

What Ketorolac Juno looks like

A clear, colourless to slight yellow solution in 1 mL glass ampoules.

Australian registration numbers

AUST R 211626

Who distributes Ketorolac Juno

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC – 3121

This leaflet was prepared in February 2022.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Ketorolac Juno

Active ingredient

Ketorolac trometamol

Schedule

S4

 

1 Name of Medicine

Ketorolac trometamol.

2 Qualitative and Quantitative Composition

Ketorolac Juno solution for injection contains the active ingredient, ketorolac trometamol. Ketorolac trometamol (synonym ketorolac tromethamine) is a non-narcotic analgesic belonging to the non-steroidal anti-inflammatory drug (NSAID) class of medicines with analgesic, anti-inflammatory and antipyretic properties.
Ketorolac Juno solution for injection is available as a 30 mg/mL (3%) sterile solution for injection for intramuscular (IM) administration only. Excipients for the solution for injection are: ethanol, sodium chloride, water for injections and sodium hydroxide to adjust pH.

3 Pharmaceutical Form

Ketorolac Juno solution for injection: 30 mg/mL clear and colourless or slightly yellow in colour, sterile solution in glass ampoules.

4 Clinical Particulars

4.1 Therapeutic Indications

Ketorolac Juno solution for injection is indicated for the short-term management of moderately severe, acute pain following surgical procedures. The total duration of ketorolac use should not exceed five days.
It is recommended that ketorolac parenteral be used in the immediate post-operative period.
Patients can then be converted to the oral formulation (dependent on their analgesic needs), as outlined in Dose and Method of Administration (see Conversion from intramuscular to oral therapy). The total period of treatment utilising the oral and/or intramuscular route of administration is not to exceed five days.
Note that oral dosage forms are available from other brands.

General.

Ketorolac Juno solution for injection is not recommended for use as an obstetrical pre-operative medication or for obstetrical analgesia because it has not been adequately studied for use in these circumstances and because the known effects of drugs that inhibit prostaglandin biosynthesis on uterine contraction and foetal circulation.
There is no satisfactory evidence for the use of Ketorolac Juno solution for injection in acute exacerbations of chronic painful inflammatory conditions (e.g. rheumatoid or osteoarthritis).

4.2 Dose and Method of Administration

Ketorolac Juno solution for injection 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.
Product is for single use in one patient only. Discard any residue.
Opiate analgesics (e.g. morphine and pethidine) may be used concomitantly, and may be required for optimal analgesic effect in the early post-operative 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 post-operative pain without evidence of adverse interactions. Ketorolac trometamol does not exacerbate opioid-related respiratory depression or sedation. When used in association with intramuscular ketorolac trometamol the daily dose of opioid is usually less than that which is normally required.
Hypovolaemia should be corrected prior to administration of Ketorolac Juno solution for injection.
The total duration of Ketorolac Juno solution for injection administration should not exceed 5 days because adverse effects may increase with prolonged usage.

Intramuscular administration.

The intramuscular injection should be given slowly and deeply into the muscle.

Adults (under 65 years of age).

The usual recommended initial intramuscular dose is 10 mg to 30 mg, followed by 10 mg to 30 mg at 4 to 6 hourly intervals, up to a maximum daily dose of 90 mg.

Elderly (65 years of age and older).

An initial intramuscular dose of 10 mg to 15 mg, followed by 10 mg to 15 mg at 4 to 6 hourly intervals, 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 Ketorolac Juno solution for injection is used in patients with mildly impaired renal function (serum creatinine values: males between 130 and 180 micromol/L; females between 120 and 180 micromol/L) the lower end of the intramuscular dosage range should be used. The total daily dose should not exceed 60 mg. Ketorolac Juno solution for injection 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 intramuscular Ketorolac Juno solution for injection dosage range is recommended. The total daily dose should not exceed 60 mg.

Conversion from intramuscular to oral therapy.

Oral dosage form is available from other brands.
For patients being converted from intramuscular administration to oral administration, the total combined daily dose should not exceed 90 mg (60 mg for the elderly, mild renally-impaired patients and patients weighing less than 50 kg) and the oral component should not exceed 40 mg (30 mg 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

Ketorolac trometamol is contraindicated in patients:
with 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);
with dehydration or hypovolaemia from any other cause;
with severe hepatic impairment;
with 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);
with active, or a history of gastrointestinal bleeding or perforation, related to previous NSAIDs 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);
with a history of haemorrhagic diatheses, including coagulation disorders (see Section 4.4 Special Warnings and Precautions for Use, Haematologic effects);
who have had 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, Haematologic effects);
with suspected or confirmed cerebrovascular (intracranial) bleeding (see Section 4.4 Special Warnings and Precautions for Use, Haematologic effects);
on anticoagulation therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
receiving aspirin, other NSAIDs, oxpentifylline, probenecid or lithium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
with hypersensitivity to ketorolac trometamol or other NSAIDs and those 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);
with the complete or partial syndrome of nasal polyps, angioedema or bronchospasm (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions);
with a history of asthma (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions);
with a 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)).
Ketorolac trometamol is also contraindicated for:
neuraxial (epidural or intrathecal) administration due to the alcohol content of the solution for injection;
prophylactic administration before 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);
children under 16 years-of-age.

4.4 Special Warnings and Precautions for Use

Cardiovascular thrombotic events.

Observational studies have indicated that non-selective 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 has not 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 cardiovascular events even in the absence of previous cardiovascular symptoms. Patients should be informed about signs and/or symptoms of serious cardiovascular 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 anti-hypertensives with NSAIDs may have an impaired anti-hypertensive 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 3 - 6 months and in about 2 - 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 gastro-protective 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 (65 years of age and older) 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 anti-platelet 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 gastro-protective 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 physician 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 non-randomised, in-hospital post-marketing 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 90 mg of ketorolac administered intramuscularly as compared to those patients receiving parenteral opioids.

Haematologic 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 post-operative bleeding was 5/1170 (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 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 post-operative 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 post-marketing experience, post-operative wound haemorrhage has been reported in association with the immediate peri-operative use of intramuscular ketorolac trometamol. Therefore, ketorolac 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 trometamol. Physicians should be aware of the pharmacological similarity of ketorolac to other NSAIDs that inhibit cyclo-oxygenase 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 physician 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 intramuscularly 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 intramuscular 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 non-steroidal anti-inflammatory agents; 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 intramuscular 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 pre-operative or intra-operative 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 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 (3 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 etc.), 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 a 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 trometamol, 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 pre-treatment 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 clearance is reduced to approximately half the normal rate and terminal half-life increases approximately three-fold.

Use in the elderly.

Because ketorolac trometamol is cleared somewhat more slowly by the elderly (see Section 5.2 Pharmacokinetic Properties) 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 vs. 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 medicine and present in low concentrations in plasma, it would not be expected to displace other protein bound medicines 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 itself or other medicines. Hence, ketorolac trometamol would not be expected to alter the pharmacokinetics of other medicines due to enzyme induction or inhibition mechanisms.

Warfarin.

The concurrent use of NSAIDs and warfarin has been associated with severe, 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 medicines should be closely monitored.

Anticoagulant therapy and other drugs affecting haemostasis.

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

Aspirin and other NSAIDs.

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).

Oxpentifylline.

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

Probenecid.

Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately 3-fold from 5.4 to 17.8 microgram/h/mL) and terminal half-life increased approximately 2-fold from 6.6 to 15.1 hours. Therefore the concomitant use of ketorolac 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 medicines. 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.

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 trometamol on methotrexate clearance has not been studied.

ACE-inhibitors.

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

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory medicines and thiazide diuretics (triple whammy).

The use of an ACE inhibiting medicine (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory medicine (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time (Triple Whammy) increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of medicine. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly during initiation of the combination. The combination of medicines 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 medicines 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 anti-platelet agents and SSRIs are combined with NSAIDs.

Antiepileptic medicines.

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

Psychoactive medicines.

Hallucinations have been reported when ketorolac trometamol was used in patients taking psychoactive medicines (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.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (1.2 times human parenteral AUC) and 16 mg/kg (2.1 times the human parenteral AUC) respectively.
(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 closure of the foetal ductus arteriosus (see Premature closure of foetal ductus arteriosus), foetal 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.
Ketorolac trometamol and its metabolites have been shown to pass into the foetus. Safety in human pregnancy has not been established. Not recommended in pregnancy.
Reproduction studies 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 foetus. 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 nursing mothers (see Section 4.3 Contraindications).
Ketorolac trometamol is excreted in the milk of lactating rats and rabbits, and has been detected in human breast milk. A peri/postnatal study in rats showed reductions in postnatal growth and survival of the offspring when ketorolac trometamol was administered to lactating rats at oral dose levels greater than 4.8 mg/kg/day. Thus, use of ketorolac trometamol in lactating mothers is not recommended.
After a single oral administration of 10 mg of ketorolac trometamol 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 (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)

Parenteral administration.

Physicians using ketorolac trometamol Injection should be alert for the usual complications of non-steroidal 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 post-operatively administered ketorolac trometamol 30 mg intramuscularly and in clinical trials in which patients received up to 8 doses in two days, of post-operatively 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 multi-dose 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.
The following incidence of adverse effects not observed in patients receiving IM injection, but observed in approximately 600 patients and subjects receiving short-term oral therapy with the 10 mg tablet (less than 2 weeks) are listed below (oral dosage form is available from other brands).
Incidence between 1% and 2%.

Vascular disorders.

Hypertension.
Incidence 1% or less.

Gastrointestinal disorders.

Gastritis.

Post-marketing adverse effects.

The following international post-marketing 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, nephrotic syndrome, haemolytic uraemic syndrome, oliguria, flank pain with or without haematuria and/or azotemia (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Pregnancy, puerperium and perinatal conditions.

Oligohydamnios, 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, post-operative 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

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 cyclo-oxygenase enzyme system and hence synthesis of prostaglandins. It is considered to be a peripherally-acting analgesic. It does not have known effects on opiate receptors. It has no intrinsic effects on respiration and does not exacerbate opioid-related respiratory depression or sedation. Ketorolac trometamol has no significant CNS effects in animals and possesses no sedative or anxiolytic properties.

Clinical trials.

Intramuscular.

Controlled clinical trials studying acute severe pain following major surgical procedures such as 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 post-operatively, ketorolac trometamol 30 mg IM has an onset of action and peak analgesic efficacy comparable to morphine 12 mg IM or pethidine 100 mg IM, and is more effective than morphine 6 mg IM or pethidine 50 mg IM.
Ketorolac trometamol 30 mg IM has a longer duration of action than morphine 12 mg IM or pethidine 100 mg IM. Ketorolac trometamol 10 mg IM gives efficacy equal to or greater than morphine 6 mg IM or pethidine 50 mg IM.

5.2 Pharmacokinetic Properties

The pharmacokinetics of ketorolac in young healthy adult volunteers following single or multiple IM doses are linear.

Absorption.

The IM form of ketorolac trometamol is rapidly and completely absorbed (100% bioavailable). Steady-state plasma levels are achieved after dosing every 6 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.

Distribution.

More than 99% of ketorolac 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 (96%) or the pharmacologically inactive p-hydroxyketorolac.
The mean apparent volume (Vβ) of ketorolac trometamol following complete distribution is approximately 13 litres (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 was 0.116 and this ratio increased as the time from injection to sampling increased). Ketorolac 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 5-6 hours. No changes in clearance occur with chronic dosing.

Pharmacokinetics in special populations.

Elderly patients (65 years of age or older).

In the elderly, the mean terminal plasma half-life of ketorolac trometamol increases from 5 to 7 hours compared with young healthy volunteers (based on single dose data) (see Section 4.2 Dose and Method of Administration). There is little difference in the Cmax for the two groups.

Renally-impaired patients.

The mean half-life of ketorolac trometamol in renally-impaired patients 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 AUC increases 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 remains similar, indicating there is no selective excretion of either enantiomer in patients compared to healthy subjects.

Hepatically-impaired patients.

Patients with impaired hepatic function do not have any clinically important changes in ketorolac 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.

Ketorolac trometamol was not genotoxic in a series of assays for gene mutations and DNA damage. Ketorolac trometamol did not cause chromosome breakage in the mouse micronucleus test in vivo at 1590 microgram/mL, approximately 1000 times the average human plasma levels, but increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells in vitro at higher concentrations.

Carcinogenicity.

An 18 month study in mice at oral doses of ketorolac trometamol of 2 mg/kg/day (equal to 1.2 times the human systemic exposure at the maximum recommended IM dose of 90 mg/day, based on AUC) and a 24 month study in rats at oral doses of 5 mg/kg (0.7 times the human parenteral AUC) showed no evidence of tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

Shelf-life 2 years.

6.4 Special Precautions for Storage

Protect from light, store below 25°C.

6.5 Nature and Contents of Container

Ketorolac Juno solution for injection: sterile solution in amber 1 mL type I glass ampoules.

Pack size.

Ketorolac Juno solution for injection is available in packs of five ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Ketorolac trometamol is a member of the pyrrolo-pyrrole group of NSAIDs. Ketorolac trometamol is (RS)-5- benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, 2-amino-2-(hydroxymethyl) propane-1,3-diol salt. The medicine is structurally and pharmacologically related to tolmetin and indomethacin, however, unlike these pyrrole acetic acid derivatives, ketorolac is a cyclic propionic derivative. Ketorolac trometamol is a racemic mixture of [-] S and [+] R enantiomers, with the S-form having analgesic activity. Ketorolac is a white to off-white crystalline substance which discolours on exposure to light. It is soluble in water and has a pKa of 3.54.

Chemical structure.


CAS number.

74103-07-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only Medicine.

Summary Table of Changes