Consumer medicine information

Maxigesic IV

Paracetamol; Ibuprofen

BRAND INFORMATION

Brand name

Maxigesic IV

Active ingredient

Paracetamol; Ibuprofen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Maxigesic IV.

SUMMARY CMI

Maxigesic® IV

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 MAXIGESIC® IV?

Maxigesic® IV contains the active ingredients: paracetamol and ibuprofen sodium dihydrate. Maxigesic® IV is used as an an analgesic medicine which relieves pain and reduces fever due to paracetamol and also contains ibuprofen sodium dihydrate, which belongs to a group of medicines called non-steroidal anti-inflammatory drugs

For more information, see Section 1. Why am I using Maxigesic® IV? in the full CMI.

2. What should I know before I use Maxigesic® IV?

Do not use if you have ever had an allergic reaction to Maxigesic IV 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 Maxigesic® IV? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Maxigesic® IV 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 MAXIGESIC® IV?

  • Maxigesic® IV will be given as a slow infusion (drip) into a vein. Maxigesic® IV must only be given by a doctor or nurse.
  • Your doctor will decide how much Maxigesic® IV you need. You will usually be given 100 mL of Maxigesic® IV every 6 hours, as necessary.
  • More instructions can be found in Section 4. How do I use Maxigesic® IV? in the full CMI.

5. What should I know while using MAXIGESIC® IV?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Maxigesic® IV and you have, or have had, any of the following medical conditions:
  • Liver disease, kidney disease, heart disease or high blood pressure gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines,
Things you should not do
  • If you are about to be started on any new medicine tell your doctor, pharmacist or dentist that you are taking Maxigesic® IV.
  • Do not start taking any other medicine including any that you buy without a prescription from your pharmacy, supermarket, health food shop, naturopath or herbalist without first telling your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how Maxigesic® IV affects you.
  • As with other NSAIDs, Maxigesic® IV may cause dizziness, light-headedness, drowsiness, or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Your doctor may advise you to avoid alcohol as it may interfere with Maxigesic® IV
Looking after your medicine
  • Maxigesic® IV is usually stored at the hospital. However, if you need to store Maxigesic® IV:
  • keep it where children cannot reach it,
  • keep it in the original pack until it is time for it to be given,
  • keep it in a cool dry place where the temperature stays below 25°C.
  • Do not refrigerate or freeze.

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

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Maxigesic® IV.

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

Maxigesic® IV

Active ingredient(s): paracetamol and ibuprofen sodium dihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Maxigesic® IV. 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 Maxigesic® IV.

Where to find information in this leaflet:

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

1. Why am I using MAXIGESIC® IV?

Maxigesic® IV contains the active ingredients paracetamol and ibuprofen sodium dihydrate. Maxigesic® IV is used as an an analgesic medicine which relieves pain and reduces fever due to paracetamol and contains ibuprofen sodium dihydrate, which belongs to a group of medicines called non-steroidal anti-inflammatory drugs. Ibuprofen relieves pain, inflammation and fever.

Maxigesic® IV is a solution which is given by intravenous (IV) infusion directly into a vein, and is used to relieve pain or reduce fever. Your doctor may have prescribed Maxigesic® IV for another reason.

Ask your doctor if you have any questions about why Maxigesic® IV has been prescribed for you.

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

2. What should I know before I use MAXIGESIC® IV?

Warnings

Do not use Maxigesic® IV if:

  • you are allergic to paracetamol, ibuprofen, or any of the ingredients listed at the end of this leaflet.
  • you are allergic to aspirin or any other NSAIDs
    (Symptoms of an allergic reaction may include:
    - asthma, wheezing or coughing,
    - shortness of breath, difficulty breathing,
    - swelling of the face, lips, tongue which may cause difficulty in swallowing or breathing,
    - hives, itching or skin rash,
    - stomach ache, fever, chills, nausea and vomiting,
    - fainting.)
  • You regularly drink large quantities of alcohol.
  • You are having heart bypass surgery. It may increase your chance of a heart attack or a stroke (damage to part of the brain caused by an interruption to its blood supply).
  • You have impaired kidney function, impaired liver function, heart problems or heart failure.
  • You have (or have previously):
    - vomited blood or material that looks like ground coffee,
    - bled from the rectum (back passage), have black sticky bowel motions (stools) or bloody diarrhoea,
    - had a peptic ulcer (i.e. ulcer in the stomach or part of the small intestine), a recent history of one, or have had peptic ulcers before,
    - had ulcerative colitis (inflammation of the colon) or Crohn's disease.
  • You have a spinal cord injury. It may increase the risk of bleeding in this area.
  • You are pregnant or planning to become pregnant.
  • You are breastfeeding or planning to breastfeed.
  • If you are not sure whether you should be given Maxigesic® IV, talk to your doctor.

Check with your doctor if you:

  • have any other medical conditions such as allergies to:
  • any other medicines including aspirin or any other NSAID, or any other substances such as, foods, preservatives or dyes.
  • take any medicines for any other condition
  • liver disease (including Gilbert's syndrome)
  • kidney disease
  • alcoholism
  • heart disease or high blood pressure
  • heart failure
  • swelling of ankles or feet
  • shortness of breath
  • fatigue, chest pain, palpitations
  • heartburn, indigestion, or an uncomfortable feeling in the stomach or belching after eating
  • diarrhoea
  • vomiting blood or material that looks like ground coffee
  • bled from the back passage, have black sticky bowel motions (stools) or bloody diarrhoea
  • a peptic ulcer (i.e. ulcer in the stomach or part of the small intestine), a recent history of one, or have had peptic ulcers before
  • ulcerative colitis (inflammation of the colon) or Crohn's disease
  • any other stomach or bowel problem
  • eating disorders (anorexia, bulimia)
  • a wasting syndrome including unexplained weight loss, fatigue, weakness and loss of appetite (cachexia)
  • malnutrition (low reserves of glutathione)
  • a metabolic condition called glucose-6-phosphate dehydrogenase deficiency (G6PD)
  • hypovolaemia (decreased blood volume)
  • a severe skin rash, flaking or peeling of the skin or reactions such as Stevens-Johnson syndrome
  • asthma, breathlessness, wheezing, a cough sometimes brought on by exercise and/or a feeling of tightness in the chest
  • vision problems
  • liver or kidney disease or impairment
  • dehydration
  • tendency to bleed, disease of blood clotting or other blood problems
  • recent spinal or epidural pain relief
  • tiredness, headaches, dizziness and looking pale
  • systemic lupus erythematosus (SLE) and/or related connective tissue diseases
  • signs or symptoms of an infection.

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

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

There are no adequate, well-controlled studies in pregnant women. As there is insufficient information on the use of Maxigesic® IV during pregnancy, its use during pregnancy or in patients planning to become pregnant is contraindicated.

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 Maxigesic® IV and affect how it works.

  • aspirin, salicylates or other NSAIDs, medicines used to treat pain, inflammation or swelling,
  • aminoglycoside medicines, used to treat certain infections,
  • antibiotics, including chloramphenicol, and those containing amoxicillin plus clavulanic acid,
  • anticonvulsants, medicines used to treat epilepsy or fits, such as phenytoin or carbamazepine,
  • antidiabetic medicines,
  • barbiturates, such as amytal sodium or phenobarbitone,
  • busulfan, an anti-cancer drug,
  • diflunisal, an anti-inflammatory drug,
  • warfarin or other anti-coagulant medicines used to prevent blood clots,
  • cardiac glycosides, medicines used to treat heart failure such as digoxin,
  • medicines used to treat high blood pressure or other heart conditions,
  • corticosteroids, such as prednisone or cortisone,
  • cyclosporine or tacrolimus, medicines used to treat certain problems with the immune system or to help prevent organ transplant rejection,
  • diuretics, may also be called water tablets,
  • flucloxacillin (antibiotic), due to a serious risk of blood and fluid abnormality (called metabolic acidosis) that must have urgent treatment,
  • gingko biloba, a herbal medicine,
  • isoniazid, an anti-tuberculosis drug,
  • lithium, a medicine used to treat some types of depression including bipolar disorder,
  • other forms of paracetamol, such as tablets, liquid preparations or capsules,
  • methotrexate, a medicine used to treat arthritis and some types of cancer,
  • mifepristone, a medicine used for medical abortion,
  • probenecid, a medicine used to treat gout, or that is given with antibiotics,
  • quinolone antibiotics, medicines used to treat certain infections,
  • zidovudine, a medicine used to treat HIV.

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

4. How do I use Maxigesic® IV?

How much to take / use

Maxigesic® IV will be given as a slow infusion (drip) into a vein.

Maxigesic® IV must only be given by a doctor or nurse. Your doctor will decide how much Maxigesic® IV you need. You will usually be given 100 mL of Maxigesic® IV every 6 hours, as necessary.

Your doctor may give you a different amount depending on your condition. Your doctor will decide how long you need to be given Maxigesic® IV.

Follow the instructions provided and use Maxigesic® IV until your doctor tells you to stop.

If you use too much Maxigesic® IV

Maxigesic® IV must only be given by a doctor or nurse so overdose is unlikely.

If you think you have been given too much Maxigesic® IV, You should immediately:

  • phone the Poisons Information Centre in Australia (by calling 13 11 26), or the National Poisons Centre in New Zealand (telephone 0800 POISON or 0800 764 766)
  • 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.

Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.

5. What should I know while using Maxigesic® IV?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using Maxigesic® IV.

Do not start taking any other medicine including any that you buy without a prescription from your pharmacy, supermarket, health food shop, naturopath or herbalist without first telling your doctor.

Call your doctor straight away if you:

  • You have allergies to:
    - any other medicines including aspirin or any other NSAID,
    - any other substances such as, foods, preservatives or dyes.
  • You are pregnant or intend to become pregnant.
    Maxigesic® IV should not be used during pregnancy.
  • You are breastfeeding or planning to breastfeed. It is not known whether Maxigesic® IV passes into breast milk.
  • You have, or have had, any of the following medical conditions:
    - liver disease (including Gilbert's syndrome)
    - kidney disease
    - alcoholism
    - heart disease or high blood pressure
    - heart failure
    - swelling of ankles or feet
    - shortness of breath
    - fatigue, chest pain, palpitations
    - heartburn, indigestion, or an uncomfortable feeling in the stomach or belching after eating
    - diarrhoea
    - vomiting blood or material that looks like ground coffee
    - bled from the back passage, have black sticky bowel motions (stools) or bloody diarrhoea
    - a peptic ulcer (i.e. ulcer in the stomach or part of the small intestine), a recent history of one, or have had peptic ulcers before
    - ulcerative colitis (inflammation of the colon) or Crohn's disease
    - any other stomach or bowel problem
    - eating disorders (anorexia, bulimia)
    - a wasting syndrome including unexplained weight loss, fatigue, weakness and loss of appetite (cachexia)
    - malnutrition (low reserves of glutathione)
    - a metabolic condition called glucose-6-phosphate dehydrogenase deficiency (G6PD)
    - hypovolaemia (decreased blood volume)
    - a severe skin rash, flaking or peeling of the skin or reactions such as Stevens-Johnson syndrome
    - asthma, breathlessness, wheezing, a cough sometimes brought on by exercise and/or a feeling of tightness in the chest
    - vision problems
    - liver or kidney disease or impairment
    - dehydration
    - tendency to bleed, disease of blood clotting or other blood problems
    - recent spinal or epidural pain relief
    - tiredness, headaches, dizziness and looking pale
    - systemic lupus erythematosus (SLE) and/or related connective tissue diseases
    - signs or symptoms of an infection.

If you have not told your doctor about any of the above, tell him/her before you are given Maxigesic® IV.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Maxigesic® IV affects you.

As with other NSAIDs, Maxigesic® IV may cause dizziness, light-headedness, drowsiness, or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol. Your doctor may advise you to avoid alcohol as it may interfere with Maxigesic® IV.

Looking after your medicine

Maxigesic® IV is usually stored at the hospital. However, if you need to store Maxigesic® IV:

  • keep it where children cannot reach it,
  • keep it in the original pack until it is time for it to be given,
  • keep it in a cool dry place where the temperature stays below 25°C.

Do not refrigerate or freeze.

Follow the instructions in the carton on how to take care of your medicine properly.

When to discard your medicine

Maxigesic® IV should not be given to you:

  • if the expiry date (EXP) printed on the pack has passed,
  • if the package is torn or shows signs of tampering.

Your doctor or nurse will check these things for you.

Getting rid of any unwanted medicine

If you no longer need to use 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.

Do not be alarmed by this list of possible adverse effects.

You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • feeling unwell,
  • nausea or vomiting,
  • loss of appetite or changes to the taste of food,
  • cramps, wind, constipation or diarrhoea,
  • heartburn /indigestion or an uncomfortable feeling in the stomach or belching after eating,
  • headache,
  • tiredness,
  • dizziness or light-headedness,
  • numbness or ‘pins and needles’,
  • fever or feeling hot,
  • sleeplessness,
  • itchy, red or painful skin,
  • excessive sweating.
The above list includes the more common side effects of your medicine. They are usually mild.		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
  • allergic reaction - 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,
  • severe pain or tenderness in the stomach,
  • eye problems such as blurred vision, sore red eyes, itching,
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers,
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin,
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale,
  • yellowing of the skin and/or eyes, also called jaundice,
  • unusual weight gain, swelling of ankles or legs,
  • severe or persistent headache,
  • fast or irregular heartbeats, also called palpitations,
  • excessive thirst, weakness, tiredness.
The above list includes serious side effects that may require medical attention. Serious side effects are rare.		Call your doctor straight away if you notice any of these serious side effects.
  • bleeding from the back passage, 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, breathlessness sudden or severe itching, skin rash, hives,
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens-Johnson Syndrome),
  • fever, generally feeling unwell, nausea, stomach ache, headache and stiff neck,
  • vomiting blood or material that looks like ground coffee,
  • severe nausea, dizziness, numbness, drooping in your mouth or eye, difficulty in speaking or paralysis,
  • sudden and oppressive chest pain,
  • breathlessness, difficulty breathing when lying down, or swelling of the feet or legs.
  • metabolic acidosis (a blood and fluid abnormality) in patients with severe illnesses, including severe renal impairment or sepsis or malnutrition, chronic alcoholism or if you are also taking flucloxacillin when paracetamol is used at regular doses for a prolonged period or when paracetamol is taken together with flucloxacillin. Symptoms of metabolic acidosis may include serious breathing difficulties with deep rapid breathing, drowsiness, nausea and vomiting.
The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.
Other adverse effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these 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:
In Australia: Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems.
In New Zealand: Centre for Adverse Reactions Monitoring (CARM) at pophealth.my.site.com/carmreportnz/s/. 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.

What Maxigesic® IV contains

One 100 mL vial of Maxigesic® IV contains:

Active ingredient
(main ingredient)
  • Paracetamol 1000 mg (1 g)
  • Ibuprofen (as sodium dihydrate) 300 mg
Other ingredients
(inactive ingredients)
  • Cysteine hydrochloride monohydrate
  • Dibasic sodium phosphate dihydrate
  • Mannitol
  • Hydrochloric acid (for pH adjustment)
  • Sodium hydroxide (for pH adjustment)
  • Water for injections
Potential allergensThis medicine contains 35.06 mg of Sodium per 100 mL (0.35 mg/mL)

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

What Maxigesic® IV looks like

Maxigesic® IV is a clear, colourless solution free from visible particles. It is supplied in a clear glass vial that is closed with a stopper and an aluminium flip-off cap. (Aust R 301145).

Who distributes Maxigesic® IV

Maxigesic® IV is distributed in Australia by:

AFT Pharmaceuticals Pty Ltd113 Wicks Road
North Ryde
NSW 2113
Phone: 1800 238 74276

Maxigesic® IV is distributed in New Zealand by:

AFT Pharmaceuticals Ltd
PO Box 33-203
Takapuna
Auckland 0740
Phone: 0800 423 823

This leaflet was prepared in May 2025.

Published by MIMS July 2025

BRAND INFORMATION

Brand name

Maxigesic IV

Active ingredient

Paracetamol; Ibuprofen

Schedule

S4

 

1 Name of Medicine

Paracetamol 1000 mg/ibuprofen (as sodium dihydrate) 300 mg in 100 mL solution for infusion.

2 Qualitative and Quantitative Composition

Each 100 mL vial contains paracetamol 1000 mg and ibuprofen (as sodium dihydrate) 300 mg.

Excipients with known effect.

Sodium 35.06 mg per 100 mL (0.35 mg/mL).
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for infusion.
Clear, colourless solution, free from visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Maxigesic IV is indicated in adults for the relief of mild to moderate pain and the reduction of fever, where an intravenous route of administration is considered clinically necessary.

4.2 Dose and Method of Administration

Dose.

Administer one vial (100 mL) Maxigesic IV as a 15-minute infusion every 6 hours, as necessary. Do not exceed a total daily dose of 4000 mg (4 g) paracetamol.
Special populations.

Paediatric population.

The safety and efficacy of Maxigesic IV in children aged under 18 years have not been established.

Elderly.

Clinical studies of Maxigesic IV did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently to younger subjects. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients are at increased risk for serious GI adverse events (see Section 4.4, Gastrointestinal effects: risk of ulceration, bleeding, and perforation).

Renal impairment.

Caution is also recommended in patients with pre-existing renal disease. No information is available from controlled clinical studies regarding the use of Maxigesic IV in patients with advanced renal disease. If Maxigesic IV therapy must be initiated in patients with advanced renal disease, closely monitor the patient's renal function.

Hepatic impairment.

The use of paracetamol at higher than recommended doses can lead to hepatotoxicity and even hepatic failure and death.
A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), Maxigesic IV should be discontinued.

Adverse gastrointestinal events.

To minimise the potential risk for an adverse GI event in patients treated with a NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected.
This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Method of administration.

Maxigesic IV should be administered as a 15-minute intravenous infusion.
Visually inspect Maxigesic IV for particulate matter and discolouration prior to administration, whenever solution and container permit. If visibly opaque particles, discolouration or other foreign particulates are observed, the solution should not be used.
Maxigesic IV should be used in one patient on one occasion only. It contains no antimicrobial preservative. Unused solution should be discarded.
As for all solutions for infusion presented in glass vials, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of administration route. This monitoring at the end of the infusion applies particularly for central route infusion, in order to avoid air embolism.
It is recommended that for the administration of Maxigesic IV a syringe or giving set with a diameter equal to or below 0.8 mm should be used for solution sampling. In addition, it is recommended that the bung is pierced at the location specifically designed for needle introduction (where the thickness of the bung is the lowest). If these recommendations are not adhered to the likelihood of bung fragmentation or the bung being forced into the vial is increased.
To facilitate administration, the label attached to the vials of Maxigesic IV allow for hanging.

4.3 Contraindications

Maxigesic IV is contraindicated:
in patients with hypersensitivity to the active substances or to any of the excipients listed, see Section 6.1;
in patients with active alcoholism, as chronic excessive alcohol ingestion may predispose patients to paracetamol hepatoxicity (due to the paracetamol component);
in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients (see Section 4.4);
for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see Section 4.4);
in patients with impaired kidney function, impaired liver function, heart problems or heart failure;
in patients with active gastrointestinal bleeding, peptic ulceration or other stomach disorders;
in patients with spinal cord injuries;
during pregnancy or in patients planning to become pregnant;
during breastfeeding.
It is recommended to use a suitable analgesic oral treatment as soon as this administration route is possible.
In order to avoid the risk of overdose, check that other medicines administered do not contain paracetamol.
Doses higher than the recommended entail a risk of very serious liver damage. Clinical symptoms and signs of liver damage are usually seen first after two days with a maximum usually after 4 to 6 days.
Treatment with antidote should be given as soon as possible (see Section 4.2).

4.4 Special Warnings and Precautions for Use

Maxigesic IV should be used with caution in cases of:
Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency (may lead to haemolytic anaemia);
anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione);
dehydration, hypovolemia. (See Section 4.2; Section 5.2).

Maximum daily dose.

The total dose of paracetamol should not exceed 4 g per day. It is important to consider the contribution of all paracetamol-containing medications, including non-prescription, oral or PR forms of the drug to this total daily paracetamol dose prior to administering Maxigesic IV. If the daily dose of paracetamol from all sources exceeds the maximum, severe hepatic injury may occur (see Section 4.9).

Duration of dosage.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Maxigesic IV should be administered as a 15-minute intravenous infusion of 1000 mg paracetamol and 300 mg ibuprofen (as sodium dihydrate) in 100 mL, every 6 hours as necessary. Do not exceed a total daily dose of 4000 mg (4 g) paracetamol. Use of the recommended maximum dose of Maxigesic IV of 100 mL every 6 hours has only been studied for a period of up to 2 days.

Hepatic injury.

Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition or dehydration may be at a higher risk of liver damage following administration of Maxigesic IV.

Cardiovascular thrombotic events.

All NSAIDs, including the ibuprofen in Maxigesic IV, have been associated with an increased risk of cardiovascular and thrombotic adverse events when taken long-term.
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimise the potential risk for an adverse CV event in patients treated with a NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and a NSAID does increase the risk of serious gastrointestinal (GI) events.

Hypertension.

NSAIDs, including the ibuprofen in Maxigesic IV, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including Maxigesic IV, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking ACE inhibitors, thiazides, or loop diuretics may have an impaired response to these therapies when taking NSAIDs.

Congestive heart failure and oedema.

Fluid retention and oedema have been observed in some patients taking NSAIDs. Use Maxigesic IV with caution in patients with fluid retention or heart failure.

Gastrointestinal effects: risk of ulceration, bleeding, and perforation.

Serious GI toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to 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 thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
Studies have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
Most reports of spontaneous fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.
To minimise the potential risk for an adverse GI event in patients treated with a NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Serious skin reactions.

NSAIDs, including the ibuprofen in Maxigesic IV, can cause serious skin adverse reactions such as acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), Drug Reaction with Eosinophilia with Systemic Symptoms (DRESS) (see Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome) and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue Maxigesic IV at the first appearance of skin rash or any other sign of hypersensitivity (also see Section 4.3).

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

DRESS syndrome has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS syndrome 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 syndrome 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 the NSAID and evaluate the patient immediately.

Pre-existing asthma.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, including bronchospasm, Maxigesic IV is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma (also see Section 4.3).

Ophthalmological effects.

Blurred or diminished vision, scotomata, and changes in colour vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and colour vision testing.

Hepatic effects.

Borderline elevations of one or more liver tests may occur in some patients taking NSAIDs, including the ibuprofen in Maxigesic IV. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in small numbers of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions have been reported, including jaundice, fulminant hepatitis, liver necrosis and hepatic failure, some with fatal outcomes. A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), Maxigesic IV should be discontinued.

Renal effects.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose dependent reduction in renal prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors, or angiotensin receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
Caution is also recommended in patients with pre-existing renal disease. No information is available from controlled clinical studies regarding the use of Maxigesic IV in patients with advanced renal disease. If Maxigesic IV therapy must be initiated in patients with advanced renal disease, closely monitor the patient's renal function.
Renal tubular acidosis and hypokalaemia may occur following treatment with ibuprofen. The risk is increased with higher doses of ibuprofen and following acute overdose, however it may also occur within the recommended dose range.
Presenting signs and symptoms may include reduced level of consciousness and generalised weakness. Ibuprofen induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis.

Aseptic meningitis.

Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease.
If signs or symptoms of meningitis develop in a patient on Maxigesic IV, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy.

Haematological effects.

Anaemia may occur in patients receiving NSAIDs, including the ibuprofen in Maxigesic IV. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. In patients on long-term treatment with NSAIDs, including ibuprofen, check haemoglobin or haematocrit if they exhibit any signs or symptoms of anaemia or blood loss.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effects on platelet function are less severe quantitatively, of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

High anion gap metabolic acidosis.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

Masking inflammation and fever.

The pharmacological activity of ibuprofen in Maxigesic IV in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed non-infectious, painful conditions.

Anaphylactoid reactions.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. Maxigesic IV is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (also see Section 4.3).

Patients receiving spinal or epidural analgesia.

As potential bleeding around the spinal cord has serious consequences, caution should be exercised when treating patients undergoing spinal and epidural analgesia.

Monitoring.

Serious GI tract ulcerations and bleeding can occur without warning symptoms, therefore physicians should monitor for signs or symptoms of GI bleeding.
Patients on long-term treatment with NSAIDs should have full blood count (FBC) and chemistry profiles checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash), or abnormal liver tests persist or worsen, discontinue Maxigesic IV.

Special precautions.

In order to avoid exacerbation of disease or adrenal insufficiency, patients who have been on prolonged corticosteroid therapy should have their therapy tapered slowly rather than discontinued abruptly when products containing ibuprofen are added to the treatment program.

In-house compounded solutions.

Maxigesic IV has been specifically formulated to provide a stable solution of paracetamol and ibuprofen. Commercially available formulations of each active ingredient alone should not be mixed together in order to produce a substitute for Maxigesic IV, as precipitation may occur.

Use in the elderly.

Decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy, are more common in the elderly population. In addition, elderly patients are at increased risk of serious GI adverse events. Dose selection in elderly patients should be cautious (see Section 4.2; Section 4.4, Gastrointestinal effects: risk of ulceration, bleeding, and perforation).

Paediatric use.

Maxigesic IV is indicated for use in adults only; safety and efficacy in children aged under 18 years have not been established (see Section 4.2).

Effects on laboratory tests.

Using current analytical systems, paracetamol does not cause interference with laboratory assays. However, there are certain methods with which the possibility of laboratory interference exists, as described below.

Blood tests.

Paracetamol at recommended doses does not appear to interfere with glucose analysis using currently marketed blood glucose meters. For further detail, it may be advisable to contact the specific laboratory instrumentation manufacturer.

Urine tests.

Paracetamol in therapeutic doses may interfere with the determination of 5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may be eliminated by avoiding paracetamol ingestion several hours before and during the collection of the urine specimen.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Aminoglycosides.

NSAIDs may decrease the excretion of aminoglycosides.

Anticoagulants.

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a higher risk of serious GI bleeding than users of either drug alone (see Section 4.4).

Antidiabetic medicines.

These medicines may interact with ibuprofen.

Aspirin.

When ibuprofen is administered with aspirin, ibuprofen's protein binding is reduced, although the clearance of free ibuprofen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Maxigesic IV and aspirin is not generally recommended because of the potential for increased adverse effects.

Busulfan.

Busulfan is eliminated from the body via conjugation with glutathione. Concomitant use with paracetamol may result in reduced busulfan clearance.

Cardiac glycosides.

NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma cardiac glycoside levels. Care should therefore be taken in patients treated with cardiac glycosides.

Chloramphenicol.

Paracetamol may increase chloramphenicol plasma concentrations.

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

NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Ibuprofen, like other NSAIDs, can reduce the antihypertensive effect of ACE inhibitors and beta-blockers with possible loss of blood pressure control and can attenuate the natriuretic effects of thiazide diuretics and frusemide. Diuretics can also increase the risk of nephrotoxicity of NSAIDs. The combined use of the three classes of drugs, thiazides, an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist) and an anti-inflammatory drug (NSAID or COX-2 inhibitor) all at the same time increases the risk of renal impairment (see Section 4.4, Renal effects).

Corticosteroids.

Increased risk of gastrointestinal bleeding.

Cyclosporine or tacrolimus.

Increased risk of nephrotoxicity when used with NSAIDs.

Diflunisal.

Concomitant diflunisal increases paracetamol plasma concentrations and this may increase hepatotoxicity.

Diuretics.

Clinical studies and postmarketing observations have shown that ibuprofen can reduce the natriuretic effects of frusemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe patients closely for signs of renal failure, as well as to assure diuretic efficacy (see Section 4.4).

Enzyme-inducing agents.

Caution should be paid to the concomitant intake of enzyme-inducing agents. These substances include but are not limited to: barbiturates, isoniazid, anticoagulants, zidovudine, amoxicillin + clavulanic acid, carbamazepine and ethanol. Induction of metabolism of paracetamol from enzyme inducers may result in an increased level of hepatotoxic metabolites.

Flucloxacillin.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see Section 4.4).

Herbal extracts.

Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

Lithium.

Maxigesic IV should be avoided in patients taking lithium as NSAIDs have produced elevations of plasma lithium levels and a reduction in renal lithium clearance.

Methotrexate.

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.

Mifepristone.

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Phenytoin.

Phenytoin administered concomitantly may result in decreased paracetamol effectiveness and an increased risk of hepatotoxicity. Patients receiving phenytoin therapy should avoid large and/or chronic doses of paracetamol. Patients should be monitored for evidence of hepatotoxicity. Phenytoin may also interact with ibuprofen.

Probenecid.

Probenecid causes an almost 2-fold reduction in clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction of the paracetamol dose should be considered for concomitant treatment with probenecid. Probenecid may also interact with ibuprofen.

Quinolone antibiotics.

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Zidovudine.

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Monitoring.

Serious GI tract ulcerations and bleeding can occur without warning symptoms, therefore physicians should monitor for signs or symptoms of GI bleeding.
Patients on long-term treatment with NSAIDs should have FBC and chemistry profiles checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash), or abnormal liver tests persist or worsen, discontinue Maxigesic IV.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Maxigesic IV on fertility are unknown.
Intravenous paracetamol (administered as propacetamol) had no effect on fertility of rats at systemic exposure levels (based on AUC) greater than twice those anticipated at the maximum clinical dose.
In rats, fertility was not affected by dietary administration of ibuprofen 20 mg/kg/day to males and females from prior to mating through organogenesis, or by oral administration to females at up to 180 mg/kg/day throughout gestation. In rabbits, oral administration of ibuprofen 60 mg/kg/day throughout gestation was associated with reduced implantations and live litter size, along with maternotoxicity; the no-effect dose was 20 mg/kg/day (also see Section 4.6, Use in pregnancy).
(Category C)
There are no adequate, well-controlled studies in pregnant women. As there is insufficient information on the use of Maxigesic IV during pregnancy, its use during pregnancy or in patients planning to become pregnant is contraindicated (also see Section 4.3 Contraindications).
Ibuprofen is contraindicated in 3rd trimester of pregnancy.
Ibuprofen should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. If there is a compelling need for NSAID treatment during the first or second trimester, limit use to the lowest effective dose and shortest duration possible.
Data from epidemiological studies suggest an increased risk of miscarriage and congenital malformation associated with NSAIDs use in early pregnancy.
Use of NSAIDs in the second or third trimester may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Oligohydramnios is generally seen after days to weeks of treatment, although it has been reported as soon as 48 hours after NSAID initiation. Oligohydramnios is usually, but not always, reversible after treatment discontinuation. Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with ibuprofen if oligohydramnios occurs.
NSAID use during the 3rd trimester may cause premature closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation, and may delay labour and birth. NSAID use in the 3rd trimester of pregnancy is therefore contraindicated.
Prior to week 30 of pregnancy, Maxigesic IV should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. From week 30 of pregnancy, Maxigesic IV and other NSAIDs can cause foetal harm and should be avoided by pregnant women. During the last few days before expected birth, NSAIDs should be avoided.
There was no evidence of developmental abnormalities following oral administration of ibuprofen to rats and rabbits throughout gestation at respective doses up to 180 and 60 mg/kg/day.
Paracetamol has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
The reproductive toxicity of IV paracetamol has not been directly tested in animal studies. IV administration of maternotoxic doses of the pro-drug, propacetamol, to pregnant rats and rabbits during organogenesis increased the incidence of extranumerary ribs and sacral vertebrae (normal variations in these species) at 0.7-fold (rabbits; mg/m2 basis) and 7-fold (rats; AUC basis) the maximum anticipated clinical exposure to paracetamol. The clinical significance of these findings is not known. No signs of pre/post-natal toxicity were observed in rats treated with IV propacetamol at maternal exposures (based on AUC) greater than 3-fold those anticipated at the maximum clinical dose.

Labour and delivery.

The effects of Maxigesic IV on labour and delivery in pregnant women are unknown but, based on the known pharmacology of ibuprofen, administration is not recommended as the onset of labour may be delayed and the duration increased with a greater bleeding tendency in both mother and child (also see Section 4.6, Use in pregnancy).
 After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported.
No signs of toxicity were observed in rat pups of dams that received IV propacetamol postpartum at maternal exposures (based on AUC) greater than twice those anticipated at the maximum clinical dose.
It is not known whether ibuprofen and/or its metabolites are excreted in human milk. Because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants from IV ibuprofen, Maxigesic IV is contraindicated for use in nursing mothers (also see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned about the potential for drowsiness, dizziness, light-headedness, or blurred vision and advised not to drive or operate machinery if these symptoms occur or until their individual susceptibility is known.

4.8 Adverse Effects (Undesirable Effects)

a. Summary of the safety profile.

Clinical trials with Maxigesic IV have not indicated any undesirable effects other than those for paracetamol alone or ibuprofen alone.
In a phase III study in 276 patients undergoing bunionectomy surgery, the most common treatment emergent adverse events (TEAEs) were gastrointestinal disorders (38.8%), followed by nervous system disorders (28.6%). The incidence of TEAEs was comparable between the Maxigesic IV, ibuprofen, paracetamol and placebo groups, with the exception of vomiting which was significant for the comparison between Maxigesic IV and ibuprofen or placebo (but not paracetamol), suggesting that the vomiting reported by patients in the Maxigesic IV group is attributable to the paracetamol component of the combination, rather than an effect unique to the combination (Table 1).

b. Tabulated summary of adverse reactions.

A tabulated summary of TEAEs is presented in Table 2. These TEAEs are consistent with the postoperative setting and the use of paracetamol or ibuprofen for analgesia.

Post-marketing experience.

Oligohydramnios, neonatal renal impairment.

Adverse reactions with 'unknown' frequency.

Skin and subcutaneous tissue disorders.

Drug reaction with eosinophilia with systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), photosensitivity reactions, renal tubular acidosis*, hypokalaemia*, high anion gap metabolic acidosis.
*The risk is increased with higher doses of ibuprofen and following acute overdose, however it may also occur within the recommended dose range.

Description of selected adverse reactions.

High anion gap metabolic acidosis.

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see Section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

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 https://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting (New Zealand).

4.9 Overdose

There is a risk of poisoning, particularly in elderly subjects, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition and in patients receiving enzyme inducers. Poisoning may be fatal in these cases. Acute overdose with paracetamol may also lead to acute renal tubular necrosis.
Renal tubular acidosis and hypokalaemia may occur. Symptoms may include reduced level of consciousness and generalised weakness (see Section 4.4; Section 4.8).

Symptoms.

Symptoms of paracetamol overdose generally appear within the first 24 hours and comprise of nausea, vomiting, anorexia, pallor and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. Acute renal failure with acute tubular necrosis may develop in the absence of severe liver damage. Cardiac arrhythmias have been reported. Overdose, 7.5 g or more of paracetamol in a single administration in adults, causes cytolytic hepatitis likely to induce complete and irreversible hepatic necrosis, resulting in acute or fulminant hepatic failure, hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death.
Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with decreased prothrombin levels that may appear 12 to 48 hours after administration. Clinical symptoms of liver damage are usually evident initially after two days, and reach a maximum after 4 to 6 days.
The following signs and symptoms have occurred in individuals following an overdose of oral ibuprofen: abdominal pain, nausea, vomiting, drowsiness, dizziness, convulsion, and rarely, loss of consciousness.

Treatment.

The Rummack-Matthews nomogram relates plasma levels of paracetamol and the time after oral ingestion to the predicted severity of liver injury. The relation of parental paracetamol levels in overdose to liver toxicity has not been examined. Advice or treatment protocols based on oral paracetamol overdoses may not accurately predict the incidence of liver toxicity or need for antidote therapy in Maxigesic IV overdose.

Emergency measures.

Immediate hospitalisation.
Before beginning treatment, take blood for plasma paracetamol assay, as soon as possible after the overdose.
Treatment of paracetamol overdose may include the antidote N-acetyl cysteine (NAC) by the IV or oral route. In overdoses of oral paracetamol NAC is administered, if possible, before 10 hours but may give some degree of protection from liver toxicity even after this time. The optimal time for administration of NAC and necessary duration of therapy have not been established for overdoses of Maxigesic IV.
Symptomatic treatment.
Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases hepatic transaminases return to normal in one to two weeks with full restitution of the liver function. In very severe cases, however, liver transplantation may be necessary.
There are no specific measures or known antidote to treat acute ibuprofen overdosage.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or the New Zealand National Poisons Centre on 0800 POISON (0800 764766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other Analgesics and Antipyretics, Anilides; ATC code: N02BE51.

Mechanism of action.

The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.
Ibuprofen's mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Maxigesic IV possesses anti-inflammatory, analgesic, and antipyretic activity.

Pharmacodynamic effects.

In a phase III study in 276 patients with at least moderate pain following bunionectomy surgery, perceptible pain relief occurred within 10 minutes and meaningful pain relief occurred within 75 minutes following the administration of Maxigesic IV. The peak analgesic effect was obtained at 4 hours, before the pain relief gradually declined to lower levels by 6 hours. Maxigesic IV has not been studied in the reduction of fever; however, both paracetamol and ibuprofen have antipyretic properties.

Clinical trials.

In a phase III efficacy study in 276 patients with at least moderate pain following bunionectomy surgery, the analysis of the primary endpoint, the time-adjusted Summed Pain Intensity Difference (SPID) 0-48 hours, demonstrated that Maxigesic IV (mean=23.41, SE=2.50) provided more effective pain relief than placebo (mean=-1.30, SE=3.07), paracetamol (mean=10.42, SE=2.50) or ibuprofen (mean=9.51, SE=2.49), with a high level of statistical significance (p < 0.001). See Table 3.
Figure 1 shows the pain intensity differences over the 48-hour treatment period. As shown in the figure, Maxigesic IV provided generally greater pain relief than placebo, paracetamol and ibuprofen over this period.
The highest response rate was observed in patients treated with Maxigesic IV, with 51% of patients achieving at least a 50% reduction from baseline pain (Figure 2).
Fewer patients in the Maxigesic IV group (75%) required rescue medication (oxycodone or morphine) compared with 92% of patients in the ibuprofen group, 93% of patients in the placebo group and 96% in the placebo group. See Figure 3.
Over the entire 48-hour double blind treatment period, the median oral morphine milligram equivalent (MME) of all rescue medication consumed was lowest in the Maxigesic IV group (30 mg), and lower than consumption in the ibuprofen (43.5 mg, p=0.008), paracetamol (45 mg, p=0.004) and placebo groups (67.5 mg, p < 0.001).

5.2 Pharmacokinetic Properties

Absorption.

Maxigesic IV is administered as a 15-minute infusion, and the peak plasma concentration of each drug is reached at the end of the infusion. The two active drugs in Maxigesic IV reach peak plasma levels in the same time frame and have similar plasma half-lives.
The pharmacokinetic parameters of Maxigesic IV, as determined by a study in 29 healthy volunteers, are presented in Table 4.
Pharmacokinetic parameters were similar following a single dose of Maxigesic administered either intravenously or orally, except the Cmax of the intravenous formulation was twice that of the oral formulation and, as expected, the Tmax following intravenous administration was achieved much faster (in 15 minutes) than with the oral formulation.
The relative bioavailability of paracetamol (93.73%) and ibuprofen (96.60%) confirmed the pharmacokinetic equivalence of the oral and intravenous Maxigesic formulations.

Distribution.

Paracetamol is distributed into most body tissues. Ibuprofen is highly protein bound.

Metabolism.

Paracetamol is metabolised extensively in the liver and excreted in the urine, mainly as inactive glucuronide and sulphate conjugates. Less than 5% is excreted unchanged. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This active intermediate is detoxified by conjugation with glutathione, however, it can accumulate following paracetamol overdosage and if left untreated has the potential to cause severe and even irreversible liver damage.
Paracetamol is metabolised differently by premature infants, newborns, and young children compared with adults, the sulphate conjugate being most predominant.
Ibuprofen is highly bound (90-99%) to plasma proteins and is extensively metabolised to inactive compounds in the liver, mainly by glucuronidation.
The active drugs are metabolized by different pathways and pharmacokinetic studies conducted with Maxigesic IV confirm that the co-administration of paracetamol and ibuprofen does not alter the pharmacokinetics of either ingredient when administered intravenously or orally.

Excretion.

Paracetamol elimination half-life varies from about 1 to 3 hours.
Both the inactive metabolites and a small amount of unchanged ibuprofen are excreted rapidly and completely by the kidney, with 95% of the administered dose eliminated in the urine within four hours of ingestion. The elimination half-life of ibuprofen is in the range of 1.9 to 2 hours.

5.3 Preclinical Safety Data

In single and repeat-dose toxicity studies conducted in rats, co-administration of paracetamol and ibuprofen at a ratio matching that in Maxigesic IV (i.e. at a paracetamol-to-ibuprofen ratio of 3.3-to-1) and at dose levels approximately equal to those that patients would receive when using Maxigesic IV at the maximum recommended dose did not increase the risk of GI or renal toxicity.
The effect of single intravenous or perivenous doses of Maxigesic IV in an acute local irritation study in male rabbits showed that Maxigesic IV has little potential to produce local irritation when administered intravenously at the recommended dose level. Moreover when conducting an in vitro blood compatibility assessment, no additional haemolysis, plasma protein flocculation/precipitation or platelet aggregation was observed with Maxigesic IV than with paracetamol IV or ibuprofen IV alone.

Genotoxicity.

Paracetamol was not mutagenic in the bacterial mutagenicity assay, but it was clastogenic in mammalian cell assay systems in vitro (mouse TK, human lymphocyte) and in a mouse micronucleus assay in vivo. The clastogenic effect was dose-dependent, and the mechanism appears to involve inhibition of replicative DNA synthesis and ribonucleotide reductase at above threshold doses. The clinical significance of clastogenic findings is equivocal as positive findings in vivo only occurred at exposures (ca. 8 times the maximum anticipated clinical exposure, based on Cmax) greater than that for hepatotoxicity, and at doses that were associated with significant cytotoxicity.
Ibuprofen was not mutagenic in bacterial gene mutation assays in vitro with or without metabolic activation. A weak positive response was observed in the Sister Chromatid Exchange (SCE) assay in mouse bone marrow cells at an oral dose of 270 mg/kg and at intraperitoneal doses of 50 and 100 mg/kg, with no-effect at a dose of 25 mg/kg.

Carcinogenicity.

No evidence of carcinogenic potential was observed for paracetamol in long-term oral studies in mice (up to 3000 mg/m2/day, similar to human exposure) and male rats (up to 1800 mg/m2/day, 0.7 times human exposure). Equivocal evidence of carcinogenic potential (mononuclear cell leukaemia) was observed only in female rats at 1900 mg/m2/day, or 0.7 times the maximum anticipated clinical exposure on a mg/m2 basis.
There was no evidence of carcinogenicity in mice and rats treated with ibuprofen orally at respective doses up to 100 mg/kg/day for 80 weeks and 60 mg/kg/day for two years.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cysteine hydrochloride monohydrate, dibasic sodium phosphate dihydrate, mannitol, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicine must not be mixed with other medicines.

6.3 Shelf Life

24 months.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate or freeze. Protect from light.

6.5 Nature and Contents of Container

Maxigesic IV is supplied in 100 mL clear glass vials, closed with a grey rubber stopper and an aluminium flip-off cap, in a pack size of 10 vials. Each vial contains an overfill of solution (between 100.5-104.2 mL) to ensure withdrawal of the label claim.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Paracetamol.

Chemical structure.

The chemical name for paracetamol is N-(4-hydroxyphenyl)acetamide. It has the following structural formula:
Molecular formula: C8H9NO2.
Molecular weight: 151.2.
Solubility: paracetamol is sparingly soluble in water, freely soluble in alcohol, and very slightly soluble in ether and methylene chloride.

CAS number.

103-90-2.

Ibuprofen (as sodium dihydrate).

Chemical structure.

The chemical name for ibuprofen sodium dihydrate is (2RS)-2-[4-(2-methylpropyl)phenyl]propanoic acid sodium dihydrate salt. It has the following structural formula:
Molecular formula: C13H17O2Na.2H2O (sodium dihydrate salt).
Molecular weight: 206.3 (free acid), 264.3 (sodium dihydrate salt).
pKa: 4.43 ± 0.03.
Solubility: ibuprofen is very slightly soluble in water (< 1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone.
Partition coefficient: n-octanol/water 11.7 at pH 7.4.

CAS number.

15687-27-1 (free acid).
527688-20-6 (sodium dihydrate salt).

7 Medicine Schedule (Poisons Standard)

Prescription Medicine (Schedule 4).

Summary Table of Changes