Consumer medicine information

CALDOLOR

Ibuprofen

BRAND INFORMATION

Brand name

Caldolor Concentrated injection

Active ingredient

Ibuprofen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using CALDOLOR.

What is in this leaflet

This leaflet answers some common questions about Caldolor®.

It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Caldolor® against the benefits they expect it will have for you. Your doctor has been provided with full information and can answer any questions you may have.

If you have any concerns about being given this medicine, ask your doctor.

Please read this leaflet carefully and keep it in a safe place.

You may need to read it again.

What Caldolor® is used for

Caldolor® contains ibuprofen, a medicine that relieves pain, inflammation (swelling, redness, heat) and fever (high temperature).

Caldolor® is a solution of ibuprofen which is given by infusion into a vein after it has been diluted. Caldolor® must only be given to you by a doctor or nurse.

Caldolor® is used:

  • to relieve pain following surgery, sometimes in addition to other medication
  • to reduce fever (high temperature).

Although Caldolor® can relieve the symptoms of pain and fever it will not cure your condition.

This medicine belongs to a group of medicines called non-steroidal anti-inflammatory drugs (or NSAIDs).

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

Your doctor may have prescribed it for another reason.

Caldolor® is only available with a doctor’s prescription.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you are given Caldolor®

When you must not be given Caldolor®

You must not be given Caldolor® if:

  1. you have an allergy to:
  • any medicine containing ibuprofen or aspirin
  • any of the ingredients listed at the end of this leaflet
  • any other NSAIDs.

Many medicines used to treat headache, period pain and other aches and pains may contain aspirin or 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.
  1. 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).
  2. 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.
  1. you have a spinal cord injury.
    It may increase the risk of bleeding in this area.
  2. you are in the last three months of pregnancy:
    It may affect the development of your baby and it may delay labour and birth.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given Caldolor®

Tell your doctor if:

  1. you have allergies to:
  • any other medicines including aspirin or any other NSAID
  • any other substances such as, foods, preservatives or dyes.
  1. you are pregnant or intend to become pregnant.
    Like most NSAIDs, Caldolor® is not recommended to be used during pregnancy. Your doctor will discuss the risks and benefits of using it if you are pregnant.
  2. you are breast-feeding or planning to breast-feed.
    It is not known whether Caldolor® passes into breast milk. Your doctor will discuss the risks and benefits of using it if you are breast-feeding.
  3. you have, or have had, any of the following medical conditions:
  • 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
  • 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 Caldolor®.

Taking other medicines

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

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

  • aspirin, salicylates or other NSAIDs, medicines used to treat pain, inflammation or swelling
  • aminoglycoside medicines, used to treat certain infections
  • warfarin or other 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,
  • gingko biloba, a herbal medicine
  • lithium, a medicine used to treat some types of depression including bipolar disorder
  • methotrexate, a medicine used to treat arthritis and some types of cancer
  • mifepristone, a medicine used for medical abortion
  • quinolone antibiotics, medicines used to treat certain infections
  • zidovudine, a medicine used to treat HIV.

These medicines may be affected by Caldolor® or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor will advise you.

Your doctor has more information on medicines to be careful with or to avoid while being given Caldolor®.

How Caldolor® is given

How it is given

Caldolor® will be given to you by a doctor or nurse.

It is diluted and given as a 30 minute infusion (slow injection) into a vein.

How much is given

Your doctor will decide how much Caldolor® you need.

Pain following Surgery
You will usually be given a 400 to 800 mg dose of Caldolor® every 6 hours, as necessary.

Fever
You will usually be given a 400 mg dose of Caldolor® every 4 to 6 hours, as necessary.

Your doctor may give you a different amount depending on your condition.

How long is it given for

Your doctor will decide how long you need to be given Caldolor®.

If you are given too much (overdose)

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

If you are given too much Caldolor®, you may feel or experience the following symptoms:

  • abdominal pain
  • nausea
  • vomiting
  • drowsiness
  • dizziness.

If you think you have been given too much Caldolor®:

  • tell your doctor or nurse immediately, or
  • telephone the Poisons Information Centre on 13 11 26

While you are being given Caldolor®

Things you must not do

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.

Things to be careful of

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

As with other NSAIDs, Caldolor® 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.

Side effects

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by the following lists of side effects.

You may not experience any of them.

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

This medicine helps most people with pain following surgery and fever, but it may have unwanted side effects in a few people.

If you are over 65 years of age you may have an increased chance of getting certain side effects.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • nausea or vomiting
  • loss of appetite
  • difficulty passing urine
  • cough
  • heartburn /indigestion or an uncomfortable feeling in the stomach or belching after eating.
  • cramps, wind, constipation or diarrhoea
  • headache
  • tiredness
  • dizziness
  • buzzing or ringing in the ears or other trouble hearing
  • sleeplessness
  • changes in mood, for example depression, confusion or nervousness
  • itching.

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

Tell your doctor as soon as possible if you notice any of the following:

  • 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.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • 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.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or nurse if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some people.

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

You may not experience any of them.

After being given Caldolor

Storage

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

  • 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.

Caldolor® 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.

Product description

What it looks like

Caldolor® is a clear, colourless to slightly yellow solution. It is supplied in a clear glass vial that is closed with a stopper and an aluminium seal that is covered with a plastic flip-off cap.

Each vial of Caldolor® contains:

  • 800 mg/8 mL in a 10 mL vial
  • 400 mg/4 mL in a 5 mL vial.

Each box of Caldolor® contains 10 vials.

Not all pack sizes may be available.

Ingredients

Active ingredients:

  • 100 mg/mL ibuprofen.

Inactive ingredients:

  • arginine
  • water for injections
  • hydrochloric acid for pH adjustment.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Ask your doctor, nurse or pharmacist if you are unsure about anything or want more information about Caldolor®.

Sponsor

bioCSL Pty Ltd
ABN 26 160 735 035
63 Poplar Road,
Parkville, VIC, 3052
Australia

This leaflet was prepared on 13 August 2015.

Australian Registration Numbers:
400 mg in 4 mL: AUST R 175190
800 mg in 8 mL: AUST R 175191

Caldolor® is a registered trademark of Cumberland Pharmaceuticals Inc. used under licence.

BRAND INFORMATION

Brand name

Caldolor Concentrated injection

Active ingredient

Ibuprofen

Schedule

S4

 

1 Name of Medicine

Ibuprofen.

6.7 Physicochemical Properties

The molecular weight of the compound is 206.3. The molecular formula is C13H18O2.

Chemical structure.


CAS number.

15687-27-1.

2 Qualitative and Quantitative Composition

Caldolor concentrated injection contains the active ingredient ibuprofen, which is (±)-2-(p-isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74-77°C. It is very slightly soluble in water (< 1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. Ibuprofen has a pKa of 4.43 ± 0.03 and an n-octanol/water partition coefficient of 11.7 at pH 7.4.
Each 1 mL of Caldolor concentrated injection contains 100 mg of ibuprofen in Water for Injections, USP. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Caldolor is sterile and is intended for intravenous (IV) administration following dilution only. Caldolor is a clear, colourless to slightly yellow solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ibuprofen's mechanism of action, like that of other nonsteroidal anti-inflammatory drugs (NSAIDs), is not completely understood but may be related to prostaglandin synthetase inhibition. Caldolor possesses anti-inflammatory, analgesic, and antipyretic activity.

Clinical trials.

Analgesia (pain).

The effect of Caldolor on acute pain was evaluated in two multicentre, randomised, double blind, placebo controlled studies.
In a study of patients who had undergone an elective orthopaedic surgery, 185 patients (65 men, 120 women) were randomised to receive Caldolor 800 mg or placebo administered every 6 hours (started preoperatively at study hour 0), and morphine on an as needed basis. Compared to placebo, patients receiving 800 mg IV ibuprofen experienced a significant reduction in pain as measured by the VAS-AUC with movement for the postoperative period, study hours 6-28. In the all-treated population, there was a 25.8% reduction in mean area under the visual analogue pain curve (VAS-AUC) (hours 6-28, with movement) in patients receiving IV ibuprofen (p < 0.001). In addition to experiencing less pain, patients receiving 800 mg IV ibuprofen used less morphine. In the all-treated population, there was a 30.9% reduction in mean morphine consumption in patients receiving IV ibuprofen for the postoperative period, study hours 6-28 (p < 0.001). There were also significant reductions in pain as measured by the VAS-AUC at rest and by the VRS for the postoperative period, study hours 6-28 (p < 0.001). In the all-treated population, there was a 31.8% reduction in mean VAS-AUC (at rest) and a 20.2% reduction in mean VRS in patients receiving IV ibuprofen (p < 0.001). This study did not reveal any increased risk of bleeding events however, the study is not powered sufficiently to confirm the safety of preoperative commencement of Caldolor.
In a study of women who had undergone an elective abdominal hysterectomy, 319 patients were randomised to Caldolor 800 mg, or placebo, administered every 6 hours (started intraoperatively). Both treatment arms were administered with morphine on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the mean morphine consumption through 24 hours in patients who received Caldolor compared to those receiving placebo (47 mg and 56 mg, respectively). The clinical relevance of this finding is supported by a greater reduction in pain intensity over 24 hours for patients treated with Caldolor, even though morphine was available on an as needed basis.

Antipyretic (fever).

The effect of Caldolor on fever was evaluated in two randomised, double blind studies.
In a multicentre study, 120 hospitalised patients (88 men, 32 women) with temperatures of 38.3°C or greater were randomised to receive either Caldolor (100 mg, 200 mg or 400 mg) or placebo, administered every 4 hours for 24 hours. Each of the three Caldolor doses, 100 mg, 200 mg, and 400 mg, resulted in a greater percentage of patients with a reduced temperature (< 38.3°C) after 4 hours, compared to placebo (61%, 70%, 77% and 32%, respectively). The dose response is shown in Figure 1.
In a single centre study, 60 hospitalised patients (48 men, 12 women) with uncomplicated P. falciparum malaria having temperatures > 38.3°C were randomised to receive either Caldolor 400 mg or placebo, administered every 6 hours for 72 hours of treatment. There was a significant reduction in fever within the first 24 hours of treatment, measured as the area above the temperature 37°C vs. time curve for patients treated with Caldolor.

5.2 Pharmacokinetic Properties

Ibuprofen is a racemic mixture of [-]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~ 60%) interconverted into the active [+]S species in adults. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of Caldolor determined in a study with volunteers are presented in Tables 3 and 4.
The pharmacokinetic parameters of Caldolor determined in a study with febrile patients are presented in Table 5.
Ibuprofen, like most NSAIDs, is highly protein bound (> 99% bound at 20 microgram/mL). Protein binding is saturable, and at concentrations > 20 microgram/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen.

5.3 Preclinical Safety Data

Genotoxicity.

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.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Caldolor is indicated in adults for the management of acute mild to moderate postoperative pain and moderate to severe postoperative pain with adjunctive reduced morphine dosage, where an intravenous route of administration is considered clinically necessary.
Caldolor is indicated for the reduction of fever in adults where an intravenous route of administration is considered clinically necessary.

4.3 Contraindications

Caldolor is contraindicated in the following.
Patients with known hypersensitivity (e.g. anaphylactoid reactions and serious skin reactions) to ibuprofen (see Section 4.4 Special Warnings and Precautions for Use).
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 Special Warnings and Precautions for Use).
For the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see Section 4.4 Special Warnings and Precautions for Use).
Patients with active gastrointestinal bleeding.
Patients with spinal cord injuries.

4.4 Special Warnings and Precautions for Use

Duration of dosage.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Caldolor, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed a total daily dose of 3200 mg ibuprofen. Use of the recommended maximum dose of Caldolor 800 mg every 6 hours has only been studied for a period of up to 2 days.

Cardiovascular thrombotic events.

All NSAIDs 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.
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see also Section 4.3 Contraindications).
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 ibuprofen, 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 ibuprofen, 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 Caldolor 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 cotherapies or comorbid 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 ibuprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), 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 to discontinue Caldolor at the first appearance of skin rash or any other sign of hypersensitivity (see also Section 4.3 Contraindications).

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, Caldolor is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma (see also Section 4.3 Contraindications).

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.

Use in hepatic impairment.

Borderline elevations of one or more liver tests may occur in some patients taking NSAIDs, including ibuprofen. 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.), ibuprofen should be discontinued.

Use in renal impairment.

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

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 ibuprofen, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy.

Haematological effects.

Caldolor is a concentrated injection that must be diluted prior to use (see Section 4.2 Dose and Method of Administration). Infusion of Caldolor without dilution can cause haemolysis.
Anaemia may occur in patients receiving NSAIDs, including ibuprofen. 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.

Masking inflammation and fever.

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

Anaphylactoid reactions.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. Caldolor 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 (see also Section 4.3 Contraindications).

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 Caldolor.

Use in the elderly.

Clinical studies of Caldolor did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from 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 Special Warnings and Precautions for Use, Gastrointestinal effects).
As with any NSAIDs, caution should be exercised when treating the elderly (65 years and older). In a study of hospitalised adult patients with sepsis, creatinine levels were analyzed in elderly patients (> 65) receiving either 10 mg/kg (up to 800 mg) IV ibuprofen or placebo every 6 hours over 48 hours. There was no statistically significant difference in creatinine levels (or in % or actual change from baseline) between IV ibuprofen and placebo treated patients during therapy and up to 5 days after initiation of therapy.

Paediatric use.

Safety and effectiveness of Caldolor for management of pain and reduction of fever has not been established in paediatric patients. Caldolor should only be used in persons 18 years and over.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Caldolor and aspirin is not generally recommended because of the potential for increased adverse effects.

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 Special Warnings and Precautions for Use).

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.

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 furosemide. 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 Special Warnings and Precautions for Use, Use in renal impairment).

Corticosteroids.

Increased risk of gastrointestinal bleeding.

Cyclosporine or tacrolimus.

Increased risk of nephrotoxicity when used with NSAIDs.

Diuretics.

Clinical studies and postmarketing observations have shown that ibuprofen can reduce the natriuretic effects of furosemide 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 Special Warnings and Precautions for Use).

Herbal extracts.

Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

Lithium.

Caldolor 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.

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 hematoma 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 Caldolor.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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 (see also Use in pregnancy - Pregnancy Category C).
(Category C)
There are no adequate, well controlled studies in pregnant women.
Data from epidemiological studies suggest an increased risk of miscarriage after the use of a prostaglandin synthesis inhibitor in early pregnancy. Prior to week 30 of pregnancy, Caldolor should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. From week 30 of pregnancy, Caldolor and other NSAIDs can cause foetal harm and should be avoided by pregnant women. NSAIDs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosis, foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. Continuous treatment with NSAIDs during the third trimester of pregnancy should only be given on sound indications. 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.

Labour and delivery.

The effects of Caldolor 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 (see also Use in pregnancy - Pregnancy Category C).
It is not known whether ibuprofen and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caldolor, a decision should be made whether to discontinue nursing or discontinue ibuprofen treatment, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

The following serious adverse reactions are discussed under Section 4.4 Special Warnings and Precautions for Use.
Cardiovascular thrombotic events.
Gastrointestinal effects.
Hepatic effects.
Hypertension, congestive heart failure and oedema.
Renal effects.
Anaphylactoid reactions.
Serious skin reactions.
The most common treatment emergent adverse effects (TEAEs) reported in clinical studies are nausea, flatulence, vomiting, and headache. The most common reason for discontinuation of Caldolor due to adverse events in controlled trials is pruritus (< 1%).

Clinical studies experience.

Clinical trials are conducted under widely varying conditions, therefore the rate of TEAEs observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical development, 659 patients were exposed to Caldolor, 537 in pain and 122 with fever. In the pain studies, Caldolor was started intraoperatively or preoperatively and administered at a dose of 400 mg or 800 mg every six hours for up to five days. In the fever studies, Caldolor was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days.
The most frequent adverse reactions occurring with oral ibuprofen are gastrointestinal.

Pain studies.

The incidence rates of TEAEs listed in Table 1 were derived from multicentre, controlled clinical studies comparing Caldolor to placebo in patients also receiving morphine as needed for postoperative pain.

Fever studies.

Fever studies were conducted in febrile hospitalised patients with malaria, and febrile hospitalised patients with varying causes of fever. In hospitalised febrile patients with malaria, the TEAEs observed in at least two Caldolor treated patients included abdominal pain and nasal congestion.
In hospitalised febrile patients (all causes), TEAEs observed in more than two patients in any given treatment group are presented in Table 2.

Study in hospitalised adult patients with sepsis.

The incidence of TEAEs in hospitalised patients with severe sepsis was similar in treated and placebo patients. Patients were systematically monitored for signs of renal or bleeding complications. Analysis of changes in urine output, changes in serum creatinine, renal related adverse events, and requirement for renal dialysis were similar in both groups. Laboratory measures of platelet count, partial thromboplastin time, prothrombin time and evaluation of bleeding events, coagulation abnormalities, requirement for red cells and requirement for other blood products failed to show any clinically significant differences between IV ibuprofen and placebo treated subjects.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

Dosage.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Caldolor, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed a total daily dose of 3200 mg ibuprofen. Use of the recommended maximum dose of Caldolor 800 mg every 6 hours has only been studied for a period of up to 2 days.
To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of Caldolor.

Analgesia (pain).

Administer 400 mg to 800 mg of Caldolor by IV infusion every 6 hours as necessary.
Caldolor is a concentrated injection that must be diluted prior to administration.

Antipyretic (fever).

Administer 400 mg of Caldolor by IV infusion, followed by 400 mg every 4 to 6 hours as necessary.
Caldolor is a concentrated injection that must be diluted prior to administration.

Dosage adjustment in special conditions.

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 Caldolor in patients with advanced renal disease. If Caldolor therapy must be initiated in patients with advanced renal disease, closely monitor the patient’s renal function.

Hepatic impairment.

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.), ibuprofen should be discontinued.

Gastroesophageal reflux.

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.

Preparation and administration.

Caldolor concentrated injection must be diluted prior to intravenous (IV) infusion.
Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline) or 5% glucose injection.
800 mg dose: dilute 8 mL of Caldolor in no less than 200 mL of diluent.
400 mg dose: dilute 4 mL of Caldolor in no less than 100 mL of diluent.
Visually inspect Caldolor 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. Once diluted the solution should be used as soon as possible. It is a sterile solution for single use and contains no antimicrobial preservative. If storage is necessary the prepared solution should be refrigerated between 2°C and 8°C and stored for no longer than 24 hours before discarding.
Infusion time is 30 minutes.
Caldolor should be used in one patient on one occasion only. It contains no antimicrobial preservative. Unused solution should be discarded.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

The following signs and symptoms have occurred in individuals following an overdose of oral ibuprofen: abdominal pain, nausea, vomiting, drowsiness, and dizziness. In serious poisoning metabolic acidosis may occur. There are no specific measures to treat acute overdosage with Caldolor. There is no known antidote to ibuprofen.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 1 mL of Caldolor also contains 78 mg of arginine at a molar ratio of 0.92:1 arginine: ibuprofen. Hydrochloric acid is added for pH adjustment. The solution pH is about 7.4.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Caldolor is a concentrated injection that is supplied in a clear glass vial, closed with a rubber stopper and an aluminium seal with a plastic flip-off cap. The stopper in the Caldolor vial does not contain natural rubber latex, dry natural rubber, or blends of natural rubber. Caldolor is a clear, colourless to slightly yellow solution.
Caldolor is available in the following pack sizes:
400 mg in 4 mL (100 mg/mL) in a 5 mL vial: Ten (10) vials per carton
800 mg in 8 mL (100 mg/mL) in a 10 mL vial: Ten (10) vials per carton
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes