Consumer medicine information

Nurofen Plus

Codeine phosphate hemihydrate; Ibuprofen

BRAND INFORMATION

Brand name

Nurofen Plus Tablets

Active ingredient

Codeine phosphate hemihydrate; Ibuprofen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nurofen Plus.

What is in this Leaflet?

This leaflet answers some common questions about NUROFEN PLUS. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking NUROFEN PLUS against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your pharmacist or doctor.

Keep this leaflet with the medicine.

You may need to read it again

What NUROFEN PLUS is used for

NUROFEN PLUS tablets contain the active ingredients Ibuprofen and Codeine phosphate. Ibuprofen belongs to a family of medicines called non-steroidal anti-inflammatory drugs (NSAIDS). These medicines work by relieving pain and/or inflammation (swelling, redness, soreness) and fever. Codeine is an opioid analgesic that works in the brain and spinal cord to relieve pain.

NUROFEN PLUS provides temporary relief of acute moderate pain and inflammation in patients over the age of 12 years.

After taking codeine, the body changes codeine into the active morphine by a special liver enzyme. However, about 8% of people may experience less pain relief compared to others, as their bodies do not change codeine to morphine as well as others.

Do not give NUROFEN PLUS to children under the age of 12 years.

Ask your doctor if you have any questions about this medicine.

Your doctor may have given it for another reason.

Before You Take NUROFEN PLUS

When you must not take it

Do not take NUROFEN PLUS if

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

Many medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAID. If you are not sure if you are taking any of these medicines, ask your pharmacist.

Symptoms of an allergic reaction to these medicines may include:
- asthma, wheezing or shortness of breath.
- swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing.
- hives, itching or skin rash.
- fainting.

If you are allergic to aspirin or NSAIDs and take NUROFEN PLUS these symptoms may be severe.

  1. you are in the last three months of pregnancy or are breast-feeding

NUROFEN PLUS should not be taken during pregnancy except during the first 6 months of pregnancy. All NSAIDS should not be taken during the last three months of pregnancy.

  1. you are vomiting blood or material that looks like coffee grounds
  2. you are bleeding from the rectum (back passage), have black sticky bowel motions (stool) or bloody diarrhoea
  3. you have peptic ulcer (i.e. stomach or duodenal ulcer), or have had one before.
  4. you are using other NSAIDS
  5. you have chronic constipation or shallow breathing, or severe diarrhoea.
  6. You consume regular and heavy amounts of alcohol.
  7. You are a CYP2D6 ultra-rapid metaboliser.

Do not take NUROFEN PLUS if the packaging is torn or shows signs of tampering.

Do not take NUROFEN PLUS if the expiry date (EXP) printed on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure whether you should start taking NUROFEN PLUS, contact your pharmacist or doctor.

Do not give Nurofen Plus to children under 12 years or to those aged 12 - 18 years in whom respiratory function may be compromised.

Before you start to take it

Tell your doctor if

  1. you have allergies to:
  • any other medicines including aspirin, or other NSAID medicines.
  • any other substances, such as foods, preservatives or dyes.
  1. you are pregnant or intend to become pregnant

NUROFEN PLUS is not recommended during the last 3 months of pregnancy. Your doctor will decide if you should take NUROFEN PLUS during the first 6 months of pregnancy.

  1. you are breast-feeding or plan to breast-feed

NUROFEN PLUS should not be taken while breastfeeding except on your doctor's advice.

Codeine passes into the breast milk.

If there is a need to consider NUROFEN PLUS while you are breast-feeding, your pharmacist or doctor will discuss with you the benefits and risks of using it.

  1. you have or have had any of the following medical conditions:
  • difficulty breathing, wheezing, chronic cough, allergies, asthma or other breathing conditions
  • a history of drug dependence, including alcohol dependence
  • skin rash (dermatitis)
  • skin irritation
  • a history of stomach ulcer.
  • liver disease.
  • kidney disease.
  • heart problems/failure, including. swelling of ankles or feet.
  • thyroid problems or low blood pressure.
  • a head injury or intracranial pressure.
  • prostatic problems.
  • stomach problems or recent stomach surgery.

Tell your doctor if you take sedatives (medicines used to help you relax or sleep).

If you have not told your doctor about any of the above, tell him/her before you start taking Nurofen Plus.

Taking other medicines

Tell your pharmacist or doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interfere with Nurofen Plus.

These include:

  • medicines used to help you relax, sleep or relieve anxiety, such as barbiturates and sedatives.
  • aspirin, salicylates or other NSAID medicines .
  • warfarin or other medicines used to prevent blood clots .
  • medicines that are used to treat high blood pressure including diuretics (fluid tablets)
  • methotrexate.
  • zidovudine.
  • lithium
  • mifeprisone, quinolone antibiotics
  • medicines used to relieve stomach cramps, prevent travel sickness and to treat Parkinson's disease.
  • medicines used to treat diarrhoea (eg. kaolin, pectin, loperamide).
  • metoclopramide, a medicine used to treat nausea and vomiting
  • selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) , medicines used to treat some types of depression
  • quinidine, a medicine used to treat abnormal or irregular heart beat
  • phenothiazines and antipsychotic agents, medicines used to treat mental disorders
  • medicines such as cyclosporin, tacrolimus, prednisone, prednisolone and cortisone which reduce the activity of your immune system
  • probenecid - medicines used to treat gout
  • phenytoin - medicine used to treat epilepsy
  • other opioid pain killers.

These medicines may be affected by NUROFEN PLUS or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your pharmacist and doctor have more information on medicines to avoid or be careful with while taking NUROFEN PLUS.

How to Take NUROFEN PLUS

Follow all directions given to you by your pharmacist or doctor carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box/bottle, ask your pharmacist or doctor for help.

How much to take

The usual dose of NUROFEN PLUS is 2 tablets then, if necessary 1 or 2 tablets every 4 to 6 hours. Do not take more than six tablets in 24 hours.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

Take NUROFEN PLUS by mouth with fluid. It may also be taken with or immediately after food.

How long to take it

You should not take NUROFEN PLUS for more than a few days.

If your symptoms persist, worsen or new symptoms develop, talk to your doctor.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (in Australia 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken too much NUROFEN PLUS. Do this even if there are no signs of discomfort or poisoning.

If you take too much of this medicine you may experience nausea or upset stomach, vomiting and/or gastric irritation, drowsiness, dizziness and/or very slow, laboured breathing. You may also experience blurred vision, ringing in the ears, or rapid uncontrollable movements of the eyes. Excitability, convulsions and unconsciousness may be experienced in rare cases.

While You Are Using NUROFEN PLUS

Things you must do

If you become pregnant while taking NUROFEN PLUS tell your doctor immediately.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are taking NUROFEN PLUS.

Tell all of the doctors, dentists and pharmacists that are treating you that you are taking NUROFEN PLUS.

If you are going to have surgery, tell your doctor you are taking NUROFEN PLUS.

Talk to doctor if your symptoms do not improve.

Your doctor will assess your condition and decide if you should continue to take the medicine.

Things you must not do

Do not give NUROFEN PLUS to anyone else, even if they have the same condition as you.

Do not use NUROFEN PLUS to treat any other complaints unless your doctor tells you to.

Do not take more than the recommended dose unless your doctor tells you to.

Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage.

Things to be careful of

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

NUROFEN PLUS may cause dizziness, light-headedness or drowsiness in some people. If this occurs, do not drive or operate machinery. If you drink alcohol, dizziness, light-headedness and/or drowsiness may be worse.

Do not take high doses of the medicine for long periods of time unless your doctor tells you to.

Products containing codeine should not be taken for prolonged periods. Codeine may be habit forming.

Side Effects

Check with your doctor as soon as possible if you have any problems while taking NUROFEN PLUS, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, NUROFEN PLUS can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

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

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

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

  • stomach upset including nausea (feeling sick), vomiting.
  • heartburn, indigestion.
  • loss of appetite
  • sleeplessness, nightmares
  • change in mood for example depression, restlessness, irritability
  • sore or dry mouth or tongue
  • diarrhoea, pain in the stomach.
  • dizziness, light-headedness, drowsiness.
  • constipation.
  • shallow breathing.
  • cough suppression.
  • headache.
  • hearing disturbance.

These are the more common side effects of NUROFEN PLUS and are usually mild and short lived.

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

  • shallow breathing or shortness of breath
  • unusual or extreme mood swings
  • dizziness, light-headedness
  • flushing of the face
  • fast heart beat
  • severe pain or tenderness in the stomach
  • eye problems such as blurred vision, sore red eyes, itching
  • severe dizziness, spinning sensation
  • severe or persistent headache
  • tingling or numbness of the hands or feet
  • difficulty hearing, deafness
  • signs of frequent or worrying 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
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • a change in the colour of urine passed, blood in the urine
  • a change in the amount or frequency of urine passed, burning feeling when passing urine
  • yellowing of the skin and eyes, also called jaundice
  • unusual weight gain, swelling of ankles or legs
  • symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than normal

The above side effect may be serious and may require urgent medical attention.

Serious side effects are rare for low doses of this medicine and when used for a short period of time.

If any of the following happen, stop taking NUROFEN PLUS and tell your doctor immediately or go to casualty at your nearest hospital:

  • vomiting blood or material that looks like coffee grounds.
  • 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, shortness of breath, pain or tightness in the chest
  • sudden or severe itching, skin rash, hives, skin peeling
  • easy bruising

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

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

Some people may get other side effects while taking NUROFEN PLUS. Tell your doctor or pharmacist if you notice anything else that worries you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After Using NUROFEN PLUS

Storage

Keep the tablets in the original pack until it is time to take the dose.

If you take them out they will not keep well.

Keep the tablets in a cool dry place where the temperature stays below 25°C.

Do not store NUROFEN PLUS or any other medicine in the bathroom or near a sink.

Do not leave the tablets in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep the tablets where children cannot reach them.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

When you stop taking NUROFEN PLUS or it has passed its expiry date, ask your pharmacist what to do with any tablets that are left over.

More Information

If you have any further questions or if you are not sure about anything relating to the use of NUROFEN PLUS, your doctor or pharmacist can best assist you.

Product Description

What it looks like

NUROFEN PLUS tablets are white capsule shaped tablets marked 'N+' on one side.

Ingredients

Each tablet of NUROFEN PLUS contains 200mg ibuprofen and 12.8mg codeine phosphate hemihydrate as the active ingredients.

The other ingredients in NUROFEN PLUS are:

  • microcrystalline cellulose
  • sodium starch glycollate
  • hypromellose
  • pregelatinised maize starch
  • talc
  • opaspray white colouring

Nurofen Plus tablets are gluten-free and lactose-free.

Packaging

Nurofen Plus is available in blister packs of *4, *6, *12, *24 & 30 tablets.

Sponsor

Reckitt Benckiser
Sydney NSW Australia

The ARTG number is:

AUST R 116620

This leaflet was prepared in February 2005.

Date of last revision: January 2018

*not available in Australia

BRAND INFORMATION

Brand name

Nurofen Plus Tablets

Active ingredient

Codeine phosphate hemihydrate; Ibuprofen

Schedule

S4

 

1 Name of Medicine

Ibuprofen and codeine phosphate hemihydrate.

2 Qualitative and Quantitative Composition

Each tablet contains ibuprofen 200 mg and codeine phosphate hemihydrate 12.8 mg. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

A white capsule-shaped tablet, containing ibuprofen 200 mg and codeine phosphate hemihydrate 12.8 mg.
The white capsule-shaped tablets are marked 'N+' on one side and plain on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

For the temporary relief of acute moderate pain and inflammation in patients over the age of 12 years.

4.2 Dose and Method of Administration

Adults and children 12 years and over.

Initial dose two tablets taken with fluid, then one or two tablets every 4 to 6 hours when necessary. Maximum 6 tablets in a 24 hour period.
Nurofen Plus should not be used for more than three days at a time unless on medical advice, in which case the patient should be reviewed regularly with regards to efficacy, risk factors and ongoing need for treatment.
The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

Children.

Do not give to children under 12 years.
Nurofen Plus is contraindicated for use in children:
younger than 12 years;
aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

4.3 Contraindications

Known hypersensitivity to ibuprofen, codeine or other opioid analgesics, or any of the excipients.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, bronchospasm or urticaria) in response to ibuprofen, acetylsalicylic acid (aspirin) or other non-steroidal anti-inflammatory drugs (NSAIDs).
Active, or a history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). As with other non-steroidal anti-inflammatory agents, ibuprofen should not be used in active gastrointestinal bleeding or in the presence of peptic ulceration.
Chronic constipation and active alcoholism.
Severe respiratory disease, acute respiratory disease and respiratory depression.
Diarrhoea caused by pseudomembranous colitis or poisoning (until the causative organism or toxin has been eliminated from the gastrointestinal tract, since codeine may slow down the elimination, thereby prolonging the diarrhoea).
Use with concomitant NSAIDs, including cyclo-oxygenase-2 specific inhibitors - increased risk of adverse reactions.
Heart (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular and cerebrovascular effects) or renal problems (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
During the last trimester of pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Concomitant treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment.
Use of codeine containing products is contraindicated in women during breast feeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
In patients younger than 12 years (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
In patients aged between 12 - 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, due to an increased risk of developing serious and life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).

4.4 Special Warnings and Precautions for Use

Use in the elderly.

Adverse effects may have more serious consequences in the elderly, and they may be more susceptible to the CNS depressant effects of opioids.
Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see below).

Gastrointestinal.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see Section 4.8 Adverse Effects (Undesirable Effects)).
Gastrointestinal bleeding, ulceration and perforation which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses and patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see Section 4.3 Contraindications) and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particularly the elderly, patients with a history of gastrointestinal bleeding or perforation or peptic ulcer haemorrhage related to previous NSAID therapy should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Care is advised in the administration of Nurofen Plus to patients with obstructive bowel disorders, recent gastrointestinal surgery, gallstones, myasthenia gravis, a history of peptic ulcer or convulsions.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When GI bleeding or ulceration occurs in patients receiving Nurofen Plus, the treatment should be withdrawn.

Respiratory.

Bronchospasm may be precipitated in patients suffering from, or with a history of bronchial asthma or allergic disease.

SLE and mixed connective tissue disease.

Use of ibuprofen in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease can increase the risk of aseptic meningitis.

Use in hepatic impairment.

As with other NSAIDs, elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may resolve with continued therapy. Meaningful elevations (three times the upper limit of normal) of ALT or AST occurred in controlled clinical trials in less than 1% of patients.
Nurofen Plus should be administered with caution in patients with hepatic impairment. Patients should be advised to remain alert for hepatotoxicity and be informed about the signs and/or symptoms of hepatotoxicity (e.g. nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms) and the steps to take should these signs and/or symptoms occur.

Use in renal impairment.

Renal impairment as renal function may deteriorate, especially in dehydrated paediatric patients (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiovascular and cerebrovascular effects.

Observational studies have indicated that NSAIDs may be associated with an increased risk of serious cardiovascular events, including myocardial infarction and stroke, which may increase with dose or duration of use. Patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or cardiovascular risk factors may also be at greater risk.
Patients should be advised to remain alert for such cardiovascular events, even in the absence of previous cardiovascular symptoms. Patients should be informed about signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur.
Fluid retention, hypertension and oedema have been reported in association with NSAID therapy. Patients taking antihypertensives with NSAIDs may have an impaired antihypertensive response.
Nurofen Plus should be administered with caution in patients with hypertension or fluid retention (see Section 4.3 Contraindications, Heart).

Dermatological.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Nurofen Plus use should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

CYP2D6 metabolism.

Nurofen Plus is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. However, if the patient is an extensive or ultra-rapid metabolizer there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation, and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal. Children are particularly susceptible due to their immature airway anatomy. Deaths have been reported in children with rapid metabolism who were given codeine for analgesia post adenotonsillectomy. Morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of rapid metaboliser mothers who take codeine.
The prevalence of codeine ultra-rapid metabolism by CYP2D6 in children is not known, but is assumed to be similar to that reported in adults. The prevalence of ultra-rapid metabolisers is estimated to be 1% in those of Chinese, Japanese and Hispanic descent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16%- 28%) occurs in North African, Ethiopian and Arab populations. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised in Table 1.
(Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation; Use in lactation.)

Paediatric use.

Nurofen Plus is contraindicated for use in children:
younger than 12 years;
aged between 12 - 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. Respiratory depression and death have occurred in some children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine due to a CYP2D6 polymorphism.

Post-operative use in children.

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see Section 4.3 Contraindications). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function.

Codeine is contraindicated for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

Effects on laboratory tests.

Opioid analgesics interfere with a number of laboratory tests including plasma amylase, lipase, bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase. Opioids may also interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

Hazardous and harmful use.

Nurofen Plus contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Nurofen Plus at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Nurofen Plus.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Nurofen Plus with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Nurofen Plus but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with renal and hepatic impairment and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Nurofen Plus with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti- emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Nurofen Plus concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Nurofen Plus.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions.
Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine).
Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Nurofen Plus in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/ exposure.

Accidental ingestion or exposure of Nurofen Plus especially by children, can result in a fatal overdose of codeine. Patients and their caregivers should be given information on safe storage and disposal of unused Nurofen Plus (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Severe skin reactions.

Severe skin reactions such as acute generalised exanthematous pustulosis (AGEP) may occur with ibuprofen-containing products. The acute pustular eruption may occur within the first 2 days of treatment, with fever, and numerous, small, mostly non-follicular pustules arising on a widespread oedematous erythema and mainly localised on the skin folds, trunk, and upper extremities. Patients should be carefully monitored. If signs and symptoms such as pyrexia, erythema, or many small pustules are observed, administration of Nurofen Plus should be discontinued and appropriate measures taken if needed.

Masking of symptoms of underlying infections.

Nurofen Plus can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Nurofen Plus is administered for fever or pain relief in relation to infection, monitoring infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Other precautions.

As with other drugs of this class, ibuprofen may mask the usual signs of infection.
Codeine may also obscure the diagnosis or the course of gastrointestinal diseases. Nurofen Plus should therefore be administered with caution in such situations.
Nurofen Plus should be administered with caution in patients who have recently had gastrointestinal surgery, paralytic ileus, as codeine may reduce gastrointestinal motility.
Nurofen Plus should be administered with caution in those with hypotension and/or hypothyroidism. The tablets should be used with caution in patients with raised intracranial pressure or head injury.
Nurofen Plus should be administered with caution in patients with prostatic hypertrophy since codeine may cause urinary retention.
Care is advised in the administration of Nurofen Plus to patients with adrenocortical insufficiency.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Nurofen Plus should be avoided in combination with:

Aspirin.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Other NSAIDs: including cyclooxygenase-2-selective inhibitors.

Avoid the use of two or more NSAIDs as this may increase the risk of adverse effects.
Nurofen Plus should be used with caution in combination with:

Abiraterone.

Abiraterone might reduce analgesic effect of codeine by CYP2D6 inhibition.

Anticholinergics.

Concurrent use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention.

Anticoagulants.

Concurrent use of NSAIDs and warfarin has been associated with severe, sometimes fatal haemorrhage. The mechanism of this interaction is not known but may involve increased bleeding from NSAID induced gastrointestinal ulceration or an additive effect of NSAID inhibition of platelet function with the anticoagulant effect of warfarin. Nurofen Plus should only be used in patients taking warfarin if absolutely necessary. Patients taking this combination must be closely monitored.

Antidiarrhoeal and anti-peristaltic agents.

Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation.

Antimuscarinics.

Concomitant use of antimuscarinics or medications with muscarinic action, e.g. atropine and some antidepressants may result in increased risk of severe constipation which may lead to paralytic ileus and/or urinary retention.

ACE inhibitors, diuretics and other antihypertensives.

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 diuretics.
Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and lead to orthostatic hypotension. NSAIDs may diminish the effects of antihypertensives and diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
The combined use of the three classes of drugs, diuretics, an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist) and an anti-inflammatory drug (NSAID or cyclooxygenase-2 (COX-2) inhibitor) all at the same time increases the risk of renal impairment. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).

Concurrent use of these agents with codeine may increase the risk of severe constipation.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRls).

Increased risk of gastrointestinal bleeding (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac glycosides.

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

Central nervous system depressants including alcohol.

Codeine may potentiate the effects of CNS depressants, including alcohol and may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Nurofen Plus with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible (see Section 4.4, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Ciclosporin.

An increased risk of nephrotoxicity.

Cimetidine.

Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations.

Corticosteroids.

An increased risk of gastrointestinal ulceration or bleeding may occur with corticosteroids (see Section 4.4 Special Warnings and Precautions for Use).

Drugs that inhibit CYP2D6 such as quinidine, phenothiazines and antipsychotic agents.

Can interfere with the metabolism of codeine to morphine, reducing the analgesic effect of codeine.

Hydroxyzine.

Concurrent use of hydroxyzine (anxiolytics) with codeine may result in increased analgesia as well as increased CNS depressant, sedative and hypotensive effects.

Lithium.

Ibuprofen has been shown to decrease the renal clearance and increase plasma concentrations of lithium. Lithium plasma concentrations should be monitored in patients on concurrent ibuprofen therapy.

Metoclopramide, cisapride and domperidone.

Codeine may antagonise the gastrointestinal effects of metoclopramide, cisapride and domperidone.

Methotrexate.

NSAIDs inhibit tubular secretion of methotrexate in animals. As a result, reduction in the clearance of methotrexate may occur. Use of high doses of methotrexate concomitantly with NSAIDs should be avoided. At low doses of methotrexate, caution should be used if ibuprofen is administered concomitantly.

Mexiletine.

Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the latter.

Mifepristone.

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

Moclobemide.

Risk of hypertensive crisis.

Monoamine oxidase inhibitors (MAOIs).

Concurrent administration or use within 14 days of ceasing monoamine oxidase inhibitors may enhance the potential respiratory depressant effects of codeine. CNS depression or excitation may occur if codeine is given to patients receiving monoamine oxidase inhibitors, or within two weeks of stopping treatment with them.

Naloxone.

Naloxone antagonises the analgesic, CNS and respiratory depressant effects of opioid analgesics. Naltrexone also blocks the therapeutic effect of opioids.

NSAIDs and aspirin.

Concurrent use of ibuprofen with aspirin or other NSAIDs can lead to increased gastrointestinal adverse effects.

Neuromuscular blocking agents.

The respiratory depressant effect caused by neuromuscular blocking agents may be additive to the central respiratory depressant effects of opioid analgesics.

Opioid analgesics.

Concurrent use of codeine and other opioid receptor agonists is usually inappropriate as additive CNS depression, respiratory depression and hypotensive effects may occur (see Section 4.4, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Probenecid and phenytoin.

Interactions may also occur with probenecid, antidiabetic medications and phenytoin.

Quinolone antibiotics.

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

Quinidine.

Quinidine can inhibit the analgesic effect of codeine.

Tacrolimus.

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Tranquillizers, sedatives and hypnotics.

Codeine may potentiate the effects of these drugs (see Section 4.4, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

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.

Incompatibilities.

Codeine has been reported to be incompatible with phenobarbitone sodium forming a codeine phenobarbitone complex, and with potassium-iodide, forming crystals of codeine periodide. Acetylation of codeine phosphate by acetylsalicylic acid (aspirin) has occurred in solid dosage forms containing the two drugs, even at low moisture levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is limited evidence that drugs which inhibit cyclo-oxygenase prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.
(Category C)
Inhibition of prostaglandin synthesis by ibuprofen may adversely affect pregnancy and/or the embryo/ foetal development. During the first and second trimester of pregnancy, this product should not be given unless clearly necessary, and is contraindicated in the third trimester.
During the third trimester, all prostaglandin synthesis inhibitors may expose the foetus to cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension) and renal dysfunction, which may progress to renal failure with oligohydramnios. At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to possible prolongation of bleeding time and inhibition of uterine contractions, which may result in delayed or prolonged labour.
Opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. The use of codeine may prolong labour. Administration of codeine during labour may cause respiratory depression in the newborn infant. Nurofen Plus is contraindicated for use during the last trimester of pregnancy (see Section 4.3 Contraindications).
The use of Nurofen Plus during breastfeeding is contraindicated (also see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in the infant. Ibuprofen appears in breast milk in very low concentrations. Analgesic doses excreted in breast milk are generally low. However, infants of breastfeeding mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultrarapid metabolizer of codeine Codeine is excreted into human breast milk. Codeine is partially metabolized by cytochrome P4502D6 (CYP2D6) into morphine, which is excreted into breast milk. If nursing mothers are CYP2D6 ultra-rapid metabolisers, higher levels of morphine may be present in their breast milk. This may result in symptoms of opioid toxicity in both mother and the breastfed infant. Life-threatening adverse events or neonatal death may occur even at therapeutic doses.
Therefore, Nurofen Plus is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended and alternative arrangement should be made for feeding the infant for any period during codeine treatment. Breastfeeding mothers should be told how to recognize signs of high morphine levels in themselves and their babies. For example, in a mother, symptoms include extreme sleepiness and trouble caring for the baby. In the baby, symptoms include signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Medical advice should be sought immediately.

4.7 Effects on Ability to Drive and Use Machines

Codeine may cause drowsiness.
Opioid analgesics can impair mental function and cause blurred vision and dizziness. Rare side effects may include convulsions, hallucinations, blurred or double vision and orthostatic hypotension. Patients should be advised not to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The most commonly observed adverse events are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding which is dependent on the dosage range and duration of treatment.
Side effects from codeine are theoretical warnings based on drug class. No clinical data is available to determine frequency.
Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.
Prolonged use of a painkiller for headache can make them worse.
The list of the following adverse events relates to those experienced with ibuprofen and codeine (maximum of 1200 mg ibuprofen per day), for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse events may occur.
Adverse events which have been associated with ibuprofen and codeine are given below, tabulated by System Organ Class (SOC) and frequency.
The frequencies of adverse effects are defined as follows.
Very common: ≥ 1/10. Common: ≥ 1/100, < 1/10. Uncommon: ≥ 1/1,000, < 1/100. Rare: ≥ 1/10,000, < 1/1,000. Very rare: < 1/10,000, including isolated reports. Not known: cannot be estimated from the available data.
Within each frequency grouping, adverse events are presented in order of decreased seriousness. See Table 2.

Description of selected adverse reactions.

1Examples include anaemia, neutropenia, aplastic anaemia, haemolytic anaemia, eosinophilia, reduction of haemoglobin and haematocrit leucopenia, thrombocytopenia, pancytopenia and agranulocytosis. First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.
2Reversible.
3Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of:
a) nonspecific allergic reactions and anaphylaxis;
b) respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnea;
c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme). Severe shock syndrome may be characterised by abdominal pain, fever, shivering, nausea and vomiting. Hepatotoxicity and aseptic meningitis which occur less frequently may also be hypersensitivity reactions.
4The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, the available data on NSID related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff, neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen in patients with existing auto-immune disorders (such as systemic lupus erythematosus and mixed connective tissue disease).
5Includes changes in visual colour perception.
6Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke), (see Section 4.4 Special Warnings and Precautions for Use).
7In patients with compromised cardiac function.
8Sometimes fatal, particularly in the elderly.
9 See Section 4.4 Special Warnings and Precautions for Use.
10Especially in long term treatment, including hepatotoxicity, hepatitis, jaundice, alterations of hepatic function tests, pancreatitis, duodenitis, oesophagitis, hepato- renal syndrome, hepatic necrosis, hepatic insufficiency.
11Especially in long-term use, associated with increased serum urea and oedema. Also includes papillary necrosis. Ibuprofen may cause cystitis and haematuria, interstitial nephritis, nephrotic syndrome, oliguria, tubular necrosis, glomerulonephritis, alteration in the renal function test, polyuria, anaphylaxis.
12Increased frequency, decrease in amount.

Reporting suspected adverse effects.

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

4.9 Overdose

Overuse of this product, defined as consumption of quantities in excess of the recommended dose, or consumption for a prolonged period, may lead to physical or psychological dependency. Symptoms of restlessness and irritability may result when treatment is stopped.

Symptoms.

The symptoms of overdose with ibuprofen include nausea, vomiting, abdominal pain, diarrhoea (rarely), headache, dizziness, drowsiness, nystagmus, vertigo, blurred vision, tinnitus and rarely, hypertension, metabolic acidosis, convulsions, excitation, disorientation, coma, renal failure, liver damage, hypotension, respiratory depression, cyanosis and loss of consciousness. Exacerbation of asthma is possible in asthmatics.
Nausea and vomiting are prominent features of codeine overdose. Respiratory depression, excitability, convulsions, hypotension and loss of consciousness may occur with large codeine overdose. Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pinpoint in size. Hypotension and tachycardia are possible.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

It is thought that ibuprofen produces an anti-inflammatory effect at least in part by inhibiting prostaglandin synthetase. Ibuprofen has shown anti-inflammatory, analgesic and antipyretic activity in both animal and human studies.
Codeine phosphate hemihydrate is a narcotic analgesic acting on central opiate receptors, although its pharmacological effects are thought to be largely due to its biotransformation to morphine.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Ibuprofen.

Absorption.

Ibuprofen is well absorbed after oral administration with peak serum levels occurring after 1 to 2 hours.

Distribution.

Apparent volume of distribution is 0.14 L/kg. Ibuprofen and its metabolites readily cross the placental barrier in pregnant rabbits and rats. It is not known if the drug enters the cerebrospinal fluid.
99% of ibuprofen is protein bound. The high protein binding of the drug should be borne in mind when prescribing ibuprofen together with other protein bound drugs that bind to the same site on human serum albumin.

Metabolism.

90% of ibuprofen is metabolised in the liver to produce two major metabolites, a hydroxylated and carboxylated compound.

Excretion.

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 1.9 to 2.2 hours.

Codeine.

Absorption.

Codeine is well absorbed from the gastrointestinal tract and peak plasma concentrations are reached one hour after oral administration. Onset of action occurs in 15 to 30 minutes and analgesia is maintained for 4 to 6 hours.

Distribution.

Codeine is rapidly distributed to skeletal muscles, kidneys, liver, gastrointestinal tract, lungs, spleen and brain. It crosses the placenta and is distributed in low levels in breast milk.

Metabolism.

Codeine is metabolised mainly in the liver. The major metabolic pathway involves glucuronidation of codeine to codeine-6-glucuronide. Codeine can also undergo O- and N-demethylation catalysed by CYP2D6 and CYP3A4 respectively.
About 10% of an administered dose of codeine is converted by O-demethylation to morphine, which subsequently undergoes glucuronidation to morphine-3 or morphine-6 glucuronide, or N-demethylation to normorphine. Approximately 8% of the general Australian population cannot convert codeine to the active metabolite morphine as they are deficient in the CYP2D6 enzyme. These patients are likely to obtain reduced pain relief from codeine. Codeine is also converted by N-demethylation to norcodeine, which subsequently undergoes glucuronidation to norcodeine glucuronide or O-demethylation to normorphine.

Excretion.

Codeine is excreted mainly by the kidneys. Of the excreted material in the urine 40-70% is free or conjugated codeine, 5-15% is free or conjugated morphine, and 10-20% is free or conjugated norcodeine. The plasma half-life of codeine is 2 to 4 hours. Only traces of codeine and its metabolites are found in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Also containing microcrystalline cellulose, sodium starch glycollate, hypromellose, pregelatinised maize starch, talc and Opaspray white colouring.
Nurofen Plus tablets are gluten-free and lactose-free.

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 degrees Celsius.

6.5 Nature and Contents of Container

Aluminium blister packed in a carton.
Packs of *4, *6, *12, *24 and 30 tablets.
*Not available in Australia.

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

Ibuprofen.

Chemical name: 2-(4-Isobutylphenyl) propionic acid. It is a white or almost white powder or crystals with a characteristic odour. Practically insoluble in water, soluble 1 in 1.5 of alcohol, 1 in 1 of chloroform, 1 in 2 of ether and 1 in 1.5 of acetone; soluble in aqueous solutions of alkali hydroxides and carbonates.

Codeine phosphate hemihydrate.

Chemical name: (5R,6S)-7,8-didehydro- 4,5-epoxy-3-methoxy- N-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate. It is a small, colourless, odourless crystal or a white, odourless crystalline powder. Codeine phosphate is soluble in four parts water, slightly soluble in ethanol (96%), practically insoluble in chloroform and ether.

Chemical structure.


Ibuprofen MW: 206.3.
Codeine phosphate hemihydrate MW: 406.4.

Chemical formula.

Ibuprofen: C13H18O2.
Codeine phosphate hemihydrate: C18H21NO3.H3PO4.1/2 H2O.

CAS number.

Ibuprofen: 15687-27-1.
Codeine phosphate hemihydrate: 41444-62-6.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes