Consumer medicine information

Brufen Plus 200/12.8

Ibuprofen; Codeine phosphate hemihydrate

BRAND INFORMATION

Brand name

Brufen Plus 200/12.8

Active ingredient

Ibuprofen; Codeine phosphate hemihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Brufen Plus 200/12.8.

What is in this leaflet

This leaflet answers some common questions about BRUFEN PLUS 200/12.8. 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 BRUFEN PLUS 200/12.8 against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What BRUFEN PLUS 200/12.8 is used for

BRUFEN PLUS 200/12.8 contains two active ingredients: ibuprofen and codeine phosphate hemihydrate.

Ibuprofen belongs to a family of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). This group of medicines work by relieving pain, inflammation (e.g. swelling, redness, soreness) and fever.

Codeine is an opioid analgesic that works in the brain and spinal cord to relieve pain.

BRUFEN PLUS 200/12.8 provides temporary relief of acute to moderate pain and inflammation in patients over the age of 12 years.

Once taken, your body processes the codeine into its active form, morphine, in the liver. In about 8% of people, they may experience less pain relief compared to others as their body doesn't convert codeine to morphine very well.

BRUFEN PLUS 200/12.8 is not recommended for use in children under the age of 12 years.

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.

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

Before you take BRUFEN PLUS 200/12.8

When you must not take it

Do not take BRUFEN PLUS 200/12.8 if you have an allergy to:

  • any medicine containing ibuprofen or codeine phosphate hemihydrate
  • any other similar medicines to ibuprofen including aspirin and other NSAID medicines
  • any other similar medicines to codeine such as other opioid analgesics including morphine or pethidine
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take BRUFEN PLUS 200/12.8 if you are also taking other medicines that contain one or more NSAID medicine, whether prescribed by your doctor or obtained without prescription. Several medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAIDs. If you are not sure if the medicines you are taking contain these ingredients, ask your doctor.

Do not take BRUFEN PLUS 200/12.8 if you are in the last three months of pregnancy. Unless advised by your doctor, do not take BRUFEN PLUS 200/12.8 during the first 6 months of pregnancy.

Do not take BRUFEN PLUS 200/12.8 if you are breastfeeding or planning to breastfeed. The active ingredients in BRUFEN PLUS 200/12.8 pass into breast milk and there is a possibility that your baby may be affected.

Do not take BRUFEN PLUS 200/12.8 if you:

  • are vomiting blood or material that looks like coffee grounds
  • are bleeding from the rectum (back passage), have black sticky bowel motions (stools) or bloody diarrhoea
  • have a stomach or duodenal ulcer or have had one in the past
  • have or have had a history of ulcerative colitis or Crohn's disease
  • have chronic constipation or severe diarrhoea
  • have shallow breathing
  • consume large amounts of alcohol regularly
  • have severe heart, liver or kidney failure
  • are an ultra-rapid CYP2D6 metaboliser
  • are aged between 12 and 18 years of age and have compromised respiratory function including having had your tonsils or adenoids removed

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if 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) and skin irritation
  • a history of stomach ulcer
  • stomach problems or recent gastrointestinal surgery
  • liver disease
  • kidney disease
  • heart problems/failure including swelling of ankles or feet
  • thyroid problems or low blood pressure
  • a head injury or intercranial pressure
  • prostate problems
  • a tendency for convulsions, fits
  • a recent head injury

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

BRUFEN PLUS 200/12.8 is not recommended during the last three months of pregnancy. Your doctor will decide if you should take BRUFEN PLUS 200/12.8 during the first six months.

BRUFEN PLUS 200/12.8 given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

BRUFEN PLUS 200/12.8 should not be taken while breastfeeding except on your doctor's advice. Codeine passes into the breast milk.

Tell your doctor if you are over 65 years of age.

If you have not told your doctor about any of the above, tell them before you start taking BRUFEN PLUS 200/12.8.

Taking other medicines

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

Some medicines and BRUFEN PLUS 200/12.8 may interfere with each other. These include:

  • medicines used to help you relax, sleep or relieve anxiety, such as benzodiazepines, barbiturates and sedatives
  • aspirin, salicylates or other NSAID medicines
  • aminoglycoside antibiotics, medicines used to treat bacterial infections
  • atropine
  • warfarin, clopidogrel, ticlopidine or other medicines used to stop blood clots or thin the blood
  • medicines that are used to treat high blood pressure, e.g. ACE inhibitors, diuretics (fluid tablets) or heart problems including heart failure
  • methotrexate, a medicine used to treat arthritis and some types of cancer
  • zidovudine, a medicine used to treat HIV infection
  • mifepristone
  • quinolone, a medicine used to treat bacterial infections
  • medicines used to relieve stomach cramps or spasms
  • medicines used to treat diarrhoea (e.g. kaolin, pectin, loperamide)
  • medicines used to prevent travel sickness, such as hydroxyzine
  • metoclopramide, a medicine used to treat nausea and vomiting
  • selective serotonin reuptake inhibitors (SSRIs) and monoamine oxide inhibitors (MAOIs), medicines used to treat depression such as moclobemide
  • phenothiazines and antipsychotic agents, medicines used to treat mental disorders
  • lithium and other medicines used to treat depression or anxiety, e.g. MAOIs (even if taken within the last 14 days)
  • medicines such as prednisone, prednisolone, cortisone, ciclosporin and tacrolimus which reduce the activity of your immune system
  • quinidine, a medicine used to treat abnormal or irregular heartbeat
  • medicines used to treat diabetes
  • probenecid, a medicine used to treat gout
  • phenytoin, a medicine used to treat epilepsy
  • medicines used to treat Parkinson's disease
  • other opioids to treat pain or suppress cough
  • colestyramine, a medicine used to treat high cholesterol
  • cimetidine, a medicine used to reduce stomach acid production
  • herbal medicines such as ginkgo biloba
  • mexiletine, a medicine used to treat abnormal heart beat
  • naloxone, a medicine used in the treatment of an opioid overdose

These medicines may be affected by BRUFEN PLUS 200/12.8 or may affect how well it works. You may different amounts of your medicines, or you may need different medicines. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take BRUFEN PLUS 200/12.8

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to take

The usual dose of BRUFEN PLUS 200/12.8 is 2 tablets followed by, if necessary, 1 or 2 tablets every 4 hours.

Do not take more than 6 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

Swallow the tablets whole with a glass of water.

It can be taken with food or on an empty stomach.

How long to take it

You should not take BRUFEN PLUS 200/12.8 for more than three days unless instructed to by your doctor.

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

If you take too much (overdose)

If you or someone else take too much(overdose), and experience one or more of the symptoms below, immediately call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then.You should follow the above steps even if someone other than you has accidentally taken BRUFEN PLUS200/12.8 that was prescribed for you.If someone takes an overdose they may experience one or more of the following symptoms:

  • slow, unusual or difficult breathing
  • drowsiness, dizziness or unconsciousness
  • slow or weak heartbeat
  • nausea or vomiting
  • convulsions or fits

If you think you or someone else may have taken too much BRUFENPLUS 200/12.8, you should immediately:

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

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

Depending on your body’s individual ability to break down codeine, you may experience signs of overdose even when you take BRUFEN PLUS200/12.8 as recommended by your doctor. If overdose symptoms occur, seek immediate medical advice.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

While you are using BRUFEN PLUS 200/12.8

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BRUFEN PLUS 200/12.8.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, stop taking it and tell your doctor immediately.

If your symptoms do not improve after a few days, talk to your doctor. Your doctor will assess your condition and decide if you should continue to take BRUFEN PLUS 200/12.8.

Things you must not do

Do not take BRUFEN PLUS 200/12.8 to treat any other complaints unless your doctor tells you to.

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

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 BRUFEN PLUS 200/12.8 affects you. This medicine may cause dizziness, light-headedness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

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

Addiction
You can become addicted to BRUFEN PLUS 200/12.8 even if you take it exactly as prescribed. BRUFEN PLUS 200/12.8 may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence
As with all other opioid containing products, your body may become used to you taking BRUFEN PLUS200/12.8. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking BRUFEN PLUS200/12.8 suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to BRUFEN PLUS200/12.8 may develop, which means that the effect of the medicine may decrease. If this happens, more maybe needed to maintain the same effect.

Withdrawal
Continue taking your medicine for as long as your doctor tells you. If you stop taking this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating

Products containing codeine should not be used for prolonged periods; codeine may be habit forming

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking BRUFEN PLUS 200/12.8.

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

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

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

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

Tell your doctor or pharmacist 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
  • changes 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 BRUFEN PLUS 200/12.8 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 your urine, 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, known as jaundice
  • symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than usual

The above list includes serious side effects that may require 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 BRUFEN PLUS 200/12.8 and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage, 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
  • shallow breathing
  • fluid retention

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

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

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

After using BRUFEN PLUS 200/12.8

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store BRUFEN PLUS 200/12.8 or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

Do not use this medicine after the expiry date.

Product description

What it looks like

BRUFEN PLUS 200/12.8 are white to off-white capsule shaped, biconvex, film-coated tablets.

BRUFEN PLUS 200/12.8 are available in blister packs containing 30 tablets.

Ingredients

BRUFEN PLUS 200/12.8 contains 200 mg ibuprofen and 12.8 mg codeine phosphate hemihydrate as the active ingredients.

The tablets also contain:

  • pregelatinised maize starch
  • microcrystalline cellulose
  • croscarmellose sodium
  • colloidal anhydrous silica
  • purified water
  • Opadry film coating system OY-58900 white

This medicine does not contain gluten, wheat, lactose, sucrose or preservatives.

Supplier

BRUFEN PLUS 200/12.8 is distributed in Australia by:

Mylan Health Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au
Phone: 1800 314 527

This leaflet was prepared in November 2020.

AUST R 298439

brufen plus_cmi\Nov20/00

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Brufen Plus 200/12.8

Active ingredient

Ibuprofen; Codeine phosphate hemihydrate

Schedule

S4

 

1 Name of Medicine

Ibuprofen and codeine phosphate hemihydrate.

2 Qualitative and Quantitative Composition

Each Brufen Plus 200/12.8 tablet contains 200 mg of ibuprofen and 12.8 mg of codeine phosphate hemihydrate. It also contains the following excipients: microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, colloidal anhydrous silica, Opadry complete film coating system OY-58900 white.
Brufen Plus 200/12.8 tablets do not contain gluten, wheat, lactose, sucrose or preservatives.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Brufen Plus 200/12.8: white to off-white capsule-shaped, biconvex, film-coated tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

For the temporary relief of acute moderate pain and inflammation.

4.2 Dose and Method of Administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.4 Special Warnings and Precautions for Use).

Adults and children 12 years and over.

Initial dose two tablets taken with fluid, then one or two tablets every 4 hours when necessary. Maximum dose is 6 tablets in a 24-hour period.
Brufen Plus 200/12.8 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.
Brufen Plus 200/12.8 is contraindicated for use in patients who are:
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

Severe respiratory disease, acute respiratory disease and respiratory depression.
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, urticaria or allergic-type reactions) in response to ibuprofen with codeine, acetylsalicylic acid (aspirin) or other non-steroidal anti-inflammatories (NSAIDs).
Severe asthma, chronic constipation and active alcoholism.
Active, or a history of ulcerative colitis, Crohn's disease, recurrent peptic ulcer or gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding). As with other NSAID agents, ibuprofen should not be used in active gastrointestinal bleeding or in the presence of peptic ulceration.
Diarrhoea caused by pseudomembranous colitis or poisoning (until the cause organism or toxin has been eliminated from the gastrointestinal tract, since codeine may slow down the elimination, thereby prolonging the diarrhoea).
Use with other concomitant NSAIDs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), including cyclo-oxygenase-2 specific inhibitors - increased risk of adverse reactions.
Severe heart failure (NYHA Class IV) and severe renal failure (see Section 4.4 Special Warnings and Precautions for Use).
Severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
During the last trimester of pregnancy, including the last few days before expected birth (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant treatment with Monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment.
In patients who 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 life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Use of codeine containing products is contraindicated in women during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).

4.4 Special Warnings and Precautions for Use

Brufen Plus 200/12.8 should be administered with caution and at lowest effective dose in patients:
with decreased respiratory reserve, e.g. asthma or COPD;
with asthma, especially those patients who have not taken an NSAID (see Section 4.4 Special Warnings and Precautions for Use, Respiratory, Respiratory depression);
who are taking other respiratory depressants or sedatives (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol);
with hepatic, renal or cardiac impairment (see Section 4.4 Special Warnings and Precautions for Use, Cardiac, renal and hepatic impairment);
with hypotension;
with previous history of gastrointestinal haemorrhage or ulcers (see Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal);
who have had recent gastrointestinal tract surgery; codeine may reduce gastrointestinal motility;
with hypothyroidism;
with a tendency for convulsions;
with prostatic hypertrophy; codeine may cause urinary retention;
with raised intracranial pressure or head injury;
who are pregnant (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation; Section 4.3 Contraindications);
who are over the age of 65 (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Hazardous and harmful use.

Brufen Plus 200/12.8 contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Brufen Plus 200/12.8 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 Brufen Plus 200/12.8.
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 Brufen Plus 200/12.8 with anyone else.
In view of the potential development of physical dependency to codeine, long-term use is not recommended.

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 Brufen Plus 200/12.8 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 (see Use in hepatic impairment and Use in renal 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, (see Section 4.2 Dose and Method of Administration), 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 Brufen Plus 200/12.8 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 Brufen Plus 200/12.8 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 Brufen Plus 200/12.8.

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 Brufen Plus 200/12.8 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; Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Brufen Plus 200/12.8, 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 Brufen Plus 200/12.8 (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.

Gastrointestinal.

NSAIDS should be given with care to patients with a history of peptic ulceration and gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see Section 4.3 Contraindications; 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.
Combination therapy with protective agents should be considered for these patients, as well as patients requiring concomitant low dose acetylsalicylic acid/aspirin, or for other drugs likely to increase gastrointestinal risk (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The concomitant administration of ibuprofen and other NSAIDs, including cyclooxygenase-2 (COX-2) selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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 Brufen Plus 200/12.8 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 anti-platelet 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 Brufen Plus 200/12.8, the treatment should be withdrawn.
Codeine should be used with caution in patients with biliary tract disease, including acute pancreatitis, as codeine may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.
Chronic use of opioids, including codeine, can cause or aggravate chronic constipation since, although a level of tolerance to the effects of opiates on bowel movements is developed, patients who take opiates to treat a chronic condition continue to suffer from constipation.

Respiratory.

Bronchospasm may be precipitated in patients suffering from, or with a history of bronchial asthma, chronic rhinitis 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 (see below).

Aseptic meningitis.

Aseptic meningitis has been observed on rare occasions in patients on 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 an underlying chronic disease.

Cardiac, renal and hepatic impairment.

Caution is required in patients with renal, hepatic or cardiac impairment since the use of NSAIDs may result in deterioration of renal function. The habitual concomitant intake of similar painkillers further increases this risk. For patients with renal, hepatic or cardiac impairment, use the lowest effective dose, for the shortest possible duration and monitor renal function especially in long-term treated patients (see Section 4.3 Contraindications). See below for further information on cardiac, renal and hepatic impairment.

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.
Brufen Plus 200/12.8 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.
Codeine is metabolised by the liver and should be used with caution in patients with hepatic disease, since increased bioavailability after oral administration or cumulative effects may occur.

Use in renal impairment.

Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.
Caution should be exercised in patients with renal impairment as renal function may deteriorate, especially in dehydrated paediatric patients (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).
As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes.
Opioids and their metabolites are excreted primarily via the kidneys. Because of this there is an increased risk of adverse effects in patients with renal function impairment.

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 with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided. Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.
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.
Brufen Plus 200/12.8 should be administered with caution in patients with hypertension or fluid retention (see Section 4.3 Contraindications).

Haematological effects.

Ibuprofen with codeine should be given with care to patients receiving anticoagulant therapy and appropriate monitoring should be conducted.

Dermatological effects.

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. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Brufen Plus 200/12.8 use should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

CYP2D6 metabolism.

Brufen Plus 200/12.8 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 metaboliser 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 in infants of rapid metaboliser mothers who take codeine.
The prevalence of codeine ultra-rapid metabolism by CYP2D6 in children is not known, but it 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% to 10% in Caucasians. The highest prevalence (16% to 28%) occurs in North African, Ethiopian and Arab populations. Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation. 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).

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.
Ibuprofen should not be taken by adults over the age of 65 without careful consideration of co-morbidities and co-medications because of an increased risk of adverse effects, in particular heart failure, gastro-intestinal ulceration and renal impairment.
The elderly are also more likely to have age related renal impairment and may be more susceptible to the respiratory depressant effects of codeine.
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 Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal).

Paediatric use.

Brufen Plus 200/12.8 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-metabolisers of codeine due to CYP2D6 polymorphism. Also see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism.

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 ultrarapid 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.

General.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
In patients with renal impairment, renal function should be monitored since it may deteriorate following the use of any NSAID.
As with other NSAIDs, excessive or prolonged use of ibuprofen may increase the risk of heart attack, stroke or liver damage.
As with other NSAIDS, ibuprofen may mask the usual signs of infection.
The concomitant use of alcohol should be avoided.
Codeine may also obscure the diagnosis or the course of gastrointestinal diseases. Brufen Plus 200/12.8 should therefore be administered with caution in such situations.
Care is advised in the administration of Brufen Plus 200/12.8 to patients with adrenocortical insufficiency and also in patients with a history of drug abuse.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Brufen Plus 200/12.8 should be avoided in combination with:

Alcohol.

Can increase the depressive effect of codeine.

Aspirin.

As with other products containing NSAIDs, concomitant administration of ibuprofen and acetylsalicylic acid/aspirin is not generally recommended because of the potential of increased adverse effects. Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid/ aspirin cannot be excluded. 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 due to the potential for additive effects, as this may increase the risk of adverse effects (see Section 4.4 Special Warnings and Precautions for Use).
Brufen Plus 200/12.8 should be used with caution in combination with:

Aminoglycosides.

NSAIDs may decrease the excretion of aminoglycosides.

Anticholinergics.

Concurrent use of codeine, and anticholinergics or other medications with anticholinergic activity may increase the risk of severe constipation and/or urinary retention, which may lead to paralytic ileus.

Anticoagulants.

Ibuprofen interferes with the stability of INR. NSAIDs may enhance the effects of anticoagulants, such as warfarin. Concurrent use of NSAIDs and warfarin has been associated with severe bleeding and 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. Brufen Plus 200/12.8 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 anti-peristaltic agents such as loperamide, pectin 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 may reduce the antihypertensive effect of ACE Inhibitors, angiotensin-II receptor antagonists, beta-blockers and diuretics, with possible loss of blood pressure control, and may cause natriuresis and hyperkalaemia in patients under these treatments.
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.

Anti-platelet agents, e.g. clopidogrel and ticlopidine, and selective serotonin reuptake inhibitors (SSRls).

Increased risk of gastrointestinal bleeding with NSAIDS (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.

Concomitant use of codeine with central nervous system depressants (e.g. barbiturates, chloral hydrate, sedatives, alcohol and centrally acting muscle relaxants) can cause additive CNS depression.

Colestyramine.

The concomitant administration of ibuprofen and colestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown.

Ciclosporin.

An increased risk of nephrotoxicity with NSAIDs.

Cimetidine.

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

Corticosteroids.

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

CYP2C9 inhibitors.

Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.

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

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

Herbal extracts.

Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

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 and caution should be used if low doses of methotrexate are administered concomitantly with ibuprofen.

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, due to the antiprostaglandin properties of NSAIDs.

Moclobemide.

Risk of hypertensive crisis.

Monoamine oxidase inhibitors (MAOIs).

Concurrent administration or use within 14 days of ceasing MAOIs 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.

Probenecid, phenytoin and antidiabetic medicines.

Interactions may also occur with probenecid, antidiabetic medications and phenytoin. NSAIDs may potentiate the effects of sulfonylurea medications. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen.

Sedative medicines such as benzodiazepines or other CNS depressants.

The concomitant use of opioid containing products (e.g. codeine) with sedative medicines such as benzodiazepines, other opioid analgesics, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, including alcohol increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see Section 4.4 Special Warnings and Precautions for Use).

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 preparations.

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. Concurrent administration with ibuprofen may prolong bleeding time in patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is limited evidence that drugs which inhibit cyclooxygenase 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/fetal 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 fetus 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.
Consequently, ibuprofen with codeine is contraindicated during the third trimester of pregnancy.
Administration of ibuprofen with codeine is not recommended during labour and delivery. The use of codeine may prolong labour. Administration of codeine during labour may cause respiratory depression in the newborn infant. It is not advisable to use it during labour if the baby is premature.
Opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate.
Codeine can cause the newly born to suffer from withdrawal syndrome in case of administration of codeine-containing medications in the days prior to delivery. It is therefore recommended to closely monitor the newly born whose mother took opiates during labour.
Brufen Plus 200/12.8 is contraindicated for use during the last trimester of pregnancy (see Section 4.3 Contraindications).
Brufen Plus 200/12.8 is contraindicated during breastfeeding (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 breast-feeding mothers taking codeine may have increased risk of morphine overdose if the mother is an ultra-rapid metaboliser of codeine.
Codeine is excreted into human breast milk. Codeine is partially metabolised by cytochrome P450 2D6 (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 (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Therefore, Brufen Plus 200/12.8 is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended, and alternative arrangements should be made for feeding the infant for any period during codeine treatment.
Breast feeding mothers should be told how to recognise 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

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs.
Codeine may cause drowsiness. Sedation with altered reaction time due to codeine may occur.
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)

Gastrointestinal disorders.

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.

Infections and infestations.

Exacerbation of skin infection-related inflammations (e.g. development of necrotising fasciitis) coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of ibuprofen the patient should immediately seek medical attention.
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 in Table 2, 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.

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.

Ibuprofen.

The most frequently reported symptoms of ibuprofen overdose include nausea, vomiting, abdominal pain, lethargy and drowsiness. CNS effects include headache, dizziness, tinnitus, convulsions and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea and depression of the CNS and respiratory system have also been rarely reported. Cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported. Symptoms of overdose also include vertigo, blurred vision, tinnitus and rarely, diarrhoea, hypertension, excitation, disorientation, and cyanosis. In cases of significant overdose, renal failure and liver damage are possible. Exacerbation of asthma is possible in asthmatics.

Codeine.

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.

Treatment.

Ibuprofen.

There is no specific antidote to ibuprofen. Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. If necessary, serum electrolyte balance should be corrected.

Codeine.

In an overdose of codeine, parenteral naloxone may be administered in connection with resuscitation if serious respiratory and/or cardiovascular depression has occurred.
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.

Ibuprofen possesses analgesic, antipyretic and anti-inflammatory properties, similar to other non-steroidal anti-inflammatory drugs (NSAIDS). Its mechanism of action is unknown but is thought to be through peripheral inhibition of cyclooxygenases and subsequent prostaglandin synthetase inhibition.
Codeine acts centrally on opiate receptors. Its analgesic effect is thought to be due mainly to its partial metabolic conversion to morphine. Codeine has about one-sixth the analgesic activity of morphine.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Ibuprofen.

It is well absorbed from the gastrointestinal tract after oral administration with peak serum levels occurring after 1-2 hours.

Codeine.

Codeine and its salts are well absorbed from the gastrointestinal tract. Peak plasma-codeine concentrations occur at about one hour after ingestion of codeine phosphate hemihydrate. Analgesic action occurs in 15 to 30 minutes and analgesia is maintained up to 4-6 hours.

Distribution.

Ibuprofen.

Apparent volume of distribution is 0.14 L/kg. Ibuprofen and its metabolites readily cross the placental barrier in pregnant animals (rabbits and rats). It is not known if ibuprofen enters the cerebrospinal fluid.

Codeine.

After ingestion 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.

Ibuprofen.

90% of ibuprofen is metabolised to inactive compounds in the liver, mainly by glucuronidation, to produce two metabolites - a hydroxylated compound and a carboxylated compound.

Codeine.

Codeine is metabolised by O- and N-demethylation in the liver (by CYP2D6 and CYP3A4 respectively) to morphine (about ten percent of a codeine dose is demethylated to morphine), norcodeine and other metabolites including normorphine and hydrocodone. The major metabolic pathway involves glucuronidation of codeine to codeine-6-glucuronide. About 8% of the general Australian population cannot convert codeine to its active metabolite morphine as they are deficient in the CYP2D6 enzyme. These persons are likely to obtain reduced pain relief from codeine.

Excretion.

Ibuprofen.

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.

Codeine.

Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. 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. Excretion is almost complete within 24 hours. The plasma half-life of codeine has been reported to be between 2 and 4 hours after oral administration. Only traces of codeine and its metabolites are found in the faeces.

Protein binding.

Ibuprofen.

It is highly bound (90-99%) to plasma proteins and consequently, this characteristic of the drug should be considered when prescribing ibuprofen together with other drugs that bind to the same site on human serum albumin.

Half-life.

Ibuprofen.

The elimination half-life of ibuprofen is in the range of 1.9 to 2.2 hours.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.
This medicinal product does not require any special storage conditions.

6.5 Nature and Contents of Container

Available in PVC/PVDC blisters in the following pack sizes: 10s, 12s, 15s, 20s, 24s and 30s.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Ibuprofen.

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.
Chemical name: 2-(4-Isobutylphenyl) propionic acid.
Molecular formula: C13H18O2.
MW: 206.3.

Codeine phosphate hemihydrate.

It is a small, colourless, odourless crystal or a white, odourless crystalline powder. Codeine phosphate hemihydrate is soluble in four parts water, slightly soluble in ethanol (96%), practically insoluble in chloroform and ether.
Chemical name: (5R, 6S)-7, 8-didehydro-4,5-epoxy-3-methoxy-N-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate.
Molecular formula: C18H21NO3.H3PO4.½ H2O.
MW: 406.4.

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