Consumer medicine information

Panafen Plus Caplets

Codeine phosphate hemihydrate; Ibuprofen

BRAND INFORMATION

Brand name

Panafen Plus Caplets

Active ingredient

Codeine phosphate hemihydrate; Ibuprofen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Panafen Plus Caplets.

What is in this leaflet

This leaflet answers some common questions about PANAFEN 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 pharmacist or doctor has weighed the risks of you taking PANAFEN 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 PANAFEN PLUS is used for

This medicine is for the temporary relief of strong pain where ibuprofen alone is not effective.

You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 days, you should see your doctor for advice.

This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days.

PANAFEN PLUS caplets 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, inflammation (swelling, redness, soreness) and fever. Codeine is an opioid analgesic that works in the brain and spinal cord to relieve pain.

PANAFEN PLUS relieves strong pain and discomfort associated with migraine or tension headache, period pain, toothache, cold & flu symptoms, back or muscular pain, arthritis and neuralgia. It also reduces any fever associated with these pain conditions.

PANAFEN PLUS should not be used in children under the age of 18 years.

Your doctor or pharmacist may have given you this medicine for another use.

If you need more information ask your doctor or pharmacist.

Do not use PANAFEN PLUS if

When you must not take it

Do not take PANAFEN PLUS if you are under the age of 18 years.

Do not take PANAFEN PLUS if you have an allergy to:

  • ibuprofen, codeine or other opioid pain reliever
  • any of the ingredients listed at the end of this leaflet
  • aspirin
  • any other NSAID medicine.

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
  • fainting
  • hives, itching or skin rash.

If you are allergic to aspirin or NSAID medicines and take PANAFEN PLUS, these symptoms may be severe.

Do not take PANAFEN PLUS if you are also taking any other medicines that contain NSAIDS, whether prescribed by your doctor or obtained without prescription.

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

Do not take PANAFEN PLUS during pregnancy.

PANAFEN PLUS should not be taken whilst breast-feeding.

The use of codeine containing products while breast-feeding may harm your baby.

Do not take PANAFEN Plus if you have been told by your doctor that you breakdown codeine rapidly since the following side effects may develop: feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than usual, feeling confused and have breathing problems.

Do not take PANAFEN PLUS if:

  • you are vomiting blood or material that looks like coffee grounds
  • you are bleeding from the back passage (rectum), have black sticky bowel motions (stools) or bloody diarrhoea
  • you have a stomach or duodenal ulcer, perforation or bleeding of the stomach or have had one in the past
  • you have asthma that is sensitive to aspirin or NSAIDs
  • you have chronic constipation
  • you have shallow breathing
  • you have severe diarrhoea
  • you consume regular and heavy amounts of alcohol
  • you have heart failure
  • you have liver or kidney disease
  • you are using NSAIDs including COX-2 specific inhibitors, e.g. Celecoxib (Celebrex), Meloxicam (Mobic)
  • patients undergoing treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).

PANAFEN PLUS should not be used if you have kidney problems or severe liver problems.

Do not take PANAFEN PLUS after the expiry date (EXP) printed on the pack.

If you take this medicine after the expiry date has passed, it may have no effect at all, or worse, have an entirely unexpected effect.

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

Do not use this medicine to treat any other complaint unless your doctor or pharmacist says it is safe. Do not give this medicine to anyone else even if they have the same symptoms as you.

Before you start to take it

You must tell your pharmacist or doctor if:

  • you are pregnant or intend to become pregnant
    PANAFEN PLUS is not recommended for use during pregnancy. PANAFEN PLUS is not recommended in women attempting to conceive, as NSAIDS like ibuprofen may impair fertility in women. This effect is reversible upon stopping the medicine.
  • you are breast-feeding or plan to breast-feed
    PANAFEN PLUS is not recommended if you are breast-feeding.
  • you have any medical conditions, especially the following:
    - a history of stomach or duodenal ulcer
    - stomach problems or recent stomach surgery
    - liver or kidney disease
    - heart failure including
    - swelling of feet or ankles
    - high blood pressure
    - asthma or have suffered in the past from asthma or allergic disease
    - bowel or intestinal problems including ulcerative colitis and Crohn's disease
    - history of cholecystectomy
    - had an operation to remove your gallbladder
    - Systemic Lupus Erythematosus (SLE)
    - a history of drug dependence
    - thyroid problems or low blood pressure
    - head injury or raised intracranial pressure
    - prostate problems.
  • you currently have an infection
    If you take Panafen Plus while you have an infection the medicine may hide some of the signs of an infection. This may make you think, mistakenly, that you are better or that it is not serious.
  • you have liver disease
    Remain alert for signs and/or symptoms of liver toxicity (e.g. nausea, fatigue, lethargy, itching, yellowing of the skin and/or eyes (jaundice), abdominal tenderness in the right upper quadrant and "flu-like" symptoms).

Talk to your pharmacist or doctor about taking this medicine if you are over 65 years of age.

Taking this medicine may increase the risk of you getting stomach, heart or kidney problems.

Ibuprofen may be associated with an increased risk of serious cardiovascular events, including heart attack and stroke, which are more likely with high doses and prolonged treatment. There may be a greater risk for patients with cardiovascular disease, history of atherosclerotic disease or cardiovascular risk factors. Even in the absence of previous cardiovascular symptoms, remain alert for such cardiovascular events. Talk to your doctor about signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur.

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 each other. These include:

  • aspirin, salicylates or other NSAID medicines including COX-2 specific inhibitors
  • warfarin or other medicines used to stop blood clots or thin the blood including low dose aspirin
  • digoxin, a medicine to treat heart failure
  • medicines that are used to treat high blood pressure
  • diuretics, also called fluid or water tablets
  • methotrexate, a medicine to treat arthritis and some cancers
  • cyclosporine, a medicine that suppresses the immune system
  • corticosteroids which reduce the activity of your immune system
  • quinolone antibiotics
  • zidovudine, a medicine used to treat HIV infection
  • lithium and other medicines used to treat depression, e.g. MAOIs (even if taken within the last 14 days) and SSRIs
  • anticholinergic medicines such as those used to relieve stomach cramps, to prevent travel sickness and to treat Parkinson's disease
  • medicines used to treat diarrhoea (e.g. kaolin, pectin, loperamide)
  • metoclopramide, a medicine used to treat nausea and vomiting
  • antidiabetic medications
  • other opioid pain killers
  • medicines to help you relax, sleep or relieve anxiety, such as barbiturates and sedatives
  • phenothiazines and antipsychotic agents used to treat mental disorders
  • probenecid, a medicine to treat gout
  • phenytoin, a medicine to treat epilepsy
  • quinidine, a medicine to treat certain heart conditions.

These medicines may be affected by PANAFEN 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 or pharmacist will advise you.

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

How to take PANAFEN PLUS

How much to take

Take 2 caplets of PANAFEN PLUS then, if necessary, 1 or 2 caplets every 4 hours.

Do not take more than six caplets in 24 hours.

If symptoms persist or worsen, please consult your doctor.

This product should be taken at the lowest dose for the shortest time necessary to relieve your symptoms. Taking this medicine regularly for a long time can lead to addiction.

Do not take for more than 3 days without asking your doctor.

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

PANAFEN PLUS is not recommended for children under 18 years.

Do not exceed the stated dose and do not take more frequently than every 4 hours.

Do not take this product with any other product containing ibuprofen or codeine.

How to take it

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

How long to take it

You should not take PANAFEN PLUS for more than 3 days.

PANAFEN PLUS should not be used for more than a few days at a time unless on medical advice.

If your symptoms persist, get worse or new symptoms develop, talk to your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre telephone 13 11 26 (Australia) or 0800 764 766 (New Zealand) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much PANAFEN PLUS.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention because of the risk of liver failure and breathing problems. Keep telephone numbers of these places handy.

If you take too much of this medicine you may experience the following:

  • nausea or an upset stomach
  • vomiting and gastric irritation
  • drowsiness
  • dizziness
  • very slow, laboured breathing.
  • blurred vision
  • ringing in the ears
  • rapid, uncontrollable movements of the eyes.

In rare cases you may experience the following:

  • excitability
  • convulsions
  • unconsciousness.

While you are taking PANAFEN PLUS

Things you must do

Take PANAFEN PLUS exactly as your pharmacist or doctor has told you to.

Tell all your doctors, dentists and pharmacists that you are taking PANAFEN PLUS.

Tell your doctor or pharmacist if you become pregnant while taking PANAFEN PLUS.

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

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

Things you must not do

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

Do not use PANAFEN PLUS to treat any other complaints.

Things to be careful of

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

PANAFEN PLUS may cause dizziness, light-headedness, drowsiness, fatigue or visual disturbances in some people. If this occurs, do not drive or operate machinery.

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

Products containing codeine should not be taken for prolonged periods.

Codeine may be habit-forming.

About 5-10% of people are poor metabolisers of codeine and PANAFEN PLUS may not work as well if you are one of those people.

Products containing ibuprofen should not be used for prolonged periods.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while taking PANAFEN PLUS.

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

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
  • diarrhoea, pain in the stomach
  • dizziness, light-headedness, drowsiness
  • constipation
  • cough suppression
  • headache
  • hearing disturbance.

These are the more common side effects of PANAFEN 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.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking PANAFEN 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
  • you experience breathlessness and/or swelling of legs or feet
  • you experience a skin rash or peeling, or mouth ulcers
  • asthma, wheezing, shortness of breath, pain or tightness in the chest
  • you have previously had gallbladder removal surgery and experience severe abdominal pain, nausea and vomiting
  • sudden or severe itching, skin rash, hives, skin peeling
  • you experience unexplained bruising or bleeding, fever, sore throat, extreme pallor or weakness
  • your existing bowel disease (ulcerative colitis or Crohn's disease) worsens
  • you have an existing autoimmune disorder (e.g. Systemic Lupus Erythematosus, mixed connective tissue disease) and develop a stiff neck, headache, nausea, vomiting, fever or feel disorientated
  • you pass less or more urine than normal, your urine is cloudy, there is blood in your urine, or you experience pain in the back and/or swelling (particularly of the legs)
  • you experience liver problems including jaundice, symptoms could include yellowing of the skin and whites of the eyes.

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

Some people may get other side effects while taking PANAFEN 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 taking PANAFEN PLUS

Storage

Keep the caplets in the pack until it is time to take them.

If you take them out they will not keep well.

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

Heat and dampness can destroy some medicines. Do not leave PANAFEN PLUS in the car on hot days.

Keep PANAFEN PLUS 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.

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

Disposal

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

This is not all the information that is available on PANAFEN PLUS. If you have any more questions or are not sure about anything, ask your doctor or pharmacist.

Product description

What it looks like

PANAFEN PLUS caplets are white capsule shaped tablets marked on one side with a "+" sign surrounded by an oval.

They come in cartons of 15 and 30 caplets.

Ingredients

Active ingredients:

Each PANAFEN PLUS caplet contains:

  • Ibuprofen 200 mg
  • Codeine phosphate 12.8 mg.

Other ingredients:

  • Cellulose-microcrystalline
  • Vegetable oil-hydrogenated
  • Sodium starch glycollate
  • Silica-colloidal anhydrous
  • Lactose
  • Cellulose-powdered
  • Hypromellose
  • Macrogol 400.

Manufacturer/Supplier

PANAFEN PLUS caplets are supplied in Australia and New Zealand by:

GlaxoSmithKline Consumer Healthcare Australia Pty Ltd

82 Hughes Avenue, Ermington NSW and Auckland, New Zealand

AUST R 106616

Date of preparation: January 2016.

PANAFEN is a registered trade mark of the GSK group of companies or its licensor.

BRAND INFORMATION

Brand name

Panafen Plus Caplets

Active ingredient

Codeine phosphate hemihydrate; Ibuprofen

Schedule

S4

 

Name of the medicine

Ibuprofen 200 mg, codeine phosphate 12.8 mg.

Excipients.

Microcrystalline cellulose, hydrogenated vegetable oil, sodium starch glycollate, anhydrous colloidal silica, lactose, powdered cellulose, hypromellose, macrogol 400.

Description

Ibuprofen.

Chemical name: 2-(4-isobutylphenyl) propionic acid. Molecular formula: C13H18O2. MW: 206.3. CAS: 15687-27-1. Ibuprofen 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.

Chemical name: (5R,6S)-7,8-didehydro- 4,5-epoxy-3-methoxy- N-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate. Molecular formula: C18H21NO3H3PO4.½H2O. MW: 406.4. CAS: 41444-62-6. Codeine phosphate is a small, colourless, odourless crystal or a white, odourless crystalline powder. It is soluble in four parts water, slightly soluble in ethanol (96%), practically insoluble in chloroform and ether.

Pharmacology

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 is a narcotic analgesic acting on central opiate receptors, although its pharmacological effects are thought to be largely due to its biotransformation to morphine.

Pharmacokinetics.

Ibuprofen.

Absorption.

Ibuprofen is well absorbed after oral administration with peak serum levels occurring after one to two hours.

Distribution.

The apparent volume of distribution for ibuprofen 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 and elimination.

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

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 5 to 10% of the Caucasian population cannot convert codeine to 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.
Codeine is excreted mainly by the kidneys. Of the excreted material in the urine, 40 to 70% is free or conjugated codeine, 5 to 15% is free or conjugated morphine and 10 to 20% is free or conjugated norcodeine. The plasma half-life of codeine is two to four hours. Only traces of codeine and its metabolites are found in the faeces.

Clinical Trials

Ibuprofen.

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 disease or cardiovascular risk factors may also be at greater risk.

Codeine.

Adverse events from clinical trials of codeine are sparse and are based on higher doses of codeine than that contained in this product. These data are unreliable for determining the nature and frequency of adverse reactions at the dose of codeine contained in this product.

Indications

For the temporary relief of strong pain and discomfort associated with migraine headache, tension headache, period pain, toothache, cold and flu symptoms, back or muscular pain, arthritis and neuralgia. Reduces fever.

Contraindications

Known hypersensitivity to ibuprofen, codeine or other opioid analgesics or any of the excipients in the product.
Children under the age of 18 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see Pharmacology).
Known hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Patients with gastrointestinal bleeding or with an active or previous peptic ulcer.
Patients with a history of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Patients who are taking concomitant NSAIDs including cyclooxygenase-2 (COX-2) specific inhibitors (see Interactions with Other Medicines).
Panafen Plus should not be used in heart failure.
Panafen Plus should not be used in renal impairment or severe liver impairment.
Respiratory depression, chronic constipation and active alcoholism.
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 and thereby prolonging the diarrhoea).
Patients who are pregnant (see Precautions, Use in pregnancy).
Patients who are breastfeeding unless the product has been prescribed by a doctor (see Precautions, Use in lactation).
Patients who are known to be CYP2D6 ultrarapid metabolisers. If the patient is an extensive or ultrarapid CYP2D6 metaboliser, there is an increased risk of developing symptoms of opioid toxicity, even at commonly prescribed doses (see Pharmacology). 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.
Patients undergoing treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).

Precautions

If symptoms persist, medical advice must be sought.
Do not take for more than 3 days unless advised by a doctor.
Prolonged or excessive consumption can result in dependence (see Adverse Effects).
Panafen Plus should be used with caution in patients who have a history of drug abuse.
Use with caution in elderly patients who are more prone to adverse events.
Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration.
Panafen Plus should be administered with caution to patients with asthma or allergic disease, and especially those patients who have not taken an NSAID before.
Patients who have been diagnosed with liver or kidney impairment must seek medical advice before taking this product. The use of NSAIDs may result in deterioration of renal function.
Patients with a history of hypertension and/or heart failure should seek medical advice before use, as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Use with caution in patients with chronic inflammatory intestinal disease (ulcerative colitis, Crohn's disease), obstructive bowel disorders or acute abdominal conditions, as these conditions may be exacerbated.
Use with caution in patients with a history of cholecystectomy as NSAIDs may cause acute pancreatitis in some patients.
Use with caution in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease due to increase risk of aseptic meningitis.
Gastrointestinal (GI) bleeding, ulceration or 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. When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn and patients should consult a doctor (see Adverse Effects).
Discontinue at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. As 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 Adverse Effects).
Panafen Plus should be administered with caution in patients with decreased respiratory reserve, e.g. asthma or chronic obstructive pulmonary disease (COPD). Bronchospasm may be precipitated in patients suffering from or with a previous history of asthma or allergic disease.

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 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. Therefore, Panafen Plus should only be used under medical advice in patients with hypertension (see also Contraindications, heart failure).

Hepatic.

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.
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).
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. Panafen Plus should therefore be administered with caution in such situations.
Panafen Plus should be administered with caution to patients who have recently had gastrointestinal surgery, as codeine may reduce gastrointestinal motility.
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may result in deterioration of renal function.
Panafen Plus should be administered with caution to those with hypotension and/or hypothyroidism. The caplets should be used with caution in patients with CNS depression, raised intracranial pressure or head injury, since codeine may increase the risk of respiratory depression and further elevate intracranial pressure.
Panafen Plus should be administered with caution to patients with prostatic hypertrophy since codeine may cause urinary retention.
Patients taking other medications should consult a physician prior to taking this product.
Keep out of sight and reach of children.
Panafen Plus contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect on female fertility.

There is some evidence that drugs which inhibit cyclooxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment. Therefore, Panafen Plus is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs should be considered.

Use in pregnancy.

(Category C)
This product should not be used during pregnancy. The safety of codeine during pregnancy has not been established relative to the possible adverse effects on foetal development. Maternal use of codeine during labour may cause respiratory depression in the child. There is an ibuprofen related risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension during the third trimester of pregnancy. The onset of labour maybe delayed and its duration increased, with an increased risk of bleeding tendency for both mother and child.

Use in lactation.

In limited studies, ibuprofen appears in breast milk in very limited concentrations and is unlikely to affect the breastfed infant adversely. Codeine is excreted in breast milk. The use of Panafen Plus caplets should be avoided if possible during lactation and should not be used while breastfeeding unless prescribed by a doctor.
In nursing mothers, who are ultrarapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. The lowest effective dose should be used, for the shortest period of time. Nursing mothers should be informed about carefully monitoring the infant during treatment for any sign and symptom of morphine toxicity such as increase drowsiness or sedation, difficulty breastfeeding, breathing difficulties and decrease tone and seeking immediate medical care if such symptoms or signs are noticed.

Use in the elderly.

NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events. The elderly may also be more susceptible to the CNS depressant effects of opioids.

Effect on ability to drive or operate machinery.

Codeine may cause dizziness or drowsiness. Those affected should not drive or operate machinery.
Following treatment with ibuprofen, the reaction time of patients may be affected. NSAIDs may cause dizziness, drowsiness, fatigue and visual disturbances. If affected patients should not drive or operate machinery.

Interactions

Ibuprofen containing products should not be used in combination with other NSAIDs including aspirin and cyclooxygenase-2 (COX-2) specific inhibitors as these may increase the risk of adverse effects (see Contraindications).
Ibuprofen containing products may inhibit the antiplatelet effect of low dose aspirin. Patients on low dose aspirin should be instructed to consult their doctor or pharmacist before taking ibuprofen (see Precautions).
Ibuprofen containing products should be used with caution in combination with the following drugs as interactions have been reported.

ACE inhibitors, beta-blockers and diuretics.

Ibuprofen, like other NSAIDs, can reduce the antihypertensive effect of ACE inhibitors and β-blockers with possible loss of blood pressure control and can attenuate the natriuretic effects of diuretics.

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

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time, increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drugs. Concomitant use of all three classes of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the treatment. The combination of drugs from these three classes should be used with caution.

Aminoglycosides.

Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentration.

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. Panafen Plus should only be used in patients taking warfarin if absolutely necessary. Patients taking this combination must be closely monitored.

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.

Corticosteroids.

An increased risk of gastrointestinal bleeding may occur with corticosteroids.

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.

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.

Cyclosporin.

Increased risk of nephrotoxicity.

Hypoglycemic agents (oral).

Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Quinolones.

NSAIDs can increase the risk of convulsions associated with quinolone antibiotics.

Zidovudine.

Increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs.

Selective serotonin reuptake inhibitors (SSRIs).

Increased risk of gastrointestinal bleeding.

Diuretics.

Reduced diuretic effect.
Codeine containing products should be used with caution in combination with the following drugs as interactions have been reported.

Anticholinergics.

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

Antihypertensives.

Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and lead to orthostatic hypotension.

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).

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

Central nervous system depressants.

Codeine may potentiate the effects of CNS depressants including alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.

Metoclopramide and domperidone.

Codeine may antagonise the effects of these antiemetics on gastrointestinal motility.

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. Codeine may interact with monoamine oxidase inhibitors (MAOI) and result in serotonin syndrome.

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 and phenytoin.

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

Quinidine.

Interferes with the metabolism of codeine to morphine, lowering the analgesic effect of codeine.
It is possible that interactions could occur between drugs that can inhibit CYP2D6 (such as quinidine, phenothiazines and antipsychotic agents) and codeine.

Adverse Effects

Postmarketing data.

Adverse reactions reported from extensive postmarketing experience are listed below by system organ class and frequency. The following convention has been utilised for the classification of undesirable effects: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Ibuprofen.

The following list of adverse effects relate to those experienced with ibuprofen at OTC doses, for short-term use. The treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Gastrointestinal disorders.

Uncommon: abdominal pain, nausea, dyspepsia.
Rare: diarrhoea, flatulence, constipation and vomiting.
Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn's disease (see Precautions).

Nervous system disorders.

Common: headache, drowsiness, dizziness, hearing disturbance (tinnitus).

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, itching.
Very rare: severe forms of skin reactions, exfoliative and bullous dermatoses such as erythema multiforme and epidermal necrolysis.

Renal and urinary disorders.

Very rare: acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatobiliary disorders.

Very rare: liver disorders.

Blood and lymphatic disorders.

Very rare: haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Immune system disorders.

Uncommon: hypersensitivity reactions including urticaria and pruritus.
Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock), exacerbation of asthma and bronchospasm.

Other.

Unknown: oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment (see Precautions).
In patients with existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see Precautions).

Codeine.

Psychiatric disorders.

Not known: drug dependency can occur after prolonged use of codeine at higher doses (see Precautions).

Gastrointestinal disorders.

Not known: constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy (see Precautions).

Nervous system disorders.

Not known: dizziness, worsening of headache with prolonged use and drowsiness.

Skin and subcutaneous tissue disorders.

Not known: pruritus, sweating.

Dosage and Administration

18 years-adults.

Initial dose two caplets taken with fluid, then one or two caplets every four hours when necessary preferably with or after food. Maximum six caplets in a 24 hour period.

Children (under 18 years).

Must not be used in patients under 18 years.
Do not exceed the stated dose.
Should not be used with other ibuprofen, NSAID or codeine containing products.
Minimum dosing interval: 4 hours.
Maximum duration of continued use without medical advice: 3 days.
If symptoms persist or worsen, medical advice must be sought.
Panafen Plus should not be used for more than 3 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.

Overdosage

The Poisons Information Centre can be contacted (telephone 131 126) for current information on the treatment of oral overdoses.

Ibuprofen.

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more severe poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning, metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Treatment should be symptomatic and supportive including the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Activated charcoal may reduce absorption of the drug if given within one hour after ingestion of a potentially toxic amount. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

Codeine.

An overdose of codeine is characterised, in the first phase, by nausea and vomiting. An acute depression of the respiratory centre can cause cyanosis, slower breathing, drowsiness, ataxia and, more rarely, pulmonary oedema. Respiratory pauses, miosis, convulsion, collapse and urine retention as well as signs of histamine release have been observed as well. In severe cases, this may include symptoms of circulatory and respiratory depression which may be life threatening and very rarely fatal.
Treatment should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Activated charcoal may reduce absorption of the drug if given within one hour after ingestion by an adult of more than 350 mg of codeine or a child more than 5 mg/kg of codeine. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Give naloxone if coma or respiratory depression is present. Observe for at least four hours after ingestion.

Presentation

Caplets (white, capsule shaped tablet, marked + surrounded by an oval): 15's, 30's (blister pack).

Storage

Store below 25 degrees Celsius. Keep out of reach of children.

Poison Schedule

S3.