Ibuprofen and Codeine 200mg/12.8mg film-coated Tablets

For full list of excipients, see section 6.1

Film Coated Tablet (Tablet)

White capsule-shaped tablet embossed with 'I +'

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as: rheumatic and muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea.

For oral administration and short-term use only.

Recommended dosage:

Adults and children over 12 years: One or two tablets every four to six hours.

Children under 12 years: Not recommended.

Elderly:

No special dosage modifications are required for elderly patients, unless renal or hepatic function is impaired, in which case dosage should be assessed individually.

Do not take more than 6 tablets in 24 hours.

Leave at least four hours between doses.

Do not take for more than 3 days continuously without medical review.

The minimum effective dose should be used for the shortest time necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 3 days.

Hypersensitivity to ibuprofen, codeine or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe hepatic failure, renal failure or heart failure (See section 4.4, special warnings and precautions for use).

Last trimester of pregnancy (See section 4.6 Pregnancy and lactation).

Respiratory depression, chronic constipation.

Use of codeine containing products is contraindicated in mothers who are breastfeeding unless prescribed by a doctor.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, Posology and method of administration and GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

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

Other NSAIDs:

The use of this medicine with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease -increased risk of aseptic meningitis (see section 4.8 Undesirable effects).

Renal:

Renal impairment as renal function may further deteriorate (See section 4.3 and Section 4.8)

Hepatic:

Hepatic dysfunction (See section 4.3 and Section 4.8)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. 1200mg daily) is associated with an increased risk of myocardial infarction.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (See section 4.8 Undesirable effects).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime 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, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, selective serotonin-reuptake inhibitors, anti-platelet agents such as aspirin or anticoagulants such as warfarin. In patients receiving anticoagulant therapy, prothrombin time should be monitored daily for the first few days of combined treatment (see section 4.5 Interactions).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for 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. This medicine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Codeine should be used with caution in those with hypotension and/or hypothyroidism. The tablets should be used with caution in patients with raised intracranial pressure or head injury. The effects of CNS depressants (including alcohol) may be potentiated by codeine.

Codeine is a narcotic analgesic. No more than the stated dose of this medicine should be taken. Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped. It is important to consult a doctor if a patient experiences the need to use this product all the time.

The label will state:

Front of pack

• Can cause addiction

• For three days use only

Back of pack

Read the enclosed leaflet before taking this product.

• List of indications as agreed in 4.1 of the SPC

• If you need to take this medicine continuously for more than 3 days you should see your doctor or pharmacist

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse

Do not take if you:

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Speak to a pharmacist or your doctor before taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, liver, heart, kidney or bowel problems

• are a smoker

• are pregnant

If symptoms persist or worsen, consult your doctor.

The leaflet (or combined label/leaflet) will state:

'Headlines' section (to be prominently displayed)

• This medicine can be used for…..(indications)

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

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take this medicine for headaches for more than 3 days it can make them worse

'What this medicine is for' section

• Succinct description of the indications from 4.1 of the SPC

'Before you take this medicine' section

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take a painkiller for headaches for more than 3 days it can make them worse

'How to take this medicine' section

• Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist

• This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms

'Possible side effects' section

• Some people may have side effects when taking this medicine. If you have any unwanted side effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday-Friday) or fill in a paper form available from your local pharmacy

'How do I know if I am addicted?' section

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

• You need to take the medicine for longer periods of time

• You need to take more than the recommended amount

• When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

Ibuprofen should not be used in combination with:

Aspirin:

Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (See section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDS including cyclooxygenase-2 selective inhibitors:

Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Codeine:

Interacts with monoamine oxidase inhibitors. Therefore caution should be exercised in patients taking monoamine oxidase inhibitors.

Ibuprofen should be used with caution in combination with:

Anticoagulants:

NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Antihypertensives and diuretics:

NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids:

Increased risk of gastrointestinal ulceration or bleeding (See section 4.4 Special warnings).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (see section 4.4)

Cardiac glycosides:

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium:

There is evidence for potential increases in plasma levels of lithium.

Methotrexate:

There is a potential for an increase in plasma methotrexate.

Ciclosporin:

Increased risk of nephrotoxicity.

Mifepristone:

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

Tacrolimus:

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

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.

Quinolone antibiotics:

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

Female fertility:

See section 4.4 regarding female fertility

Pregnancy:

Whilst no teratogenic effects have been demonstrated in animal experiments, the use of this medicine should, if possible, be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).

Lactation:

Ibuprofen

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

Codeine

Codeine is excreted in breast milk. In nursing mothers who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia, miosis and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. In severe cases, naloxone may be appropriate to reverse the effects. The lowest effective dose should be used, for the shortest possible time.

Nursing mothers should be informed about carefully monitoring the infant during treatment for any signs and/or symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breastfeeding, breathing difficulties, miosis and decreased tone, and seeking immediate medical care if such symptoms or signs are noticed. The nursing mother should be informed about monitoring for signs and symptoms of maternal opioid toxicity as well. Should such signs/symptoms be noted in mother or baby, the mother should immediately stop taking all codeine-containing products and seek medical advice.

Codeine-containing products must not be used while breastfeeding unless prescribed by a doctor.

Patients may become dizzy or sedated with this medicine. If affected, patients should not drive or operate machinery.

Hypersensitivity reactions have been reported and these may consist of:

a) Non-specific allergic reactions and anaphylaxis

b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea

c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

Ibuprofen:

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

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with 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.

Gastrointestinal:

The most commonly-observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (see section 4.4).

Nervous System:

Uncommon: Headache, blurred vision

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

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

Hepatic:

Very rare: liver disorders.

Haematological:

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.

Dermatological:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Immune System:

In patients with existing auto-immune 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 section 4.4).

Cardiovascular and Cerebrovascular :

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).

Codeine

Side effects to codeine include constipation, respiratory depression, cough suppression, nausea and drowsiness.

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 pain killer for headache can make them worse.

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 of overdose with ibuprofen include;

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.

Symptoms

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 serious 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.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

Symptoms of overdose with codeine include;

Nausea and vomiting are prominent features. Respiratory depression, excitability, convulsions, hypotension and loss of consciousness may occur with large codeine overdose.

The stomach should be emptied. If severe CNS depression has occurred, artificial respiration, oxygen and parenteral naloxone may be needed. Imbalance in electrolyte levels should be considered.

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Codeine is a narcotic analgesic acting on central opiate receptors, although its pharmacological effects are thought to be due largely to its biotransformation to morphine. The combination of a well tolerated peripheral analgesic with a centrally acting analgesic provides optimum pain relief with a lower potential for producing side-effects.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400 mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81 mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

The elimination half-life of both ibuprofen and codeine is approximately three hours, and both drugs are given three to four times daily. The combination of the two drugs is therefore appropriate from a pharmacokinetic viewpoint; the tablet exhibits normal release characteristics for both active substances.

There are no preclinical data of relevance to the prescriber which are additional to that already included.

Tablet Core:

Cellulose, Microcrystalline

Hypromellose

Sodium Starch Glycloate (Type A)

Maize Starch, Pregelatinised

Film Coat :

Hypromellose

Titanium dioxide (E171)

Talc

Not applicable

24 months.

This medicine does not require any special storage conditions.

White 250 micron PVC/60gsm PVdC/20 micron hard temper aluminium foil.

Pack sizes:

6, 8, 10, 12, 14, 16, 18, 20, 24 (max otc pack IE), 28, 30, 32 (max otc pack UK)

Not all pack sizes may be marketed.

No special requirements.

The Boots Company PLC

1 Thane Road west

Nottingham.

NG2 3AA

Trading as BCM

PL00014/0662

PA 4/66/1

03/11/2010 UK and 17/12/2010 IE

October 2011