NUROFEN PLUS

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Nurofen Plus

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Active constituents: Ibuprofen Ph Eur Codeine phosphate Ph Eur 200.0 mg 12.8 mg

3

PHARMACEUTICAL FORM
Tablet

4
4.1

CLINICAL PARTICULARS
Therapeutic indications

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

4.2

Posology and method of administration For oral administration and short-term use only.

Recommended dosage: Adults: 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 and do not take more than 1200mg in any 24 hour period. 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.

4.3

Contraindications Hypersensitivity to ibuprofen or any of the constituents 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). Hypersensitivity to codeine, respiratory depression, chronic constipation. Severe heart failure.

4.4

Special warnings and precautions for use Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly are at 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 Nurofen Plus 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 (2400 mg 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. 1200 mg daily) is associated with an increased risk of myocardial infarction. Nurofen Plus tablets 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. 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, Crohns 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. 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, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (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 of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Nurofen PLUS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers. The label will include: Front of pack: Can cause addiction For three days use only List of indications as agreed in 4.1 of the SmPC

Back of pack:



If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse

Read the enclosed leaflet before taking this product. 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 this product 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 will include: Headlines section (to be prominently displayed at the start of the PIL) This medicine can only be used for .(indications) You should only take this product for a maximum of three days at a time. If you need to take it for longer than three 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 three 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 three days it can make them worse Section 2 : Before taking Do not take This medicine contains codeine which can cause addiction if you take it continuously for more than three 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 three days it can make them worse The leaflet will state in the Pregnancy and breast-feeding subsection of section 2 Before taking your medicine: Usually it is safe to take Nurofen Plus while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk



of developing side effects at any dose may have higher levels in their breast milk. If any of the following side effects develop in you or your baby stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing. Section 3: Dosage (In the dosage warning section): Do not take for more than 3 days. If you need to use this medicine for more than three 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 three 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. Section 4: Side effects 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? 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: o You need to take the medicine for longer periods of time o You need to take more than the recommended dose o When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again



4.5

Interaction with other medicinal products and other forms of interaction 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. 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 exacerabate 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 hematological 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.

4.6

Pregnancy and lactation Whilst no teratogenic effects have been demonstrated in animal experiments, the use of Nurofen Plus should, if possible, be avoided during the first 6 months of pregnancy. During the 3rd trimester, ibuprofen is contraindicated as there is 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). In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely. At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant. If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects. See section 4.4 regarding female fertility.

4.7

Effects on ability to drive and use machines Patient may become dizzy or sedated with NUROFEN PLUS tablets. affected, patients should not drive or operate machinery. If

4.8

Undesirable effects Hypersensitivity reactions have been reported and these may consist of: (a) Non-specific allergic reactions and anaphylaxis. (b) Respiratory tract reactivity, bronchospasm, dyspnoea. e.g. asthma, aggravated asthma,

(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme). 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 ulcerative colitis and Crohns disease (See section 4.4). Nervous System: Uncommon: Headache 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-Johnsons 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). 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 painkiller for headache can make them worse.

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 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.

5
5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swelling 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 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), 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.

5.2

Pharmacokinetic properties The elimination half-life of both ibuprofen and codeine is approximately three hours, and both drugs are given three to fours 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.

5.3

Preclinical safety data Not applicable.

6
6.1

PHARMACEUTICAL PARTICULARS
List of excipients Tablet core: Microcrystalline cellulose, Sodium starch glycollate, Starch pregelatinised, Hypromellose Film coating: Hypromellose Ph Eur Opaspray White M-1-17111B Talc Ph Eur

6.2

Incompatibilities None known.

6.3

Shelf life 36 months.

6.4

Special precautions for storage Store in a dry place below 25C.

6.5

Nature and contents of container Blister packs containing 6, 8, 12, 16, 18, 24 or 32 tablets.

6.6

Special precautions for disposal Not applicable.

7

MARKETING AUTHORISATION HOLDER
Reckitt Benckiser Healthcare (UK) Ltd Slough SL1 4AQ

8

MARKETING AUTHORISATION NUMBER(S)
PL 00063/0376

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16 May 1994 / 19 September 2008

10

DATE OF REVISION OF THE TEXT
14/01/2011