Nurofen Plus (which contains codeine) is indicated in patients older than 12 years of age 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 considered to be relieved by other analgesics such as paracetamol, ibuprofen or aspirin alone.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4).

Posology:

Recommended dosage:

Adults, the elderly and children over 12 years of age:

One or two tablets every four to six hours.

Children aged 12-18 years:

One or two tablets every four to six hours.

Children under 12 years:

Nurofen plus (which contains Codeine) should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

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.

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

For short term use only. Codeine should be used at the lowest effective dose for the shortest period of 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.

Method of administration

For oral administration

Hypersensitivity to Ibuprofen, Codeine or to any of the constituents listed in section 6.1.

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

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

History of 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).

In women during breastfeeding (see section 4.6)

Respiratory depression.

Chronic constipation

Concomitant treatment with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of stopping treatment (see section 4.5).

In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life threatening adverse reactions (see section 4.4)

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers

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 (see section 4.2).

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 due to 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). There is a risk of renal impairment in dehydrated children and adolescents.

Hepatic:

Hepatic dysfunction (See section 4.3 and Section 4.8).

Cardiovascular and cerebrovascular effects:

Cases of Kounis syndrome have been reported in patients treated with Nurofen Plus Tablets. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

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 effects:

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).

Gastrointestinal 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, ulceration or bleeding, such as oral corticosteroids, or anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as Acetylsalicylic Acid (aspirin) (see section 4.5 Interactions).

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

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with the use of ibuprofen (see section 4.8). Most of these reactions occured within the first month. If signs and suggestive of these reactions appear, ibuprofen should be withdrawn immediately, and an alternative treatment considered (as appropriate).

Sleeping disorder where your body stops and starts your breathing in a way that disrupts your sleep: Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

Increased sensitivity to pain: Hyperalgesia has been reported with the use of opioids, particularly following long-term use and/or at high doses. Hyperalgesia may resolve with opioid dose reduction, discontinuation, or switching to a different opioid

Masking of symptoms of underlying infections

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

Excipients

• This medicine contains less than 1 mmol sodium (23mg) per dose, that is to say essentially 'sodium-free'.

Do not take concurrently with any other Codeine containing compounds.

Care is advised in the administration of Codeine to patients with hypotension, hypothyroidism, adrenocortical insufficiency, shock, obstructive bowel disorders, acute abdominal conditions (e.g. peptic ulcer), recent astrointestinal surgery, gallstones, myasthenia gravis, a history of peptic ulcer or convulsions and also in patients with a history of drug abuse.

Elderly patients may metabolise or eliminate opioid analgesics more slowly than younger adults. Codeine should be used with caution in the elderly and debilitated patients as they may be more susceptible to the respiratory depressant effects.

Prolonged regular use of Codeine, 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.

If you are pregnant or are being prescribed medicines by your doctor, seek this advice before taking this product. Care is advised in the administration of this product in patients with severe renal or severe hepatic impairment (hepatic disease).

CYP2D6 metabolism

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.

Estimates indicate that up to 7% of the Caucasian population may have this deficiency. 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. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

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 also section 4.3). 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 not recommended 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.

The label will include:

Front of pack:

Back of pack:

Read the enclosed leaflet before taking this product.

Do not take if you

Speak to a pharmacist or your doctor before taking this product if you

If symptoms persist or worsen, consult your doctor.

The leaflet will include:

• Headlines section (to be prominently displayed at the start of the PIL)

• Section 2: Before taking – Do not take

• Section 3: Dosage

• Section 4: Side effects

The following drug-drug interactions are known to occur in association with the Ibuprofen active substance in the product:

Ibuprofen should be avoided in combination with:

Acetylsalicylic Acid (Aspirin): Unless low-dose acetylsalicylic acid (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 Acetylsalicylic Acid (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).

Serotonergic drugs: Serotonin syndrome has been reported during concomitant use of serotonergic drugs including triptans, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), and tricyclic antidepressants, with opioids at recommended dosages

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 (ACE inhibitors and Angiotensin II Antagonists) and diuretics: NSAIDs may diminish the effect of these drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the coadministration of an ACE inhibitor or Angiotens II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. 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 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.

The following drug-drug interactions are known to occur in association with the Codeine active substance in the product:

Pregnancy:

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.

From the 20th week of pregnancy onward, Nurofen Plus use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Nurofen Plus should not be given unless clearly necessary. If Nurofen Plus is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Nurofen Plus for several days from gestational week 20 onward. Nurofen Plus should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the last trimester, ibuprofen is contraindicated as there is there is a risk of premature constriction/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).

Breast Feeding:

Codeine should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

Fertility:

See section 4.4 regarding female fertility.

Patient may become dizzy or sedated with NUROFEN PLUS tablets. Rare side effects may include convulsions, hallucinations, blurred or double vision and orthostatic hypotension (see section 4.8). If affected, patients should not drive or operate machinery.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

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). 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 following list of adverse effects relates to those experienced with ibuprofen at OTC doses (maximum 1200mg Ibuprofen per day), for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Adverse events which have been associated with Ibuprofen and Codeine are given below, tabulated by System Organ Class (SOC) and frequency. Frequencies are defined as: 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

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).

Description of Selected Adverse Reactions

¹ Examples include anaemia, leucopenia, thrombocytopenia, pancytopenia and agranulocytosis. First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

² Single cases have been reported very rarely. The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). 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).

³ 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).

⁴ The most commonly-observed adverse events are gastrointestinal in nature.

⁵ Sometimes fatal, particularly in the elderly.

⁶ See section 4.4.

⁷ Especially in long-term use, associated with increased serum urea and oedema. Also includes papillary necrosis.

⁸ Increased frequency, decrease in amount.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic Group: Ibuprofen, combinations; ATC Code: M01 AE51

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 centrally acting weak narcotic analgesic. Codeine exerts its effects through μ opioid receptors, and its analgesic effect is due to its conversion 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. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

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.

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.

Not applicable.

Tablet core:

Microcrystalline cellulose, Sodium starch glycollate, Starch pregelatinised, Hypromellose

Film coating:

Hypromellose Ph Eur

Opaspray White M-1-17111B

Talc Ph Eur

None known.

36 months.

Store in a dry place below 25° C.

Blister packs containing 6, 8, 12, 16, 18, 24 or 32 tablets.

Not applicable.