4.1. Therapeutic indications

For the relief of symptoms of cold and 'flu with associated congestion, including aches and pains, headache, fever, sore throat, blocked nose and sinuses.

4.2. Posology and method of administration

Posology

For short-term use only.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4). The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Adults, the elderly and children over 12 years:

Two tablets up to 3 times a day. Leave at least four hours between doses and do not take more than 6 tablets in any 24hour period.

Not to be given to children under 12 years.

Method of administration

For oral administration

4.3. Contraindications

Hypersensitivity to ibuprofen, phenylephrine or any of the excipients listed in section 6.1.

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

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

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

Hypertension and severe coronary heart disease or cardiovascular disorder (see section 4.4).

Severe heart failure (NYHA Class IV), renal failure or hepatic failure (see Section 4.4).

Last trimester of pregnancy (see section 4.6).

Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see Section 4.5).

Hyperthyroidism.

Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors (MAOIs).

Avoid in patients with prostatic enlargement.

Phaeochromocytoma: Phenylephrine should not be used in patients with phaeochromocytoma.

4.4. Special warnings and precautions for use

Ibuprofen

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

The elderly are at increased risk of consequence 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 prvious history of bronchial asthma or allergic disease.

Other NSAIDs: The use of this product with concomitant NSAIDs, including cyclo-oxygenase-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).

Renal: Renal impairment as renal function may further deteriorate, especially in dehydrated children and adolescents (see Sections 4.3 and 4.8).

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

Hepatic: Hepatic dysfunction (see Sections 4.3 and 4.8).

Cardiovascular and cerebrovascular effects: Cases of Kounis syndrome have been reported in patients treated with Nurofen Cold & Flu Relief 200mg/5mg 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 studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) 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 (≤1200 mg/day) is associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.

Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.

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 on 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).

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.

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 the 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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelets agents such as aspirin (see Section 4.5).

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 generalized 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 occurred within the first month.

If signs and symptoms suggestive of these reactions appear ibuprofen should be withdrawn immediately and an alternative treatment considered (as appropriate).

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.

The label will include:

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 75 mg.

• Are in the last 3 months of pregnancy

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

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

• Are a smoker.

• Are pregnant.

If symptoms persist or worsen, consult your doctor.

Phenylephrine

Phenylephrine should be used with care in patients with cardiovascular disease, diabetes mellitus, closed angle glaucoma, Raynaud's Phenomenon and hypertension.

The product contains an azo colouring agent Sunset Yellow E 110 which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per 2 tablets, that is to say essentially `sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

The product is contraindicated in combination with:

• Monoamine Oxidase Inhibitors (MAOIs): Hypertensive interactions occur between sympathomimetic amines such as phenylephrine hydrochloride and monoamine oxidase inhibitors (see section 4.3).

The product should be avoided in combination with:

• Aspirin (acetylsalicylic acid): Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects, unless low-dose aspirin (not above 75 mg daily) has been advised by a doctor (see Section 4.4).

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded.No clinically relevant effect is considered to be likely for the occasional ibuprofen use (see section 5.1).

• Other NSAIDs including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse reactions (see Section 4.4).

The product should be used with caution in combination with:

• Anti-coagulants: NSAIDs may enhance the effects of anticoagulants 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 co-administration of an ACE inhibitor or Angiotensin 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. Phenylephrine may reduce the efficacy of beta-blockers and antihypertensives. The risk of hypertension and other cardiovascular side effects may be increased (see section 4.3).

• Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4).

• Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see Section 4.4).

• Digoxin and Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. Concomitant use of phenylephrine may increase the risk of irregular heartbeat or heart attack.

• Tricyclic antidepressants (e.g. amitriptyline): may increase the risk of cardiovascular side effects with phenylephrine (see section 4.3).

• Sympathomimetic amines: concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.

• Lithium: There is evidence for potential increase in plasma levels of lithium.

• Methotrexate: There is 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.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryofoetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

From the 20th week of pregnancy onward, Nurofen 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 should not be given unless clearly necessary. If Nurofen 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 for several days from gestational week 20 onward. Nurofen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

renal dysfunction (see above); which may progress to renal failure with oligohydroamniosis;

the mother and the neonate, at the end of the pregnancy, to:

possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;

inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, Nurofen is contraindicated during the third trimester of pregnancy.

Breast-feeding:

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

Fertility

See section 4.4 regarding female fertility.

4.7. Effects on ability to drive and use machines

The product has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

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

Adverse events which have been associated with ibuprofen and phenylephrine hydrochloride are given below, tabulated by system organ class 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); Not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

System Organ Class

Frequency

Adverse Events

Blood and Lymphatic System Disorders

Very rare

Haematopoietic disorders1

Immune System Disorders

Uncommon

Hypersensitivity with urticaria and pruritus2

Very rare

Severe hypersensitivity reactions, including facial, tongue and throat swelling, dyspnoea, tachycardia, and hypotension (anaphylaxis, angioedema or severe shock) 2

Nervous System Disorders

Uncommon

Headache

Very rare

Aseptic meningitis3

Cardiac Disorders

Not known

Cardiac failure, oedema4, palpitations

Not known

Kounis syndrome

Vascular Disorders

Not known

Hypertension4

Respiratory, Thoracic and Mediastinal Disorders

Not known

Respiratory tract reactivity comprising asthma, bronchospasm or dyspnoea2

Gastrointestinal Disorders

Uncommon

Abdominal pain, nausea and dyspepsia5

Rare

Diarrhoea, flatulence, constipation and vomiting

Very rare

Peptic ulcer, gastrointestinal perforation or gastrointestinal haemorrhage, melaena, haematemesis6. Mouth ulceration, gastritis

Not known

Exacerbation of colitis and Crohn's disease7

Hepatobiliary Disorders

Very rare

Liver disorder

Skin and Subcutaneous Tissue Disorders

Uncommon

Skin rash2

Very rare

Severe cutaneous adverse reactions (SCARs) (including Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Acute generalised exanthematous pustulosis (AGEP)

Photosensitivity reactions

Metabolism and Nutrition Disorders

Not known

Decreased Appetite

Not known

Hypokalaemia* (The reference numbers for the description of the selected Adverse reaction should be updated throughout the table)

Renal and Urinary Disorders

Very rare

Acute renal failure8

Not known

Urinary retention

Not known

Ureteric colic, dysuria

Not known

Renal tubular acidosis*

Investigations

Very rare

Haemoglobin decreased

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 Hypersensitivity reactions have been reported following treatment with ibuprofen and these may consist of: (a) Non-specific allergic reaction and anaphylaxis. (b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm or dyspnoea. (c) Various skin reactions, e.g. pruritus, urticaria, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

3 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). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with Ibuprofen in patients with existing auto-immune disorders (such as systemic lupus erythematosus and mixed connective tissue disease).

4 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) (see Section 4.4).

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

6 Sometimes fatal, particularly in the elderly.

7 See section 4.4.

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

*Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses.

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.

4.9. Overdose

Ibuprofen

In children, ingestion of more than 400mg/kg may cause symptoms. In adults, the dose response rate effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

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 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.

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.

Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

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.

Phenylephrine

Features of severe overdose of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression.

Treatment includes symptomatic and supportive measures. Hypertensive effects may be treated with an intravenous alpha-receptor blocking agent.

Phenylephrine overdose is likely to result in: nervousness, headache, dizziness, insomnia, increased blood pressure, nausea, vomiting, mydriasis, acute angle closure glaucoma (most likely to occur in those with closed angle glaucoma), tachycardia, palpitations, allergic reactions (e.g. rash, urticaria, allergic dermatitis), dysuria, urinary retention (most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy).

Additional symptoms may include, hypertension, and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures and arrhythmias may occur. Treatment should be as clinically appropriate. Severe hypertension may need to be treated with alpha blocking medicinal products such as phentolamine.