SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nurofen Extra Strength 400 mg Liquid Capsules Nurofen Express 400 mg Liquid Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule, soft contains Ibuprofen 400 mg

Excipients with known effect:

Sorbitol Ponceau 4R

Potassium hydroxide 50% solution (E525)

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsule, soft.

A clear red oval soft gelatin capsule printed with an identifying logo in white .

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults, elderly and Children over 12 years:

Nurofen Extra Strength 400 mg Liquid Capsules are indicated for symptomatic relief of non-serious arthritic conditions, rheumatic or muscular pain, backache, neuralgia , migraine, headaches, dental pain, dysmenorrhoea, feverishness, colds and influenza.

Posology and method of administration

For oral administration and short-term use only.

Adults, the elderly and children and adolescents between 12 and 18 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

If in children and adolescents this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.

Adults should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Children and Adolescents between 12 and 18 years: Take 1 capsule with water, up to three times a day as required.

Adults: Take 1 capsule with water, up to three times a day as required.

Leave at least 4 hours between doses.

Do not take more than 3 capsules in any 24 hour period.

4.3 Contraindications

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

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

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 heart failure, renal failure or hepatic failure (See Section 4.4)

Last trimester of pregnancy

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 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 history of, bronchial asthma or allergic disease.

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

SLE and mixed connective tissue disease:

Systemic lupus erythematosus as well as those with mixed connective tissue disease - increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8). There is a risk of renal impairment in dehydrated children and adolescents

Hepatic:

Hepatic dysfunction (see sections 4.3 and 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 cyclooxygenase/ 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).

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 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 antiplatelet agents such as aspirin (see section 4.5).

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. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

This medicine contains 27.9 mg potassium per capsule. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Contains Sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Also contains Ponceau 4R (E124) which may cause allergic reactions.

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, to any of the ingredients, or to aspirin or other painkillers

•    are taking other NSAID pain killers 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, heart, liver, kidney or bowel problems or are dehydrated

•    are a smoker

•    are pregnant

If symptoms persist or worsen, or if new symptoms occur, consult your doctor or pharmacist.

4.5 Interaction with other medicinal products and other forms of interaction

Ibuprofen (like other NSAIDs) should be avoided 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).

Ibuprofen should be used with caution in combination with:

•    Corticosteroids: As these may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4).

•    Antihypertensives (ACE inhibitors and Angiotensin II Antagonists) and diuretics: Since NSAIDs may diminish the effects 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 of NSAIDs.

•    Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4).

•    Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): These can increase the 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 increase in plasma levels of lithium.

•    Methotrexate. There is evidence for the potential increase in plasma levels of 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 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

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.

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.

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

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

renal dysfunction, 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.

Lactation/Breastfeeding:

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

See section 4.4 regarding female fertility.

4.7 Effects on ability to drive and use machines

None expected at recommended dose and duration of therapy.

4.8 Undesirable effects

Adverse events which have been associated with Ibuprofen are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <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.

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

The adverse events observed most often are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding is dependent on the dosage range and duration of 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).

System Organ Class	Frequency	Adverse Event
Blood and Lymphatic System Disorders	Very rare:	Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.
Immune System Disorders		Hypersensitivity reactions consisting of1:
	Uncommon	Urticaria and pruritus
	Very rare	Severe hypersensitivity reactions.
		Symptoms could be facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).
	Not Known	Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea.

Nervous System	Uncommon	Headache
Disorders	Very rare	Aseptic meningitis2
Cardiac Disorders	Not Known	Cardiac failure and oedema
Vascular Disorders	Not Known	Hypertension
Gastrointestinal	Uncommon	Abdominal pain, nausea, dyspepsia
Disorders	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
	Not Known	Exacerbation of colitis and Crohn's disease (section 4.4).
Hepatobiliary Disorders	Very rare	Liver disorders
Skin and Subcutaneous	Uncommon	Various skin rashes
Tissue Disorders	Very rare	Severe forms of skin reactions such as bullous reactions including Stevens-
		Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur.
Renal and Urinary Disorders	Very rare	Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.
	Not Known	Renal insufficiency
Investigations	Very rare	Decreased haemoglobin levels

Description of Selected Adverse Reactions

¹ Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or (c) assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

²The 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, mixed connective tissue disease).

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

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: M01A E01 Propionic acid derivative.

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.

Clinical evidence demonstrates that when 400mg of ibuprofen is taken the pain relieving effects can last for up to 8 hours.

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 relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic properties

Ibuprofen is well absorbed from the gastrointestinal tract. Ibuprofen is extensively bound to plasma proteins.

Nurofen Extra Strength 400 mg Liquid Capsules consist of ibuprofen 400 mg dissolved in a hydrophilic solvent inside a gelatin shell. On ingestion, the gelatin shell disintegrates in the gastric juice releasing the solubilised ibuprofen immediately for absorption. The median peak plasma concentration is achieved in approximately 30 minutes after administration when taken on an empty stomach.

The median peak plasma concentration for Nurofen tablets is achieved approximately 1-2 hours after administration. A direct comparison of the 400 mg ibuprofen capsule with 2x200 mg Nurofen tablets showed that the median peak plasma concentration was achieved more than twice as fast for the liquid capsule (32.5 min) compared to the tablets (90 min).When taken with food, peak plasma levels may be delayed.

Ibuprofen is metabolised in the liver to two major metabolites with primary excretion via the kidneys, either as such or as major conjugates, together with a negligible amount of unchanged ibuprofen. Excretion by the kidney is both rapid and complete.

Elimination half-life is approximately 2 hours.

No significant differences in pharmacokinetic profile are observed in the elderly.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical safety data

No relevant information, additional to that contained elsewhere in the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule fill

Macrogol 600

Potassium hydroxide 50% solution (E525)

Capsule shell

Gelatin

Sorbitol Liquid, Partially Dehydrated (420)

Purified Water Ponceau 4R (E124)

Lecithin (E322)

Triglycerides , medium chain

Capsule printing

Ethanol White ink *

The ink contains the following residual materials after application: Titanium Dioxide (E171), Polyvinyl Acetate Phthalate, Macrogol 400, ammonium hydroxide (E527).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Blisters formed from

Opaque Duplex PVC/PVdC 250pm/60gsm heat sealed to 20pm aluminium foil

or

opaque Tristar (Triplex) PVC/PE/PVdC 250pm/25pm/90gsm heat sealed to 20 pm aluminium foil

packed into cartons

Each carton may contain 10, 12, 16, 18, 20, 24, 28, 30, 32, 36, 48, 96 in blister strips

Not all packs will be marketed.

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 00063/0653

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/03/2011

10    DATE OF REVISION OF THE TEXT

19/03/2015