Reckitt Benckiser Ireland Limited

Nurofen 200mg Liquid Capsules

Each liquid capsule contains 200mg ibuprofen.

Excipients: Each liquid capsule contains 69.8mg liquid sorbitol and 0.6mg ponceau 4R (E124)

For a full list of excipients, see section 6.1.

Liquid capsule

An oval shaped clear capsule with a translucent red gelatin shell, containing a clear liquid, printed with 'NUROFEN' in white.

As an anti-inflammatory, analgesic and antipyretic for short term management of mild to moderate pain, fever and inflammation such as is associated with headache, dental pain, period pain, muscular strain, neuralgia, rheumatic pain and migraine and for the management of the symptoms of head colds and influenza.

For oral administration and short term use only. Do not chew.

Adults and children over 12 years: Initial dose is 400mg taken with water and subsequently if necessary, 200 to 400mg every four hours with a maximum of 1200mg in any 24 hour period.

Not for use by children under 12 years of age.

Elderly: NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events. The lowest dose compatible with adequate safe clinical control should be employed (See Section 4.4).

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or

intolerance occurs.

Known hypersensitivity to the active substance, ibuprofen, or to any of the constituents, aspirin, or other NSAIDs.

History of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding or other gastrointestinal disorders).

Patients with a history of bronchospasm, asthma, rhinitis, or urticaria associated with aspirin or other anti-inflammatory drugs.

Use in children under 12 years of age.

Patients with severe hepatic failure, severe renal failure or severe heart failure.

During the last trimester of pregnancy (see section 4.6)

The use of this product with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

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

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

Caution is required in patients with renal, cardiac and hepatic impairment since renal function may deteriorate (see section 4.3).

The dose should be as low as possible and renal function should be monitored.

As each Nurofen 200mg Liquid Capsule contains 50.5 mg of sorbitol (a source of 12.6 mg of fructose per capsule) patients with rare hereditary problems of fructose intolerance should not take this medicine.

If symptoms persist for more than 3 days, patients should be advised to consult their doctor.

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Prolonged use of NSAIDs in the elderly is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without any warning symptoms or a previous history of serious GI events.

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

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5).

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

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's Disease) as their condition may be exacerbated (see section 4.8 – undesirable effects).

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

Cardiovascular and cerebrovascular effects

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.

As NSAIDs can interfere with platelet function, they should be used with caution in patients with idiopathic thrombocytopenic purpura (ITP), intracranial haemorrhage and bleeding diathesis.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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

Caution is advised in patients with systemic lupus erythematosus as well as those with connective tissue disease (see section 4.8)

There is some 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.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of 'Medication Overuse Headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Care should be taken in patients treated with any of the following drugs as interactions have been reported:

Anti-coagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4).

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

Anti-hypertensives: reduced anti-hypertensive effect.

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive 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 ibuprofen 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.

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

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Zidovudine: there is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Lithium: decreased elimination of lithium.

Methotrexate: decreased elimination of methotrexate.

Cyclosporin: increased risk of nephrotoxicity with NSAIDs.

Other NSAIDs: avoid concomitant use of two or more NSAIDs.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Probenecid: reduction in metabolism and elimination of NSAID and metabolites.

Oral hypoglycaemic agents: inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelets aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding the 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 use (see section 5.1)

There is insufficient experience about the safety of use of ibuprofen in humans during pregnancy. As the influence of prostaglandin synthesis inhibition is unclear, it is recommended not to use ibuprofen during the first six months of pregnancy.

In the last trimester of pregnancy use of ibuprofen is contraindicated. Due to the mechanism of action, inhibition of uterine contractions, premature closure of ductus arteriosus and pulmonary hypertension of the neonate, an increased bleeding tendency in mother and child and increased formation of oedema in the mother could occur.

Ibuprofen and its metabolites can pass in very small concentrations (0.0008% of the maternal dose) into the breast milk. No harmful effects to infants are known, so it is not necessary to interrupt breast-feeding for short-term treatment with the recommended dose for mild to moderate pain and fever.

See Section 4.4 on Special Warnings and Precautions for Use regarding female fertility.

No or negligible influence.

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed.

The list of the following 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.

The frequencies are defined as follows

• Very common (1/10)

• Common (1/100 to <1/10)

• Uncommon (1/1000 to <1/100)

• Rare (1/10000 to <1/1000)

• Very Rare (<1/10000)

• Not known (cannot be estimated from the available data)

Clinical trial and epidemiological data suggest that the 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).

a) Symptoms of Overdosing

The symptoms of overdose can include nausea, vomiting, abdominal pain, headache, dizziness, drowsiness, nystagmus, blurred vision, tinnitus and, rarely, hypotension, metabolic acidosis, renal failure and loss of consciousness.A dose in excess of 200mg/kg carries a risk of causing toxicity.

b) Therapeutic Measure in Overdosing

No specific antidote is available.

Patients should be treated symptomatically as required. Use supportive care where appropriate. Within one hour of ingestion activated charcoal or if the dose is greater than 400 mg/kg in adults only, gastric lavage followed by activated charcoal can be used.

ATC Code: M01AE01

Ibuprofen is a propionic acid derivative, having analgesic, anti-inflammatory and antipyretic activity. The drug's therapeutic effects as a non-steroidal anti-inflammatory are thought to result from inhibitory activity on prostaglandin synthetase. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelets 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 (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 ibuprofen from Nurofen Liquid Capsules is absorbed to the same extent as ibuprofen from Nurofen tablets, the AUC_0-α being equivalent. Ibuprofen is rapidly absorbed from Nurofen Liquid Capsules with maximum plasma concentration achieved in 30 minutes. In comparison, the maximum plasma concentration of Nurofen tablets is achieved in 90 minutes. When taken with food, plasma peak levels may be delayed.

Ibuprofen is extensively bound to plasma proteins. Ibuprofen diffuses into the synovial fluid.

Ibuprofen is metabolised in the liver to two major inactive metabolites and these together with unchanged ibuprofen are excreted by the kidney either as such or as conjugates. 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.

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

Capsule contents

Macrogol 600,

Potassium hydroxide 50% solution (for pH adjustment)

Capsule shell

Gelatin

Sorbitol liquid, partially dehydrated

Purified water

Ponceau 4R (E124),

Lecithin,

Fractionated coconut oil

Printing ink

Opacode NSP-78-18022 (contains the following residual materials after application: titanium dioxide (E171), propylene glycol, polyvinyl acetate phthalate, polyethylene glycol 400)

Ribbon print solvent (ethanol and purified water).

Not applicable.

2 years.

Do not store above 25^oC. Store in the original package.

Blisters from

• Clear polyvinyl chloride (PVC)/ polyvinylidene chloride (PVdC) 250μm/60gsm (Duplex), or

• Opaque PVC/PVdC 250μm/60gsm (Duplex), or

• Clear PVC/polyethylene (PE)/PVdC 250 μm/25μm/90gsm (Tristar*), or

• Opaque PVC/PE/PVdC 250μm/25μm/90gsm (Tristar*)

heat sealed to 20μm aluminium foil and packed into cartons. Each blister tray contains 2, 4, 6, 8, 10, 12, 14, 16 20, 24, 30, 32, 36, 40 or 48 capsules. The blister trays are packed in a cardboard carton.

Not all packs are marketed.

(*Tristar is also known as Triplex. All types are sealed with 20μm hard tempered aluminium lidding foil)

No special requirements.

Reckitt Benckiser Ireland Ltd.,

7 Riverwalk,

Citywest Business Campus,

Dublin 24.

PA 979/32/12

Date of first authorisation: 24^th July 2009.