SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Advil 400 mg Effervescent Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each effervescent tablet contains 400 mg ibuprofen.

Excipients:

Each effervescent tablet contains 4.3 mmol (170 mg) potassium, as potassium carbonate.

Each effervescent tablet contains 17.7 mmol (407 mg) sodium, as sodium hydrogen carbonate,

monosodium citrate, sodium carbonate and saccharin sodium.

Each effervescent tablet contains up to 0.4 mg sucrose, present in saccharose palmitate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Effervescent tablet.

Round, white tablet, flat-faced on both sides.

4    CLINICAL PARTICULARS

This medicinal product is suitable for adults and children over 30 kg (around 12 years old) for the relief of mild to moderate pain such as headache, previously diagnosed migrane (with or without aura), muscular pain, period pain/dysmenorrhoea, dental pain, feverishness and pain associated with a common cold.

4.2 Posology and method of administration

For oral use.

For short-term use only.

The minimum effective dose should be used for the shortest time necessary to relieve symptoms. If the medicinal product is required for more than 5 days for pain or 3 days for fever or if the symptoms worsen, the patient should consult a doctor.

The effervescent tablets should be dissolved in a glass of water and the solution drunk immediately after dissolution. Do not swallow effervescent tablets whole. If people experience mild indigestion it is recommended to take this medicine with food or milk to avoid gastrointestinal problems.

Suitable for adults, the elderly and adolescents over 30 kg (around 12 years old).

Adults, the elderly and adolescents over 30 kg in weight (around 12 years old): 400 mg (one effervescent tablet).

Adults, the elderly and adolescents over 30 kg (around 12 years old): 400 mg (one

tablet) to be repeated, if necessary, every 4-6 hours. Do not take more than

1200 mg ibuprofen (three

effervescent tablets) in any 24 hour period.

The elderly and patients with renal and hepatic impairment should always start treatment with the lowest effective dose.

Hypersensitivity to ibuprofen or any of the excipients.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis or urticaria) in

response to acetylsalicylic acid or other NSAIDs.

Active or previous peptic ulcer.

Active or history of upper gastrointestinal bleeding or perforation (two or more different episodes of

ulceration or bleeding), including that associated with previous NSAID therapy.

Bleeding diathesis or coagulation disorders.

Patients with severe hepatic failure, severe renal failure or severe heart failure (see section 4.4).

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

Use in third trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Caution is required in patients with certain conditions:

-    systemic lupus erythematosus as well as those with mixed connective tissue disease, due to

increased risk of aseptic meningitis (see section 4.8).

-    gastrointestinal disorders and chronic inflammatory intestinal disease as these conditions may

be exacerbated (ulcerative colitis, Crohn’s disease) (see section 4.8).

-    oedema, hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid

retention occur (see section 4.5).

-    renal impairment as renal function may deteriorate (see section 4.3 and 4.8).

- hepatic dysfunction (see section 4.3 and 4.8).

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 minimum effective dose for the shortest possible duration (see gastro-intestinal (GI) and cardiovascular risks below).

The elderly are at increased risk of the serious consequences of adverse reactions.

Gastrointestinal 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.

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

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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, or antiplatelet agents such as acetylsalicylic acid (see section 4.5). Caution is also advised in patients taking selective serotonin reuptake inhibitors (SSRIs).

The use of ibuprofen in patients who usually consume three or more units of alcohol per day may produce gastrointestinal bleeding.

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.

Dermatological effects

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 for 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. Advil Effervescent Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The use of NSAIDs may mask the sysmptoms of infection.

This medicine contains 4.3 mmol (170 mg) potassium per effervescent tablet. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

This medicine also contains 17.7 mmol (407 mg) sodium per effervescent tablet. To be taken into consideration by patients on a controlled sodium diet.

The medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Ibuprofen should not be used in combination with:

-    Acetylsalicylic acid: (above 75 mg daily): as this may increase the risk of adverse reactions (see section 4.3).

-    Other NSAIDs: as these may increase the risk of adverse reactions (see section 4.3).

Ibuprofen should be used with caution in combination with:

-    Acetylsalicylic acid, when used as an anti-aggregant because this may increase the risk of gastrointestinal bleeding and decrease the benefit of taking acetylsalicylic acid.

-    SSRIs (selective serotonin-reuptake inhibitors): may increase the risk of gastrointestinal bleeding.

-    Corticosteroids: may increase the risk of adverse reactions, especially of the gastrointestinal tract (see section 4.4).

-    Antihypertensives and diuretics: NSAIDs may diminish the effects of these medicinal products.

In particular, concomitant use of potassium-sparing diuretics may increase the risk of

hyperkalaemia.

-    Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin and

ticlopidin (see section 4.4).

-    Lithium: there is evidence for potential increase in plasma levels of lithium.

-    Methotrexate: there is the potential for increased plasma levels of methotrexate.

-    Cyclosporin: inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of cyclosporin and the risk of cyclosporin-induced nephrotoxicity.

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

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).

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 embryo-foetal 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 trimesters of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first and second trimesters 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 oligo-hydroamniosis;

the mother and the neonate, at the end of 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, ibuprofen is contraindicated during the third trimester of pregnancy.

Lactation:

In limited studies Ibuprofen appears in breast milk in very low concentrations. Fertility:

There is some evidence that medicinal products which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness, drowsiness, vertigo or visual disturbances while they are taking ibuprofen, should avoid driving or using machinery. Single administration or short term use of ibuprofen does not usually warrant the adoption of any special precautions.

4.8 Undesirable effects

Hypersensitivity reactions have been reported and these may consist of:

a)    Anaphylaxis and non-specific allergic reactions,

b)    Respiratory tract reactivity comprising bronchospasm, asthma, aggravated asthma, or dyspnoea,

c)    Various skin reactions, e.g. rarely, exfoliative and bullous dermatoses (including toxic epidermal necrolysis and erythema multiforme), angioedema, pruritus and urticaria.

The following list of adverse reactions relates to those experienced with ibuprofen at OTC doses, from short-term use. In chronic conditions, under long-term treatment, additional adverse reactions may occur.

Adverse reactions have been ranked under headings of frequency using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Investigations	Very rare:	Decreased haematocrit and haemoglobin levels
Cardiac disorders	Very rare:	Cardiac failure
Blood and lymphatic Disorders	Very rare:	Haematopoietic disorders: pancytopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, thrombocytopenia, anaemia. First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding.
Nervous system Disorders	Uncommon:	Dizziness and headache
Eye disorders	Very rare:	Visual disturbance
Ear and labyrinth Disorders	Very rare:	Tinnitus and vertigo
Respiratory, thoracic and mediastinal disorders	Very rare:	Asthma, bronchospasm, dyspnoea and wheezing
Gastrointestinal Disorders	Uncommon:	Abdominal pain, dyspepsia, nausea, abdominal distention, and gastritis
	Rare:	Diarrhoea, flatulence, constipation and vomiting
	Very rare:	Peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4). Mouth ulceration
Renal and urinary	Very rare:	Renal failure, interstitial nephritis, renal

insufficiency, nephritic syndrome, renal

Disorders

Skin and    Uncommon:

subcutaneous tissue

disorders

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

Pharmacotherapeutic group: Propionic acid derivatives ATC code: M01 AE01

Ibuprofen is a phenylpropionic 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.

In clinical trials, plasma levels of ibuprofen which are achieved with ibuprofen effervescent tablets are associated with a rapid onset of analgesic effect, with pain relief first observed within approximately 30-40 minutes of dosing. In addition, when a dose of 400 mg is taken, the analgesic effect of ibuprofen is maintained for up to 8 hours. In the majority of these clinical trials, ibuprofen resulted in faster onset of clinically significant pain relief, significantly greater overall pain relief and significantly longer duration of action than paracetamol. Ibuprofen 400 mg has been shown in clinical trials to be effective in migraine

attacks in relieving headache and the associated symptoms of photophobia, phonophobia and nausea.

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

After oral administration, solubilised ibuprofen is quickly absorbed when the effervescent tablets are administered under fasting conditions. Cmax is achieved within 0.36 hours (approximately 22 minutes) compared to 45-90 minutes with conventional film-coated tablets.

When taken with food, peak levels are observed after 1-2 hours with conventional film-coated tablets.

Ibuprofen protein binding is approximately 99%. After an oral dose, ibuprofen is 75-85% excreted via kidneys during the first 24 hours (mainly in the form of two metabolites), the remainder being eliminated in the faeces following excretion in bile. Excretion is complete within 24 hours.

The half-life of ibuprofen is about 2 hours.

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

5.3 Preclinical safety data

The subchronic and chronic toxicity of ibuprofen in animal experiments consisted mainly of lesions and ulcerations in the gastro-intestinal tract.

In-vitro and in-vivo investigations have produced no clinically relevant evidence of ibuprofen having mutagenic effects. In studies in rats and mice, no evidence of carcinogenic effects of ibuprofen was found.

Ibuprofen led to an inhibition of ovulation in rabbits and impaired implantation in various animal species (rabbit, rat, mouse). Experimental studies in rats and rabbits have shown that ibuprofen crosses the placenta. Following administration of maternotoxic doses, an increased rate of malformations (ventricular septal defects) occurred in the progeny of rats.

In animal studies it has been observed that the use of NSAIDs, known to inhibit prostaglandin synthesis, may increase the incidence of dystocia and delayed parturition.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Potassium carbonate (E501)

Sodium carbonate, anhydrous (E500) Citric acid, anhydrous (E330) Monosodium citrate (E331)

Sodium hydrogen carbonate (E500) Hypromellose (E464)

Saccharin sodium (E954)

Saccharose palmitate (contains sucrose) Menthol flavour Grapefruit flavour Magnesium stearate (E470b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

Special precautions for storage

Do not store above 30°C.

Store in the original package to protect from moisture.

6.5    Nature and contents of container

Foil strip, paper/PE/aluminium, in a cardboard outer.

Pack sizes: 2, 4, 8, 10, 12, 16, 20, 32 and 40 effervescent tablets Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Pfizer Consumer Healthcare Ltd

Ramsgate Road

Sandwich

Kent

CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00165/0368

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28/04/2009

DATE OF REVISION OF THE TEXT

16/06/2010