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1. Advil 400mg Tablets
2. Advil 400mg Tablets

1.    NAME OF THE MEDICINAL PRODUCT

Advil 400 mg Tablet

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 400 mg ibuprofen.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

Brown, film coated capsule-shaped tablet printed on one side in black ink.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

For the relief of mild to moderate pain including rheumatic and muscular pain, backache, headache, toothache, dysmenorrhoea, feverishness and for the relief of symptoms of colds and influenza.

4.2    Posology and method of administration

For oral administration and short-term use only.

For all indications:

Adults, older people and children and adolescents between 12-18 years of age:

If in children or adolescents between 12 -18 years of age, this medicinal product is required for more than 3 days, or if symptoms worsen, a doctor should be consulted.

For adults aged 18 years or older, the lowest effective dose should be used for the shortest duration necessary to relieve symptoms and minimise undesirable effects (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.

One tablet up to three times per day as required. The respective dosing interval should be chosen in line with the observed symptoms and the maximum recommended daily dose. Doses should be given approximately every 6-8 hours, with a minimum interval of 4 hours between each dose. A total dose of 1200 mg of ibuprofen (3 tablets) should not be exceeded in any 24 hour period. The tablets should be taken with water.

Not to be used for children under 12 years of age.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the other ingredients.

Use in patients hypersensitive to aspirin or with bronchospasm, asthma, rhinitis, angioedema or urticaria associated with non-steroidal anti-inflammatory drugs (NSAIDs).

Ibuprofen should not be given to patients with active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation or other bleeding conditions related to previous NSAID therapy.

Cerebrovascular bleeding, other active bleeding or haematological disease.

Severe hepatic failure, severe renal failure or severe heart failure (NYHA Class IV). Last trimester of pregnancy (see section 4.6).

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 gastrointestinal and cardiovascular risks below).

Older people:

Older people 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 previous history of bronchial asthma or allergic disease and Advil 400 mg Tablets should not be used where other NSAIDs have produced reactions.

Other NSAIDs:

The use of Advil 400 mg Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Systemic Lupus Erythematosus (SLE) and mixed connective tissue disease:

Caution should be taken when ibuprofen is given to patients with SLE and autoimmune diseases - increased risk of aseptic meningitis has been reported (see section 4.8).

Renal, Cardiac and Hepatic:

Caution is required in patients with renal, cardiac or hepatic impairment since renal function may deteriorate (see sections 4.3 and 4.8). The dose should be as low as possible and renal function should be monitored.

There is a risk of renal impairment in dehydrated children or adolescents between 12 -18 years of age.

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 studies suggest that use of ibuprofen, particularly at high doses (2400mg/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 (e.g. < 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 and 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 upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (e.g. 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 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 (SSRIs) or anti-platelet agents such as aspirin (see section 4.5).

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

Dermatological:

Severe 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 400 mg Tablets should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

The pharmacological activity of ibuprofen may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting underlying conditions.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you:

•    have ever had a stomach ulcer, perforation or bleeding.

•    are allergic to ibuprofen (or anything else in this medicine), 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 asthma, diabetes, high cholesterol, high blood pressure, had a stroke, heart, liver, kidney or bowel problems.

•    are    a smoker.

•    are    pregnant.

If symptoms do not get better or get worse, or if you get new symptoms, talk to your doctor.

4.5 Interaction with other medicinal products and other forms of interaction

Ibuprofen should be avoided in combination with:

Aspirin:

Concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential of increased adverse effects.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin 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 aspirin cannot be excluded . No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDs:

Ibuprofen should not be used with other pain relievers such as NSAIDs.

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4). When taking anticoagulants it should be taken into account that long-term use of ibuprofen may increase the risk of bleeding.

Antihypertensives and diuretics: NSAIDs may diminish the effects of antihypertensives or thiazide diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: When taking corticosteroids and ibuprofen concomitantly there is an 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)

Cardiac glycosides: Ibuprofen may increase serum digitalis concentrations. Serum digitalis concentrations should therefore be monitored in patients with decreased renal function or congestive heart failure.

Lithium: Increases in serum lithium concentrations following administration of ibuprofen may be clinically significant.

Methotrexate: Concomitant administration of ibuprofen with moderate and high doses of methotrexate may lead to serious and fatal methotrexate toxicity. Patients with reduced renal function may be at additional risk of toxicity from the combination even when low doses of methotrexate ( 20 mg/week) are used.

Ciclosporin: Increased risk of nephrotoxicity.

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.

Phenytoin: Ibuprofen may increase pharmacologically active free phenytoin. Patients taking ibuprofen for long-term use should be monitored.

Antacids: Certain antacids may increase the gastrointestinal absorption of ibuprofen. This is considered to be of clinical relevance particularly during long-term use of ibuprofen.

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 trimester 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 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 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. Based upon the low level detected (0.0008% of maternal dose), it 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 doses and duration of therapy.

4.8    Undesirable effects

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

The adverse effects have been listed in order of decreasing 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), not known (cannot be estimated from the available data).

Investigations:	Very rare:	Decreased haematocrit and haemoglobin levels.
Cardiac Disorders:	Not known:	Oedema, hypertension, angina pectoris and cardiac failure, have been reported in association with NSAID treatment.
		Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400mg /day ) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Blood and Lymphatic System Disorders:	Very rare:	Haematopoietic disorders (anaemia, haemolytic anaemia, aplastic anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, influenza-like symptoms, severe exhaustion, unexplained bleeding and bruising.
Nervous System Disorders: Eye Disorders:	Uncommon: Very rare: Very rare:	Headache, dizziness, cerebrovascular accident Aseptic meningitis - single cases have been reported very rarely. 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:		The most commonly-observed adverse events are gastrointestinal in nature.
	Uncommon:	Abdominal pain, abdominal distension, nausea and dyspepsia.
	Rare:	Diarrhoea, flatulence, constipation and vomiting.

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

Pharmacotherapeutic group: Propionic acid derivatives ATC code: M01A E01

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 400 mg of ibuprofen are taken, pain relieving effects can last for up to 8 hours.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400mg were taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these data to the clinical situation, (for) the possibility that regular, long-term use of ibuprofen may reduce cardioprotective effect of low-dose aspirin cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

5.2 Pharmacokinetic properties

Ibuprofen is quickly absorbed from the gastrointestinal tract. Maximum plasma concentration is achieved after % - 1/ hours.

Ibuprofen protein binding is approximately 99%. After an oral dose ibuprofen is 75 - 85% excreted in the urine 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 in plasma is approximately 2 hours.

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

5.3. Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. No teratogenic effect has been demonstrated in animal experiments, however, use of ibuprofen during pregnancy should, if possible, be avoided.

Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical

use.

6.1 List of excipients

Maize starch Pregelatinised starch Croscarmellose sodium Colloidal silicon dioxide Stearic acid Sodium lauryl sulfate Hydroxypropyl methylcellulose Macrogol 6000 Titanium dioxide (E171)

Iron oxide (E172)

Black ink (shellac, iron oxide black E172, propylene glycol and ammonium hydroxide E527)

Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf-Life

3 years

6.4 Special Precautions for Storage

Do not store above 30°C.

6.5 Nature and contents of container

The tablets are packed into blister strips in a cardboard box or into a bottle.

Pack A:

Blister: Clear or white opaque PVC (250pm)/ PVdC (40g/sqm)

Foil: Aluminium foil (25pm)/hot-sealable lacquer containing copolymers of vinyl chloride and vinyl acetate.

Pack B:

Blister: Clear or white opaque PVC (250pm)/PVdC (40g/sqm)

Foil: Aluminium foil (9pm)/glassine paper (35gsm)/hot-sealable lacquer containing polymers of vinyl chloride and vinyl acetate.

Pack C:

Bottle: Round, 30mL or 85mL capacity, white HDPE with 28/400 or 33/400 screw finish.

Cap: Round, white PP, with 28/400 or 33/400 screw finish.

Cap liner: 0.035” pulpboard, wax adhered to aluminium foil, faced with polyester and coated with polyethylene.

Filler: Regenerated cellulose fibre (rayon).

A pack range consists of blister packs of 10, 12, 20, 24, 30, 36, 40, 48, 50, or 60 tablets, or bottle packs of 20 or 50 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

00165/0140

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/11/2009

10 DATE OF REVISION OF THE TEXT

20/11/2015