SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Extra Strength Ibuprofen Caplets 400 mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Ibuprofen 400 mg

3    PHARMACEUTICAL FORM

Tablets

White, sugar coated, capsule shaped tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Rheumatic or muscular pain, pain of non-serious arthritic conditions, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, symptoms of cold and influenza

4.2    Posology and method of administration

For oral administration

To be taken preferably with or after food.

For short-term use only.

The minimum effective dose should be used for the shortest time necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than ten days.

400 mg, up to three times a day as required.

Leave at least four hours between doses and do not take more than 1200 mg in any 24 hour period.

Do not give to children under 12 years of age.

4.3.    Contraindications

Ibuprofen should not be administered to patients with bleeding disorders.

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

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

Severe hepatic, renal and cardiac failure (See section 4.4 - Special warnings and precautions for use).

During the last trimester of pregnancy (See section 4.6 - Pregnancy and lactation).

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 NSAID’s therapy.

High doses of non-steroidal anti-inflammatory drugs are contraindicated with concomitant mifamurtide (See section 4.5 - Interactions with other medicinal products and other forms of interaction).

4.4.    Special warnings and precautions for use

In all patients:

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).

Other NSAIDs: The use of this ibuprofen product with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided (See section 4.5 Interactions).

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 Posology and administration).

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma or allergic disorders, since NSAIDs have been reported to precipitate bronchospasm in such patients.

Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. The dose should be kept as low as possible and renal function should be monitored in these patients. Hepatic impairment is also associated with an increased risk of gastro-intestinal bleeding. (See also Section 4.3 - Contraindications).

Caution in patients with a history of renal or hepatic impairment, as fluid retention and oedema have been reported in association with NSAID therapy. Sodium and water retention may occur and renal function may deteriorate.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are-required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Although 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), non-selective NSAIDs are also associated with a small increased risk of thrombotic events even when used short-term in those with no cardiovascular risk factors. Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. < 1200mg daily) is associated with an increased risk of myocardial infarction.

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).

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 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), in the elderly, and in patients who smoke. 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 corticosteroids, or anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or anti-platelet agents such as aspirin (See section 4.5 Interactions).

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

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 - Undesirable effects) and because of the potential for gastrointestinal bleeding.

Systemic as well as local effects of NSAIDs contribute to gastrointestinal damage; taking oral formulations with milk or food, or using enteric-coated formulations, or changing the route of administration may only partially reduce symptoms such as dyspepsia.

Skin and subcutaneous tissue disorders:

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

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (See section 4.8 - Undesirable effects).

Infections:

NSAIDs should be used with caution in patients with infections, as symptoms such as fever, pain and inflammation may be masked.

Varicella (chickenpox) can be at the origin of serious cutaneous and soft tissue infectious complications. To date, the contributing role of NSAIDs in the worsening of varicella infections cannot be ruled out. Ibuprofen should be

used with caution in patients, particularly children, with varicella infection, particularly if there is a possibility of secondary infection.

Female fertility:

The use of ibuprofen may impair female fertility and is not recommended in women attempting to conceive. The reduction in female fertility is reversible on stopping

treatment.In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of ibuprofen should be considered.

Patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you

•    have or have ever had 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 75mg

•    are in the last three months of pregnancy

Speak to a pharmacist or your doctor before taking this product if you

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

•    are pregnant or trying to get pregnant

•    are elderly

•    are a smoker.

If symptoms persist consult your doctor.

Do not exceed the stated dose. Keep out of the reach and sight of children.

4.5 Interactions with other medicinal products and other forms of interaction

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

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs, including aspirin (unless low-dose aspirin, not above 75mg daily, has been advised by a doctor) as this may increase the risk of gastrointestinal side effects and toxicity including ulceration or haemorrhage (See section 4.4 Special Warnings and Precautions).

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).

Alcohol: Increased risk of gastro-intestinal bleeding or ulceration in susceptible patients.

Antibacterials: Increased risk of nephrotoxicity with concomitant administration of ibuprofen and aminoglycosides. 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.

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin and heparin (See section 4.4 - Special warnings and precautions for use).

Antidepressants: Selective serotonin re-uptake inhibitors (SSRIs) may increase the risk of gastro-intestinal bleeding and ulceration.

Antidiabetics: May enhance the hypoglycaemic effects of sulphonylureas.

Antiepileptics: May enhance the effects of phenytoin by inhibiting its metabolism.

Antihypertensives: Reduced antihypertensive effect of antihypertensives, including ACE inhibitors, angiotensin-II antagonists, beta-blockers and vasodilators; increased monitoring of the effectiveness of antihypertensive therapy may be necessary. Increased risk of nephrotoxicity, renal impairment and hyperkalaemia with ACE inhibitors and of renal impairment and hyperkalaemia with angiotensin-II antagonists.

Antiplatelet drugs: Increased risk of bleeding with clopidogrel and ticlopidine.

Antivirals: Increased risk of haematological toxicity with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Ritonavir may increase plasma concentrations of ibuprofen.

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

Ciclosporin: Increased risk of nephrotoxicity.

Corticosteroids: Increased risk of gastro-intestinal ulceration and gastro-intestinal bleeding. (See section 4.4 - Special warnings and precautions for use)

Diuretics: Reduced diuretic and antihypertensive effects. Possibility of hyperkalaemia with potassium-sparing diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

Mifamurtide: High doses of non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated with concomitant mifamurtide (see section 4.3 - Contraindications), as it has been demonstrated in vitro that high-dose NSAIDs (cyclooxygenase inhibitors) can block the macrophage activating effect of liposomal mifamurtide.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Muscle Relaxants: Reduced excretion of baclofen (increased risk of toxicity).

Penicillamine: Possible increased risk of nephrotoxicity when NSAIDs are given with penicillamine.

Pentoxyfylline: May increase risk of gastrointestinal bleeding; avoid concomitant use.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

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 the limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warnings and precautions for use, 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

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: 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).

Infections and infestations Very rare: aseptic meningitis

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.

Not known: Neutropenia. Prolonged bleeding time, aplastic anaemia and haemolytic anaemia. Eosinophilia.

Immune system disorders

Uncommon: hypersensitivity reactions with 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: Other hypersensitivity reactions have been reported and these may consist of:

(a)    non-specific allergic reactions or fever

(b)    respiratory tract reactivity, e.g. rhinitis, asthma, aggravated asthma, bronchospasm or dyspnoea.

(c)    various skin reactions e.g. purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissues) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4).

Metabolism and nutrition disorders

Not known: Hyponatraemia or hyperkalaemia.

Psychiatric disorders

Not known: Depression, nervousness, insomnia, confusion, hallucinations Nervous system disorders

Uncommon: Headache

Not known: Paraesthesia, dizziness and drowsiness.

Eye disorders

Not known: Visual disturbances. Optic neuritis.

Ear and labyrinth disorders Not known: Tinnitus, vertigo

Cardiac disorders

Not known: Oedema has been reported in association with NSAID treatment.

NSAIDs may induce or aggravate hypertension. Fluid retention may precipitate congestive heart failure.

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) (see section 4.4).

Vascular disorders Not known: Vasculitis.

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 stroke) (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Not known: Pulmonary eosinophilia. Exacerbation of asthma and bronchospasm (see Hypersensitivity for other respiratory reactions).

Gastrointestinal disorders

The most commonly observed adverse events are gastrointestinal in nature. Uncommon: abdominal pain, nausea and dyspepsia.

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. Exacerbation of ulcerative colitis and Crohn’s disease (See section 4.4).

Not known: Pancreatitis.

Hepatobiliary disorders

Not known: Abnormal liver function, hepatitis and jaundice.

Skin and subcutaneous tissue disorders Uncommon: Various skin rashes

Very rare: Bullous reactions including Steven’s Johnson syndrome, erythema multiforme and toxic epidermal necrolysis.

Not known: Photosensitivity, lichen planus and pseudoporphyria have also been reported in patients receiving ibuprofen (see Hypersensitivity for other skin reactions).

Renal and urinary disorders

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema. Papillary necrosis associated with NSAIDs can lead to renal failure.

Not known: Acute renal failure with pre-existing renal impairment. Interstitial fibrosis associated with NSAIDs can lead to renal failure. Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. Acute flank pain. Haematuria.

General disorders and administration site conditions Not known: Malaise, fatigue

4.8. Overdose

In children ingestion of more than 400mg/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. Dizziness, tinnitus, fainting, 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 one hour of ingestion of a potentially toxic amount.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

Other measures may be indicated by the patient’s clinical condition.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Ibuprofen is a phenylpropionic acid derivative which has analgesic anti-inflammatory and antipyretic actions.

Many possible mechanisms for the action of NSAIDS have been postulated. However, ibuprofen in common with other NSAIDS probably achieves its antiinflammatory effect through inhibition of prostoglandin synthesis at the site of the lesion, thereby preventing the sensitizing of tissue to other pain producing mediators (e.g. histamine, 5-hydroxytryptamine and bradykinin). Most NSAIDS delay normal platelet aggregation by inhibiting thromboxane A2 production.

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 400 mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81 mg), a decreased effect of aspirin 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

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys. About 1% is excreted in urine as unchanged ibuprofen and about 14% as conjugated ibuprofen.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after one to two hours. These times may vary with different dosage forms.

Ibuprofen is extensively bound to plasma proteins and has a half life of about two hours.

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

5.3 Preclinical safety data

The only consistent pathological effect of repeated ibuprofen dose studies in experimental animals was ulceration of the gastrointestinal tract. No evidence of carcinogenicity has been seen in rats. Reproduction studies on white rabbits in the early part of pregnancy showed no treatment related abnormalities, similar satisfactory results were obtained with mice and rats. Cultures of lymphocytes from rheumatic patients taking ibuprofen showed no significant increase in chromosome aberrations.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Colloidal anhydrous silica Starch (potato)

Povidone

Microcrystalline cellulose Alginic acid Magnesium stearate Sodium lauryl sulphate Sodium starch glycollate Croscarmellose sodium

Coating Materials

PVAP sealcote (contains polyvinyl acetate phthalate & stearic acid)

Purified talc

Sucrose

Calcium carbonate Acacia

Titanium dioxide (E171)

Carnauba wax

6.2    Incompatibilities

None stated except as in ‘interactions with other medicaments’.

6.3    Shelf life

Three years from date of manufacture.

SUMMARY OF PRODUCT CHARACTERISTICS

6.4 Special precautions for storage

Do not store above 25°C. Store the blister in the outer carton in order to protect from light and moisture.

6.5 Nature and contents of container

Blister Pack

Tablets are packed individually in pre-moulded PVC film and sealed with aluminium foil.

Pack sizes available in blister packs: 8, 12, 16, 24, 32, 48, 56, 64, 72, 84 and 96.

(Pharmacy)

A.    Aluminium Foil

Coated hard tempered foil, gauge 20 microns

B.    Rigid PVC Film

Characteristics:    Standard Vacuum Forming

Polyvinyl Chloride Film Gauge:    250pm (micron)

Colour:    Opaque white

6.6 Special precautions for disposal

Return any left over tablets to the Pharmacist.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd,

Ash Road North,

Wrexham,

LL13 9UF,

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 29831/0308

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/10/2006

10    DATE OF REVISION OF THE TEXT

18/03/2013

11    DOSIMETRY (IF APPLICABLE)

12    INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)