BRUSTAN Tablet

For the temporary relief of mild to moderate pain associated with migraine,headache, backache, perieo pain, dental pain, rheumatic and muscular pain,pain of non-serious arthritis, cold and flu symptoms, sore throat and fever. This product is especially suitable for pain which requires stronger ananalgesia than ibpurofen or paracetamol alone.

For oral administration.

The lowest effective dose should be used for the shortest time necessary to relieve symptoms unless your doctor prescribes it. The patient should consult a doctor if the symptoms persist or worsen or if the product is required for more than 3 days.

Adults: 1tablet to be taken up to 3 times/day with water. Leave at least 6 hours between doses.

It the 1 tablet dose does not control symptoms, your doctor may prescribe a maximum of 2 tablets up to 3 times a day. Leave at least 6 hours between doses.

Do not take more than 6 tablets in any 24 hours period.

To minimise side effects, it is recommended that patients take this tabets with food.

Elderly: No special dosage modifications are required.

- History of hypersensitivity to ibuprofen, paracetamol and any of the ingredients of the tablet.

- In patients with a history of hypersensitivity reactions (e.g. bronchospasm, angioedema, asthma, rhinitis, or urticaria) associated with acetylsalicylic acid or other NSAIDs.

- In patients with a history of, or an existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs.

- Patients with defects in coagulation.

- In patients with severe hepatic failure, severe renal failure or severe heart failure.

- In concomitant use with other NSAID containing products, including COX-2 specific inhibitors and doses of acetylsalicylic acid above 75mg daily-increased risk of adverse reactions.

- In concomitant use with other paracetamol-containing products-increased risk of serious adverse effects.

- During the last trimester of pregnancy due to risk of premature closure of the foetal ductus arteriosus with possible pulmonary hypertension.

The following adverse effects are from pharmacovigilance data experienced by patients taking ibuprofen alone or paracetamol alone in short-term and long-term use.

Blood and lymphatic system disorders

Very rare: Haematopoietic disorders (agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia leucopenia, neutropenia, pancytopenia and thrombocytopenia).

First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising an nose bleeding.

Immune system disorders

Very rare: Hypersensitivity reactions have been reported. These may consist of non-specific allergic reactions and anaphylaxis.

Severe hypersensitivity reactions. Symptoms can include: facial, tongue and larynx swelling, dyspnea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Psychiatric disorders

Very rare: Confusion, depression and hallucinations.

Nervous disorders

Uncommon: Headache and dizziness.

Very rare: Paraesthesia, optic neuritis and somnolence.

Single cases of aseptic meningitis in patients with existing autoimmune disorders (such as systemic lupus erythematosus and mixed connective tissue disease) during treatment with ibuprofen, with symptoms such as: stiff neck, headache, nausea, vomiting, fever or disorientation have been observed.

Eye disorders

Very rare: Visual disturbance.

Ear and labyrinth disorders

Very rare: Tinnitus and vertigo.

Cardiac disorders

Very rare: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high dose (2400mg/day), and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Respiratory and thoracic and mediastinal disorders

Very rare: Respiratory reactivity including: asthma, exacerbation of asthma, bronchospasm dyspnea and wheezing.

Gastrointestinal disorders

Common: Abdominal pain, diarrhea, dyspepsia, nausea, stomach discomfort and vomiting

Uncommon: Flatulence and constipation

Peptic ulcer, perforation or gastrointestinal haemorrhage, with symptoms of melaena haematemesis sometimes fatal, particularly in the elderly.

Hepatobiliary disorders

Very rare: Abnormal liver function, hepatitis and jaundice

In overdose paracetamol can cause acute hepatic failure, hepatic failure, hepatic necrosis and liver injury.

Skin and subcutaneous tissue disorders

Uncommon: Rashes of various types including pruritis and urticaria. Angioedema and swelling face.

Very rare: Hyperhiddrosis, purpura and photosensitivity. Exfoliative dermatoses. Bullous reaction including erythema multiforme, Stevens Johnson Syndrome and Toxic Epidermal Necrosis.

Renal and urinary disorders

Very rare: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and acute and chronic renal failure.

General disorders and administration site conditions

Very rare: Fatigue and malaise.

Investigations

Common: Alanine aminotransferase increased, gamma-glutamyltransferase increase and liver function tests abnormal with paracetamol.

Blood creatinine increased and blood urea increased.

Uncommon: Aspartate aminotransferase increased, blood alkaline phosphatase increased, blood creatine phosphokinease increased, bolld creatinie increased, haemoglobin decreased and platelet count increased.

- In combination with other paracetamol containing products – increased risk of serious adverse effects.

- Acetylsalicylic acid, unless low-dose acetylsalicylic acid (not above 75mf daily) has been advised by a doctor, as this may increase the risk of adverse reactions.

- Other NSAIDs including COX-2 selective inhibitors as these may increase the risk of adverse effects.

Should be used with caution in combination with:

- Chloramphenicol: Increased plasma concentration of chloramphenicol.

- Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, cholestylamine should not be taken with on hour if maximal analgesia is required.

- Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

- Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

- Anticoagulants: NSAIDs may enhance the effects of anticoagulants, i.e.warfarin.

- Antihypertensives: NSAIDs may reduce the effects of these drugs.

- Antiplatelet agents and SSRIs: Increased risk of gastrointestinal bleeding.

- Acetylsalicylic acid: Reported experimental data suggest that Ibuprofen may inhibit the effect of low dose acetylsalicylic acid 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.

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

- Ciclosporin: Increased risk of nephrotoxicity.

- Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.

- Diuretics: Reduced diuretic effect. Diuretics may increase the risk of nephrotoxicity of NSAIDs.

- Lithium: Decreased elimination of lithium.

- Methotrexate: Decreased elimination of methotrexate.

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

- Quinolone antibiotics: Animal data indicated 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.

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

- Zidovudine: Increased risk of haematological toxicity with NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematom in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy

There is no experience of use of this product in human drug pregnancy.

Congenital abnormalities have been reported in association with NSAID administration in man; however these are low in frequency and do not appear to follow any discernible pattern. In view of the known affects of NSAIDs on the foetal cardiovascular system (risk of closure of ductus arteriosus), use in the last trimester is contraindicated. The onset of labour may be delayed and duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Reported epidemiological studies in human pregnancy have shown no ill effects due to paracetamol use at the recommended dosage. Therefore if possible, the use of this product should be avoided in the first six months of pregnancy and contraindicated in the last three months of pregnancy.

Location

Ibuprofen and its metabolites can pass in very small amounts (0.0008% of the maternal dose) into the breast milk. No harmful effects in infants are known.

Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breastfeeding.

Therefore it is not necessary in interrupt breastfeeding for short-term treatment with the recommended dose of this product.

The hazard of paracetamol overdose is greater in patients with non-cirrhotic alcoholic liver disease. Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed, serious liver damage.

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see DOSE AND METHOD OF ADMINISTRATION , gastrointestinal and cardiovascular risks below) and by patients taking the dose with food (see DOSE AND METHOD OF ADMINISTRATION).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see DOSE AND METHOD OF ADMINISTRATION).

Caution is required in patients with certain conditions:

- Respiratory disorders:

In patients suffering from , or with a history of bronchial asthma or allergic disease NSAIDs have been reported to precipitate bronchospasm.

- Cardiovascular, renal and hepatic impairment:

The administration of NSAIDs 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. Renal function should be monitored in these patients (see CONTRAINDICATIONS).

- 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.

Reported clinical trial 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 (e.g. 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.

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 long-term treatment for patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

- Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal (GI) bleeding, ulceration and 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.

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 CONTRAINDICATIONS) 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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and DRUG INTERACTIONS).

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 acetylsalicylic acid (see DRUG INTERACTIONS).

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

NSAIDs should be given with care to patients with a history of GI disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see UNDESIRABLE EFFECTS).

- SLE and mixed connective tissue disease:

In patient with systemic lupus erythematosus (SLE) and mixed connective tissue disease disorders there may be an increased risk of aseptic meningitis (see UNDESIRABLE EFFECTS).

- 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 UNDESIRABLE EFFECTS). 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. Use of this product should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissue infections complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of ibuprofen in case of varicella.

- Impaired female fertility:

The use of the product may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of the product should be considered.

The pharmacological actions of ibuprofen and paracetamol differ in their site and mode of action. These complementary modes of action are synergistic which results in greater antinociception and antipyresis than the single actives alone.

Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic activity. The drug’s therapeutic effects as an NSAID is thought to result from its inhibitory effect on the enzyme cyclo-oxygenase, which results in a marked reduction in prostaglandin synthesis.

Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, though a peripheral action by blocking pain-impulse generation. Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heart-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.