BACAGIN Tablet Ref.[115684] Active ingredients: Ibuprofen Paracetamol

This medicine is for short-term use and is not recommended for use beyond 3 days.

Paracetamol

Care is advised in the administration of Paracetamol to patients with severe renal or severe hepatic impairment. The hazard of paracetamol overdose is greater in patients with non-cirrhotic alcoholic liver disease. Do not take with any other paracetamol-containing products. 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 (see section 4.9).

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

Ibuprofen

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.2, and gastrointestinal and cardiovascular risks below) and by patients taking the dose with food (see Section 4.2).

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).

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. Treatment should be stopped in those patients who develop severe renal failure (see Section 4.3). Dose reduction is recommended in patients showing signs of worsening hepatic function. Treatment should be stopped in those patients who develop severe liver failure (see section 4.3).

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.

Clinical studies suggest that use of ibuprofen, particularly at high doses (2400 mg daily) 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 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 be exercised before initiating long-term treatment for 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.

Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal (GI) bleeding, ulceration and 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. 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 4.5).

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 Section 4.5).

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 Section 4.8).

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 Section 4.8).

Severe skin reactions:

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 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. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Use of this product should be discontinued at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

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.

Masking of symptoms of underlying infections

This medicinal product can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When this medicine is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

This product (like any other paracetamol containing products) is contraindicated in combination with other paracetamol containing products – increased risk of serious adverse effects (see Section 4.3).

This product (like any other ibuprofen containing products and NSAIDs) is contraindicated in combination with:

• Acetylsalicylic acid, unless low-dose acetylsalicylic acid (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see Section 4.4). Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelets aggregation when they are dosed concomitantly. Although, there are uncertainties regarding the 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 acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional use (see section 5.1).
• Other NSAIDs including cyclo-oxygenase-2 selective inhibitors as these may increase the risk of adverse effects (see Section 4.3).

This product (like any other paracetamol containing products) 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, cholestyramine should not be taken within one 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 anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
• Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors (see section 4.4)

This product (like any other ibuprofen containing products and NSAIDs) should be used with caution in combination with:

• Anticoagulants: NSAIDs may enhance the effects of anticoagulants, i.e. warfarin.
• Antihypertensives: (ACE inhibitors and Angiotensin II Antagonists) and diuretics: NSAIDs may reduce the effects of these 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 a coxib 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 therafter. Diuretics may increase the risk of nephrotoxicity of NSAIDS.
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see Section 4.4).
• Acetylsalicylic acid: Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid 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 acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).
• Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
• Ciclosporin: Increased risk of nephrotoxicity.
• Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4).
• 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 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.
• 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 haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy

There is no experience of use of this product in humans during pregnancy.

Paracetamol

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol use at the recommended dosage.

A large amount of data on pregnant women indicates neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Ibuprofen

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 the 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 3rd trimester of pregnancy (see section 4.3). 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 (see Section 4.3).

Breastfeeding

Ibuprofen and its metabolites can pass in very small amounts (0.0008% of the maternal dose) into the breast milk. No harmful effects to 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 to interrupt breastfeeding for short-term treatment with the recommended dose of this product.

Fertility

See Section 4.4 regarding female fertility.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected patients should not drive or operate machinery.

Clinical trials with this product have not indicated any other undesirable effects other than those for ibuprofen or paracetamol alone.

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

Examples include 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 and nose bleeding.

Hypersensitivity reactions have been reported. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity, e.g., asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) various skin reactions e.g., pruritus, urticaria, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis, and erythema multiforme).

The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, 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 (see Section 4.4).

Clinical studies suggest that use of ibuprofen, particularly at high doses (2400 mg/day) may be associated with a small increased of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

The adverse events observed most often are gastrointestinal in nature.

Sometimes fatal, particularly in the elderly.

In overdose Paracetamol can cause acute hepatic failure, hepatic failure, hepatic necrosis and liver injury (see Section 4.9).

Especially in long-term use, associated with increased serum urea and oedema. Also, includes papillary necrosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

None known.