SUMMARY OF PRODUCT CHARACTERISTICS

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Algiasdin 600 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 600 mg of ibuprofen For the full list of excipients, see Section PHARMACEUTICAL FORM Glossy white, capsule-shaped, film-coated tablets with no defects or roughness. With 600 embossed on one side and Algiasdin on the other. 4. CLINICAL PARTICULARS 4.1. Therapeutic indications Symptomatic treatment of fever. Treatment of mild to moderate pain, such as toothache, post-operative pain and headache, including migraine. Symptomatic treatment of arthritis (including juvenile rheumatoid arthritis), osteoarthritis, ankylosing spondylitis and non-rheumatic inflammation. Symptomatic relief of symptoms of primary dysmenorrhoea Posology and method of administration This medicinal product is for oral administration. Always take the lowest effective dose. Take the medicinal product with/immediately after meals or with milk if stomach upset occurs. The tablets should be swallowed whole and not chewed with a glass of water or other liquid, preferably with meals. Undesirable effects may be minimised by using the lowest effective doses for the shortest duration possible to control symptoms (see Section 4.4). Adults: Adults and adolescents aged 14 to 18 years should take one tablet (600 mg) every 6 to 8 hours, based on the severity of symptoms and treatment response. The maximum daily dose is 2400 mg in adults and 1600 mg in adolescents aged 12 to 18 years. During chronic administration, the dose should be adjusted to the lowest maintenance dose that provides adequate control of symptoms. Higher doses may be required for rheumatoid arthritis, but it is recommended not to exceed the maximum daily dose of 2400 mg of ibuprofen. For inflammatory disorders, the recommended daily dose is mg of ibuprofen in divided doses. The maintenance dose is usually mg. The maximum daily dose must not exceed 2400 mg. 1

2 For mild to moderate pain and fever, the recommended daily dose is mg in divided doses, based on the severity of symptoms and treatment response. For primary dysmenorrhoea, a dose of 400 mg of ibuprofen is recommended until pain relief is achieved with a maximum daily dose of 1200 mg. Paediatric population: Use of Algiasdin is not recommended in children and adolescents under 14 years of age as the amount of ibuprofen contained in the tablets is not suitable for the posology recommended for this group of patients. For juvenile rheumatoid arthritis, up to 40 mg/kg bodyweight daily may be administered in divided doses. Elderly patients: The pharmacokinetics of ibuprofen is not altered in elderly patients and therefore no dose or frequency adjustment is considered necessary. Nevertheless, as with other non-steroidal antiinflammatory drugs (NSAIDs), these patients should be treated with caution as they are generally more prone to undesirable effects and are more likely to have renal, cardiovascular or liver disorders and to be receiving concomitant medication. More specifically, it is recommended that the lowest effective dose be used in these patients. The dose may be increased to that recommended for the general population only after good tolerance has been ascertained. Renal failure: NSAIDs should be used with caution in patients with renal failure. The initial dose should be reduced in patients with mild to moderate renal failure. Ibuprofen should not be used in patients with severe renal failure (see Section 4.3). Renal failure: NSAIDs should be used with caution in patients with renal failure. The initial dose should be reduced in patients with mild to moderate renal failure. Ibuprofen should not be used in patients with severe renal failure (see Section 4.3). Hepatic failure: Although no differences in the pharmacokinetic profile of ibuprofen have been observed in patients with hepatic failure, it is recommended that NSAIDs be used with caution in this type of patient. Patients with mild to moderate hepatic failure should start treatment with reduced doses and be closely monitored. Ibuprofen should not be used in patients with severe hepatic failure (see Section 4.3) Contraindications Algiasdin is contraindicated: in patients with known hypersensitivity to ibuprofen, to other NSAIDs or to any of the excipients of the formulation. in patients who have had asthma attacks, acute rhinitis, urticaria, angioneurotic oedema or other allergic reactions after using substances with a similar action (e.g. acetylsalicylic acid or other NSAIDs). in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID treatment. Active or recurrent peptic ulcer/gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding) 2

3 in patients with severe heart failure (NYHA class IV) in patients with inflammatory bowel disease. in patients with severe renal failure. in patients with severe hepatic failure. in patients with bleeding diathesis or other clotting disorders. during the third trimester of pregnancy (see Section 4.6) Special warnings and precautions for use Gastrointestinal risks: Gastrointestinal bleeding, ulceration and perforation: Gastrointestinal bleeding, ulceration and perforation (which can be fatal) have been reported during treatment with non-steroidal antiinflammatory drugs (NSAIDs), including ibuprofen, at any time, with or without warning symptoms or a previous history of serious gastrointestinal events. The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with bleeding or perforation (see Section 4.3), and in elderly patients. These patients should start treatment on the lowest dose possible. Concomitant treatment with protective agents (e.g. misoprostol or proton pump inhibitors) is recommended for these patients. Such combination therapy should also be considered for patients requiring low-dose acetylsalicylic acid or other medicinal products that may increase gastrointestinal risk (see below and Section 4.5). Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be instructed to immediately report any unusual abdominal symptom (especially gastrointestinal bleeding) during treatment to their doctor, particularly in the initial stages of treatment. Special caution should be advised in patients receiving concomitant treatments that could increase the risk of ulceration or gastrointestinal bleeding, such as oral coumarin anticoagulants or anti-platelet agents such as acetylsalicylic acid (see Section 4.5). Certain caution should also be advised during concomitant administration of oral corticosteroids and selective serotonin reuptake inhibitors (SSRIs). If gastrointestinal bleeding or ulceration occurs in patients receiving Algiasdin, treatment should be discontinued immediately (see Section 4.3). NSAIDs should be administered with care to patients with a history of ulcerative colitis or Crohn's disease as their condition may get worse (see Section 4.8). Cardiovascular and cerebrovascular risks: Special care should be taken in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). In general, epidemiological studies do not suggest that ibuprofen at low doses (e.g mg/day) is associated with an increased risk of arterial thrombotic events. 3

4 Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established coronary 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. A careful assessment should also be made before starting long-term treatment in patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg/day) are required. Serious skin reaction risks: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been described very rarely in association with the use of NSAIDs (see Section 4.8). Patients appear to be at greatest risk of suffering these reactions early in the course of treatment with the onset of the adverse reaction occurring in most cases within the first month of treatment. Algiasdin should be discontinued immediately at the first sign of skin rash, mucosal lesions or any other sign of hypersensitivity. Renal and/or hepatic failure: Ibuprofen should be used with caution in patients with a history of hepatic or renal disease, especially during concomitant treatment with diuretics, as prostaglandin inhibition may result in fluid retention and further deterioration of renal function. If administered to these patients, the dose of ibuprofen should be kept as low as possible and renal function should be monitored regularly. In the event of dehydration, adequate fluid intake should be encouraged. Special care is required in children with severe dehydration, such as due to diarrhoea, as dehydration can lead to renal failure. In general, regular use of analgesics, especially the combination of different analgesic substances, can result in long-term kidney lesions with the risk of renal failure (analgesic nephropathy). Elderly patients, patients with impaired kidney function, heart failure or liver dysfunction and patients being treated with diuretics or ACE inhibitors are at greatest risk of suffering this reaction. On discontinuing NSAID therapy, recovery to the pre-treatment state is usually achieved. As with other NSAIDs, ibuprofen may cause small and transient increases in some liver function parameters and significant increases in transaminases. If a major increase in these parameters is observed, treatment should be discontinued (see Sections 4.2 and 4.3). Use in elderly patients: Elderly patients have a greater tendency to experience adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see Section 4.2). Others: Concomitant administration of Algiasdin and other NSAIDs, including selective inhibitors of cyclo-oxygenase-2 (Coxibs), should be avoided. Adverse reactions may be reduced if the lowest effective dose is used for the shortest duration possible to control symptoms (see Section 4.2 and gastrointestinal and cardiovascular risks below). NSAIDs may mask the symptoms of infections. 4

5 As with other NSAIDs, allergic reactions, such as anaphylactic/anaphylactoid reactions, may also occur without prior exposure to the active substance. This medicinal product should also be used with caution in patients suffering from or with a previous history of bronchial asthma as NSAIDs can cause bronchospasm in this type of patient (see Section 4.3). Some cases of aseptic meningitis have been reported with the use of ibuprofen in patients with systemic lupus erythematosus and therefore caution is recommended in patients with systemic lupus erythematosus and in those with mixed connective tissue disease (see Section 4.8). Like other NSAIDs, ibuprofen may reversibly inhibit platelet aggregation and function and prolong bleeding time. Caution should be exercised when ibuprofen is administered concomitantly with oral anticoagulants. The kidney function, liver function and blood counts of patients receiving long-term treatment with ibuprofen should be monitored as a precautionary measure. Special medical control is required during ibuprofen administration in patients immediately after major surgery. Adverse reactions can be minimised by using the lowest effective dose for the shortest duration possible. Headaches can occur during long-term treatment with high doses of analgesics. These must not be treated with higher doses of the medicinal product. In exceptional cases, varicella infection (chickenpox) can cause severe skin infections and soft tissue complications. To date, the role of NSAIDs in the worsening of these infections cannot be ruled out. Therefore, the use of ibuprofen in the presence of varicella should be avoided. Ibuprofen should only be used after strictly assessing the risks/benefits in patients with acute intermittent porphyria. Interference with blood tests: - Bleeding time (this may be prolonged for 1 day after discontinuing treatment). - Blood glucose level (this may be lower than usual). - Creatinine clearance (this may decrease). - Haematocrit or haemoglobin (this may be lower than usual). - Blood urea nitrogen level and serum creatinine and potassium levels (these may increase). - With liver function tests: increased transaminase values Interaction with other medicinal products and other forms of interaction In general, NSAIDs should be used with caution when taken with other medicinal products that can increase the risk of gastrointestinal ulceration, gastrointestinal bleeding or renal impairment. Interactions have been reported with the following medicinal products: - Anticoagulants: NSAIDs may enhance the effects of coumarin anticoagulants (see Section 4.4). 5

6 - Antiplatelet drugs: these increase the risk of gastrointestinal bleeding (see Section 4.4). NSAIDs should not be combined with ticlopidine due to the risk of an additive effect in the inhibition of platelet function. - Acetylsalicylic acid In general, the concomitant administration of ibuprofen and acetylsalicylic acid is not recommended due to the possibility of increased adverse effects. Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Although there is some uncertainty regarding the extrapolation of these data to the clinical situation, the possibility that habitual long-term use of ibuprofen may reduce the cardioprotective effect of low doses of acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered likely with the occasional use of ibuprofen (see section 5.1). - Corticosteroids: these may also increase the risk of gastrointestinal ulceration or bleeding (see Section 4.4). - Selective serotonin re-uptake inhibitors (SSRI): these may also increase the risk of gastrointestinal bleeding (see Section 4.4). - Other NSAIDs: concurrent use with other NSAIDs should be avoided as this may increase the risk of gastrointestinal ulceration and bleeding. - Methotrexate used at doses of 15 mg/week or more: if NSAIDs and methotrexate are administered within 24 hours of each other, plasma methotrexate levels may increase (its renal clearance may apparently be reduced by the NSAIDs), thus increasing the risk of methotrexate toxicity. Therefore, the use of ibuprofen in patients receiving high-dose methotrexate treatment should be avoided. - Methotrexate used at doses lower than 15 mg/week: ibuprofen increases methotrexate levels. When used in combination with low doses of methotrexate, the patient's blood count should be closely monitored, particularly during the first weeks of concomitant administration. Increased monitoring is also required in the presence of even mildly impaired renal function and in elderly patients. Renal function should also be monitored to prevent any possible reduction in methotrexate clearance. - Hydantoins and sulphonamides: the toxic effects of these substances may increase. Plasma phenytoin levels may increase during concomitant treatment with ibuprofen. - Lithium: NSAIDs may increase plasma lithium levels, possibly due to decreased renal clearance. Concomitant administration should be avoided, unless lithium levels are monitored. The possibility of reducing the lithium dose should be considered. - Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs may reduce the effects of mifepristone. - Digoxin and other cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate and increase cardiac glycoside levels. NSAIDs may increase plasma digoxin levels, thereby increasing the risk of digoxin toxicity. 6

7 - Pentoxifylline: the risk of bleeding may increase in patients receiving ibuprofen treatment in combination with pentoxifylline and therefore bleeding time should be monitored. - Probenecid and sulfinpyrazone: these may cause an increase in plasma ibuprofen levels; this interaction may be due to an inhibitory mechanism at the site of renal tubular secretion and glucuronidation and may require adjustment of the ibuprofen dose. - Quinolone antibiotics: animal data indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions. - Thiazides, thiazide-related substances, loop diuretics and potassium-sparing diuretics: NSAIDs may diminish the diuretic effect of these medicinal products. Concurrent use of an NSAID and a diuretic may increase the risk of NSAID-induced nephrotoxicity as a result of a reduction in renal blood flow. As with other NSAIDs, concomitant treatment with potassiumsparing diuretics may be associated with an increase in potassium levels and therefore plasma levels of this ion must be monitored. - Sulphonylureas: NSAIDs may enhance the hypoglycaemic effect of sulphonylureas due to displacement of sulphonylurea binding to plasma proteins. - Ciclosporin, tacrolimus: concomitant administration with NSAIDs may increase the risk of nephrotoxicity due to a reduction in prostaglandin synthesis in the kidney. If administered concomitantly, renal function should be closely monitored. - Antihypertensives (including ACE inhibitors or beta-blockers): NSAIDs may reduce the efficacy of antihypertensives. Concomitant treatment with NSAIDs and ACE inhibitors may be associated with a risk of acute renal failure. - Thrombolytics: these may increase the risk of bleeding. - Zidovudine: the risk of haematological toxicity may increase when NSAIDs are administered with zidovudine. There is a greater risk of haemarthrosis and bruising in HIV positive haemophiliacs receiving concomitant treatment with zidovudine and ibuprofen. - Aminoglycosides: NSAIDs may reduce aminoglycoside excretion. - Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs. - Food: Administration of ibuprofen with food slows the rate of absorption (see Section 5.2) Fertility, pregnancy and lactation Pregnancy 1) First and second trimester of pregnancy Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and heart defects and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of heart defects increased from less than 1% to approximately 1.5%. The risk appears to increase with dose and duration of treatment. During the first and second trimester of pregnancy, Algiasdin should not be used unless strictly necessary. If 7

8 Algiasdin is used by a woman who is trying to get pregnant, or if it is used during the first and second trimesters of pregnancy, the dose and duration of treatment should be reduced as much as possible. 2) Third trimester of pregnancy 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) - Impaired renal function, which may progress to renal failure with oligohydramnios. - Possible prolongation of bleeding time due to an anti-aggregating effect which may occur even at very low doses. - Inhibition of uterine contractions which may result in delayed or prolonged labour. Algiasdin is consequently contraindicated during the third trimester of pregnancy (see Section 4.3). Fertility The use of Algiasdin may impair female fertility and is not recommended in women who are trying to conceive. In women who are having trouble conceiving or who are undergoing investigation for infertility, discontinuation of this medicinal product should be considered. Lactation Although the concentration of ibuprofen excreted in breast milk is negligible and no undesirable effects are expected for the infant, the use of ibuprofen is not recommended during lactation due to the potential risk of prostaglandin synthesis inhibition in the newborn infant Effects on ability to drive and use machines Single administration or short-term use of ibuprofen does not warrant the adoption of any special precautions. Patients who experience dizziness, vertigo, visual disturbances or other central nervous system disorders while taking ibuprofen should avoid driving or using machines Undesirable effects The most common undesirable effects are gastrointestinal disorders. Peptic ulcers, perforation or gastrointestinal bleeding, in some cases fatal, may occur, especially in elderly patients (see Section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn s disease have also been reported (see Section 4.4). Less frequently, gastritis has been observed. Undesirable effects that are possibly related to ibuprofen are listed according to system organ class and frequency as follows: very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1,000, < 1/100), rare ( 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Gastrointestinal disorders: Uncommon: ulcerative stomatitis. Rare: oesophagitis, oesophageal stricture, exacerbation of diverticular disease, non-specific haemorrhagic colitis. If gastrointestinal bleeding occurs, this may cause anaemia and haematemesis. 8

9 Very rare: pancreatitis Skin and subcutaneous tissue disorders: Common: rash. Uncommon: urticaria, pruritus, purpura (including allergic purpura). Very rare: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema multiforme, alopecia, photosensitivity reactions and allergic vasculitis. In exceptional cases, serious skin infections and soft tissue complications can occur during varicella (chickenpox) infection. Immune system disorders: Uncommon: angioedema, rhinitis, bronchospasm. Rare: anaphylactic reaction. In the event of a severe generalised hypersensitivity reaction, swelling of the face, tongue and larynx, bronchospasm, asthma, tachycardia, hypotension and shock can occur. Very rare: systemic lupus erythematosus. Nervous system disorders: Common: fatigue or drowsiness, headache, dizziness. Rare: paraesthesia. Very rare: aseptic meningitis. In the majority of cases in which aseptic meningitis has been reported with ibuprofen, the patient has had some form of underlying autoimmune disease (such as systemic lupus erythematosus or other collagen diseases) as a risk factor. The symptoms of aseptic meningitis observed were stiff neck, headache, nausea, vomiting, fever or disorientation. Psychiatric disorders: Uncommon: insomnia, anxiety, restlessness Rare: psychotic reaction, nervousness, irritability, depression, confusion or disorientation. Ear and labyrinth disorders: Common: vertigo. Uncommon: tinnitus. Rare: impaired hearing. Eye disorders: Uncommon: vision problems. Rare: reversible toxic amblyopia. Blood and lymphatic system disorders: Bleeding time may be prolonged. Rare cases of blood disorders observed include thrombocytopenia, leukopenia, granulocytopenia, pancytopenia, agranulocytosis, aplastic anaemia or haemolytic anaemia. Initial symptoms include fever, sore throat, mouth ulcers, flulike symptoms, extreme tiredness, nosebleeds and bruising on the skin. Cardiac disorders and vascular disorders: Oedema, hypertension and heart failure have been reported in association with NSAID treatment. Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see section 4.4). 9

10 Patients with hypertension or renal disorders seem to be more prone to fluid retention. Renal and urinary disorders: Based on previous experience with NSAIDs in general, interstitial nephritis, nephrotic syndrome and renal failure cannot be excluded. Hepatobiliary disorders: Rare: liver lesions, abnormal liver function, hepatitis and jaundice. Frequency not known: liver failure. General disorders and administration site conditions: In very rare cases, infection-related inflammation may be aggravated. 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. Healthcare professionals are asked to report any suspected adverse reactions via the Spanish Pharmacovigilance System for Medicinal Products for Human Use: Overdose Most cases of overdose have been asymptomatic. There is a risk of symptoms at doses in excess of mg/kg of ibuprofen. The onset of symptoms due to overdose usually occurs within 4 hours. Mild symptoms are most common, including abdominal pain, nausea, vomiting, lethargy, drowsiness, headache, nystagmus, tinnitus and ataxia. Rarely, moderate or severe symptoms have occurred, such as gastrointestinal bleeding, hypotension, hypothermia, metabolic acidosis, seizures, impaired kidney function, coma, adult respiratory distress syndrome and transient episodes of apnoea (in children after ingesting large amounts). Management Treatment is symptomatic and there is no specific antidote. For amounts that are unlikely to cause symptoms (less than 50 mg/kg of ibuprofen), water may be administered to minimise gastrointestinal upset. If significant amounts are ingested, activated charcoal should be administered. Emptying of the stomach by induced vomiting should only be considered within 60 minutes of ingestion. Gastric lavage should not be considered unless the patient has ingested a potentially life-threatening amount of the medicinal product and no more than 60 minutes have passed since ingestion. Forced diuresis, haemodialysis or haemoperfusion are unlikely to be beneficial as ibuprofen is strongly bound to plasma proteins. 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, non-steroids ATC code: M01AE01. Ibuprofen is a non-steroidal propionic acid derivative with marked anti-inflammatory, analgesic and antipyretic properties. 10

11 Its mechanism of action may be due to inhibition of prostaglandin synthesis. Prostaglandins play an essential role in the onset of fever, pain and inflammation. Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Some pharmacodynamic studies show that when a single 400-mg dose of ibuprofen was administered within 8 hours before or within 30 minutes after a dose of immediate-release acetylsalicylic acid (81 mg), the effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation was reduced. Although there is some uncertainty regarding the extrapolation of these data to the clinical situation, the possibility that habitual long-term use of ibuprofen may reduce the cardioprotective effect of low doses of acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely with occasional use of ibuprofen (see section 4.5) Pharmacokinetic properties Ibuprofen is a medicinal product that shows linear pharmacokinetics up to doses of at least 800 mg Absorption: Approximately 80% of an oral dose of ibuprofen is absorbed in the gastrointestinal tract. Peak plasma concentrations (Cmax) are reached (Tmax) 1-2 hours after administration. Administration of ibuprofen with food slows Tmax (from ± 2 h on an empty stomach to ± 3 h after food), although this does not affect the extent of absorption. The pharmacokinetic parameters obtained in healthy volunteers with this formulation in the form of 600 mg tablets are similar to those reported in published literature for tablets of the same dose. Cmax is ng/ml, Tmax is 1.5 h and bioavailability (AUC0- ) is ng.h/ml. Distribution: The apparent volume of distribution of ibuprofen following oral administration is 0.1 to 0.2 L/kg and it is highly bound to plasma proteins (approximately 99%). Metabolism: Ibuprofen is extensively metabolised in the liver by hydroxylation and carboxylation of the isobutyl group through CYP2C9 and CYP2C8. Its metabolites have no pharmacological activity. Ibuprofen and its metabolites are partly conjugated with glucuronic acid. Elimination: Ibuprofen is mainly excreted by the kidneys and total clearance is achieved after 24 hours. Approximately 10% is eliminated as unchanged active substance and 90% is eliminated as inactive metabolites, mainly as glucuronides Preclinical safety data Ibuprofen was not teratogenic in different animal species. In addition, both mutagenesis and carcinogenesis study results were negative. In some animal reproduction studies, increases in dystocia and delayed parturition have been observed, which are associated with the inhibition of prostaglandin synthesis by NSAIDs. 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients Each Algiasdin film-coated tablet contains: 11

12 Core: maize starch, pregelatinised maize starch, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate. Coating: cellulose derivative/polyoxyl 40 stearate, titanium dioxide (E171), hypromellose (E464), propylene glycol and polyethylene glycol Incompatibilities Not applicable Shelf life 3 years Special precautions for storage This medicinal product does not require any special storage conditions Nature and contents of container PVC / Aluminium blisters. Pack containing 30 film-coated tablets Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER ISDIN, SA Provençals Barcelona Spain 8. MARKETING AUTHORISATION NUMBER(S) DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION April DATE OF REVISION OF THE TEXT 05/