SUMMARY OF PRODUCT CHARACTERISTICS

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1 1. NAME OF THE MEDICINAL PRODUCT Burana Comp 200 mg / 30 mg film-coated tablet Burana Comp 400 mg / 60 mg film-coated tablet SUMMARY OF PRODUCT CHARACTERISTICS 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 200/30 mg film-coated tablet contains ibuprofen 200 mg and codeine phosphate hemihydrate 30 mg. Each 400/60 mg film-coated tablet contains ibuprofen 400 mg and codeine phosphate hemihydrate 60 mg. For a full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablets. 200/30 mg tablets are white coloured, round (diameter 11 mm), biconvex, bevel edged, debossed with I1 on one side and plain on other side. 400/60 mg tablets are white coloured, caplet shaped (8.1 x 19.1 mm), biconvex, bevel edged, debossed with I and 2 on either side of the score line on one side and score line on other side. The tablet can be divided into two equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of moderate to severe pain in adults when analgesics with only peripheral effect are not sufficient. 4.2 Posology and method of administration Treatment should be initiated with the lowest possible effective dose, so that later on it can be adjusted on the basis of the therapeutic response and possible adverse effects. In the long-term treatment one must aim at low maintenance dose. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4). Adults 200 mg / 30 mg: One or two tablets 1-4 times a day. Do not take more than 8 tablets in 24 hours. 400 mg / 60 mg: One tablet 1-4 times a day. Do not take more than 4 tablets in 24 hours. Children and adolescents < 18 years of age Not recommended. Elderly The elderly are at increased risk of serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. If renal or hepatic function is impaired, dosage should be assessed individually. Renal impairment 1

2 Caution should be taken with ibuprofen dosage in patients with renal impairment. The dosage should be assessed individually. The dose should be kept as low as possible and renal function should be monitored (see sections 4.3, 4.4 and 5.2). Hepatic impairment Caution should be taken with dosage in patients with hepatic impairment. The dosage should be assessed individually and the dose should be kept as low as possible (see sections 4.3, 4.4 and 5.2). 4.3 Contraindications Hypersensitivity to ibuprofen, codeine or any of the excipients in the product. Because of cross reaction Burana Comp should not be given to patients who have experienced symptoms of asthma, rhinitis or urticaria associated with intake of acetylsalicylic acid or other nonsteroidal antiinflammatory drugs. Chronic constipation. Severe hepatic failure. Renal failure (glomerular filtration below 30 ml/minute). Heart failure. Conditions with increased haemorrhagic tendency. Active gastric or duodenal ulcer or history of recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding). History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Bile duct spasm. Third trimester of pregnancy. Women during breastfeeding (see section 4.6). Patients for whom it is known they are CYP2D6 ultra-rapid metabolisers (see section 4.4). 4.4 Special warnings and precautions for use The use of ibuprofen with concomitant NSAIDs including cyclo-oxygenase-2 selective inhibitors should be avoided. 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). Therefore the lowest effective dose should be individually adjusted for every patient. Elderly The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal (GI) bleeding and/or perforation, which may be fatal. The elderly patients more often have impaired renal, cardiac or liver function. Codeine may cause confusion and over-sedation in the elderly patients. Gastrointestinal bleeding, ulceration and perforation 2

3 Gastrointestinal bleeding, ulceration or 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. Caution should be advised in treatment of elderly patients, who generally have an increased frequency of adverse reactions. Consequences, e.g. gastrointestinal haemorrhage and/or perforation, become often more severe in the elderly and they may appear without warning symptoms and even though they have not manifested in the past. 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 possible dose. 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 section 4.5). 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 or anti-platelet agents such as acetylsalicylic acid (see section 4.5). When GI bleeding or ulceration occurs in patients receiving Burana Comp 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 their condition may be exacerbated (see section 4.8). Respiratory disorders Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease. Renal effects Ibuprofen should be used with caution and lower doses in patients with impaired renal or hepatic function, and in the elderly patients. Renal function should be monitored periodically during long-term ibuprofen therapy. Ibuprofen should be avoided in patients with severe renal impairment (see section 4.3). Caution should be exercised with regard to dehydrated patients. As with other NSAIDs, the long-term administration of ibuprofen has resulted in papillary necrosis and other pathological changes in the kidney. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of normal renal perfusion. In these patients the administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may cause kidney failure. Those who are at greatest risk of this are patients with renal impairment, heart failure, liver dysfunction, the elderly and patients on diuretics or ACE inhibitors. The symptoms are normally reversible following withdrawal of the NSAID. 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 trial and epidemiological data suggest that use of ibuprofen, particularly at a high dose (2400 mg 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. 3

4 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 disease (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking). Use of ibuprofen may decrease fertility and therefore it is not recommended for women who are attempting to get pregnant. This considers all drugs that inhibit cyclo-oxygenase/prostaglandin synthesis. The effect is reversible and it ceases when the exposure to this type of drugs is ended. The concomitant use of alcohol should be avoided. Ibuprofen may mask the signs of inflammation. Opioids Codeine can cause addiction. Regular prolonged use of codeine may lead to physical addiction. Also cross tolerance between other opioids is possible. Codeine is not recommended for long-term use. Codeine is not recommended for patients with a history of drug abuse. Opioids should be used with caution in patients with impaired respiratory function and asthma, hypotension, urethral stenosis, shock, myasthenia gravis, prostate hypertrophy, obstructive or inflammatory bowel disorders, diseases of the biliary tract and convulsive disorders. Skin reactions Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnsons 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. Burana Comp 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 tissues infectious 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 Burana Comp in case of varicella. Haematological effects Patients with gastrointestinal problems, systemic lupus erythematosus (SLE), haematological or coagulation disorders and asthma should be treated with care and be closely monitored during NSAID treatment, since their condition may be exacerbated by the NSAID. Ibuprofen can inhibit platelet aggregation, resulting in prolongation of bleeding time. Aseptic meningitis Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. CYP2D6 metabolism Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal. 4

5 Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below: Population Prevalence % African/Ethiopian 29% African American 3.4% to 6.5% Asian 1.2% to 2% Caucasian 3.6% to 6.5% Greek 6.0% Hungarian 1.9% Northern European 1%-2% 4.5 Interaction with other medicinal products and other forms of interaction Following combinations with Burana Comp should be avoided: Acetylsalicylic acid: NSAID-products should not be combined with acetylsalicylic acid because of increased risk of bleeding. 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). Other NSAIDs including cyclooxygenase-2 selective inhibitors: Concomitant use of NSAIDs with ibuprofen should be avoided due to increased risk of gastrointestinal adverse reactions. Combined use of two or more different NSAIDs does not contribute to the efficacy of the therapy and is potentially harmful. Methotrexate: NSAIDs inhibit the tubular secretion of methotrexate and some metabolic interaction with reduced clearance of methotrexate may also occur as a result. Accordingly, in high-dose treatment with methotrexate one should always avoid prescribing NSAIDs. Low-dose methotrexate therapy could be compatible with NSAID use provided that renal function is monitored carefully. Monoamine oxidase inhibitors: Codeine may enhance the effects of monoamine oxidase inhibitors resulting in CNS reactions and respiratory depression. Therefore caution should be exercised in patients taking monoamine oxidase inhibitors. Ticlopidine: NSAID-products should not be combined with ticlopidine because of additive inhibition of platelet function. Dicumarol group: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4). Experimental studies show that ibuprofen potentiates warfarin s effects on bleeding time. NSAIDs and dicumarol group are metabolized by the same enzyme CYP 2C9. Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration and increase plasma cardiac glycoside (e.g. digoxin) levels. Inhibitors of CYP2D6: Codeine is probably active through the codeine being O-demethylated to morphine via the enzyme CYP2D6. This bioactivation is inhibited by certain medications, e.g. quinidine, terbinafine, certain antidepressants and neuroleptics, etc. These drugs therefore counter the effect of codeine. This interaction has been documented in studies on healthy trial subjects and/or pilot studies on patients. Direct studies have been performed with quinidine, which is a very strong inhibitor of CYP2D6. Combination with strong inhibitors of CYP2D6 should therefore be avoided. Following combinations with Burana Comp may need dose adjustment: 5

6 Neuroleptics and antidepressants also have an inhibiting effect on CYP2D6 and concomitant administration may need dose adjustment. Neuroleptics may decrease the analgesic effect of codeine by interference with metabolism of codeine. Enzyme-inducing medications such as rifampicin, barbiturates, several antiepileptics, St John's wort (Hypericum perforatum), etc. can produce reduced plasma concentrations of codeine and morphine. NSAIDs may reduce the effect of diuretics and other antihypertensive medicinal products. ACE inhibitors and angiotensin II -antagonists: The risk of acute renal insufficiency, which is usually reversible, may be increased in patients with impaired renal function (e.g. dehydrated patients and/or elderly patients) when ACE-inhibitors or angiotensin II-receptor antagonists are combined with NSAIDs, including selective cyclooxogenase-2-inhibitors. Therefore, the combination should be administered with caution to patients with impaired renal function, 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 thereafter (see section 4.4). Beta-blockers: NSAID type anti-inflammatory drugs reduce the antihypertensive effect of beta-adrenoceptor blocking drugs. This issue has been mainly studied with indomethacin. Diuretics: NSAID-drugs (indomethacin and propionic acid derivatives) can reduce the diuretic effect of furosemide and bumetanide (loop diuretics), possibly by inhibiting prostaglandin synthesis. They can also decrease the antihypertensive effect of thiazides. Diuretics can increase the nephrotoxicity of NSAIDs. Aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides CYP2C9 inhibitors: Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors) an increased S(+)-ibuprofen exposure by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole. Anti-platelet agents: Concomitant treatment increase the risk for gastrointestinal bleeding (see section 4.4). Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4). Ciclosporin and tacrolimus: It is presumed that administering of NSAID-drugs concomitantly with ciclosporin or tacrolimus may increase the risk of nephrotoxicity because of decreased prostacyclin synthesis in kidney. Therefore in combination treatment renal function must be carefully monitored. Codeine may enhance the effects of antidepressants and alcohol. The combination with alcohol may enhance the sedative and respiratory suppressive effects of codeine. Colestyramine: The concomitant administration of ibuprofen and colestyramine retards and reduces (by 25%) the absorption of ibuprofen. These drugs should be taken at least 2 hours apart. Lithium: Ibuprofen reduces renal clearance of lithium as a result of which serum lithium levels may rise. Combination should be avoided unless frequent checks of serum lithium can be carried out and possible reduction in the dose of lithium made. Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone. Selective serotonin reuptake inhibitors, SSRIs: SSRI and NSAID each involve an increased risk of bleeding e.g. from the gastrointestinal channel. This risk increases at concomitant treatment. The mechanism may be associated with a decreased uptake of serotonin in the thrombocytes (see section 4.4). 6

7 Sulfonylureas: NSAIDs, including ibuprofen, may enhance the effects of medicinal products containing sulfonylurea. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen. 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. 4.6 Fertility, pregnancy and lactation Pregnancy: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal 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 and gastroschisis 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 prostaglandin synthesis inhibitor has been shown to result in increased pre- and postimplantation loss and embryo/fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenic period. During the first and second trimester of pregnancy the combination of ibuprofen and codeine should not be given unless clearly necessary. If ibuprofen and codeine are 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 fetus to: - cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension) - renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. At the end of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate to: - prolongation of bleeding time because of an antiaggregation effect of the platelets, which already can occur at very low dosages. - inhibition of uterine contractions resulting in delayed or prolonged labour. Regular use of codeine during pregnancy may result in addiction of the foetus leading to withdrawal syndrome in the newborn (irritability, excessive crying, tremor, hyperactive reflexes, fever, vomiting, diarrhoea, yawning). Consequently Burana Comp is contraindicated during the third trimester of pregnancy. Labour and delivery: Burana Comp is not recommended for use during labour. Burana Comp may result in delayed or prolonged labour and an increased bleeding tendency in both mother and child. Additionally, the withdrawal syndrome may cause the newborn to suffer from respiratory depression if the mother has received codeine during labour. Lactation: Both ibuprofen and codeine are excreted in breast milk. Burana Comp should not be used during breastfeeding (see section 4.3). At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal. Fertility: The use of ibuprofen and codeine may impair 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 Burana Comp should be considered. 7

8 4.7 Effects on ability to drive and use machines Treatment with Burana Comp may cause dizziness and drowsiness as an adverse effect resulting in prolonged reaction time. This must be kept in mind when sharp attention is needed e.g. when driving a car or operating machinery. 4.8 Undesirable effects The most commonly observed adverse events are gastrointestinal in nature, dyspepsia and diarrhoea, which are estimated to occur in about 10 30% of treated patients. In occasional use, with a maximum daily ibuprofen dose of 1200 mg, the adverse effects are less common. Adverse events at least possibly related to ibuprofen and codeine are displayed by MedDRA frequency convention and system organ class database. The following frequency groupings are used: Very common ( 1/10), Common ( 1/100 to <1/10), Uncommon ( 1/1000 to <1/100), Rare ( 1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). System organ class Infections and infestations Blood and lymphatic system disorders Frequencies Common (>1/100) Uncommon (1/100-1/1000) Rare (< 1/1000) Aplastic anaemia, leukopenia, thrombocytopenia Anaphylactic reactions Not known Cystitis Agranulocytosis Immune system disorders Metabolism and Hyperkalemia, nutrition disorders hyponatremia Psychiatric disorders Insomnia, mild Depression, confusion Nervousness, paranoid anxiety ideation, mood changes, hallucinations, restlessness, euphoria, dysphoria Nervous system Headache Aseptic meningitis, Sedation, seizures, disorders dizziness, optic neuritis cerebrovascular accident, syncope Eye disorders Visual Toxic amblyopia disturbances Ear and labyrinth Hearing effects Tinnitus Vertigo disorders Cardiac disorders Heart failure Vascular disorders Hypertension Vasodilatation, postural hypotension Respiratory, thoracic and Asthma, rhinitis mediastinal disorders Gastrointestinal disorders Hepatobiliary disorders Vomiting, diarrhoea, abdominal pain, dyspepsia, nausea, constipation Hemorrhages, ulcus, ulcerative stomatitis Biliary dyskinesia Perforation, pancreatitis, haematemesis, melaena, colitis, exacerbation of ulcerous colitis and Crohn s disease, gastritis, flatulence Hepatic injuries, hepatic failure, hepatitis, jaundice Heartburn, bloating, feeling of fullness in the GI tract 8

9 Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions Investigations Eczema Angioedema, urticaria, purpura, itching and elevation of liver enzymes Bullous reactions including Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme, photosensitivity, alopecia Acute renal failure and interstitial nephritis, renal papillary necrosis, renal impairment Tiredness Edema, fluid retention Pyrexia Dermatitis herpetiformis, fixed drug eruption, maculopapular rash, hidrosis Systemic lupus erythematosus syndrome, muscle rigidity Nephrotic syndrome, haematuria, proteinuria, bladder dysfunction Sexual dysfunction Serum creatinine increased Dyskinesia of the bile duct can occur in predisposed patients. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Persons with known allergy or asthma have increased risk of hypersensitivity reactions. Exceptionally, occurrence of serious cutaneous and soft tissues infectious complications during varicella have been reported. Ibuprofen may cause prolongation in bleeding time by reversible inhibition of thrombocyte aggregation. In most cases when aseptic meningitis has been reported some form of underlying autoimmune disease (such as systematic lupus erythematosus, and related connective tissue disease) has existed. It has also been reported in patients who do not have underlying chronic disease. 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 a high dose (2400 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke, see section 4.4). 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 national reporting system. 4.9 Overdose Ibuprofen Toxicity: 9

10 Ingestions of less than mg/kg rarely cause significant toxicity; ingestions of greater than 400 mg/kg may result in serious effects. In children doses below 100 mg/kg are unlikely to cause toxicity, whereas clinical features will occur in children who have ingested more than 400 mg/kg. 560 mg/kg caused severe intoxication for 15 months old child. 3.2 g to 6-year-old child caused mild to moderate intoxication, g to 1½-year-old child and 6 g to 6-year-old child after gastric lavage caused severe intoxication. 8 g to a 16- year-old and 12 g in combination with alcohol administered to a teenager resulted in acute tubular necrosis. Overdoses up to 48 g have been well tolerated by healthy adults. Symptoms: Nausea, abdominal pain, vomiting (eventually bloody). Headache, tinnitus, dazed, unconsciousness, cramps. Nystagmus, blurred vision. Bradycardia, hypotension. Metabolic acidosis, hypernatremia, hyponatremia, hyperkalemia with cardiac arrhythmias. renal effects, haematuria, eventually liver impairment. Hypothermia. Coma, Isolated cases of adult respiratory stress syndrome. Treatment: For adults and children supportive treatment is sufficient if the ingested dose is < 100 mg/kg. If the dose is > 100 mg/kg activated charcoal should be given. Gastric lavage is rarely, if ever, indicated as ibuprofen is absorbed rapidly and severe toxicity is exceedingly rare. Antacids if needed. If blood pressure has fallen fluid i.v., inotropic support if needed. Take care of good diuresis. Correction of acid-base balance and electrolyte disturbances. Codeine The main symptoms are of the same type as for morphine intoxication: reduced consciousness, respiratory depression, miotic pupils, hypotension, tachycardia, flushing, lassitude. In children in particular there may be convulsions, erythema and facial oedema. At higher doses, hypoxia, respiratory arrest, loss of consciousness, circulatory failure and pulmonary oedema may develop. Toxicity: Large individual variations. Tolerance development. Small children and the elderly are especially susceptible. A lethal dose for adults is estimated to be (0.5-)0.8-1 g. 20 mg in 24 hours to babies (3 kg) produced severe intoxication. 30 mg to an 11-month-old produced mild intoxication. At doses of > 5 mg/kg there is a risk of severe respiratory depression in children. 640 mg to an adult produced severe intoxication. Treatment: Treatment is symptomatic and aims to secure respiration. Naloxone is the antidote and corrects respiratory depression. However, naloxone cannot replace ventilation in severe intoxication. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Codeine, combinations excl. psycholeptics ATC code: N02AA59. Burana Comp is a combination analgesic containing ibuprofen and codeine, which are two analgesic substances with different mechanisms of action. Ibuprofen belongs to the group of non-steroidal anti-inflammatory/ antirheumatic drugs (NSAID). It contains 2-(4-isobutylphenyl) propionic acid called ibuprofen as its generic name. Ibuprofen has anti-inflammatory, analgesic, and anti-pyretic effect. The anti-inflammatory effect is comparable with the effect of acetylsalicylic acid and indomethacin. The pharmacologic properties of ibuprofen are thought to result from its ability to reduce prostaglandin synthesis. Ibuprofen prolongs bleeding time by reversible inhibition of thrombocyte aggregation. Ibuprofen inhibits the renal prostacyclin synthesis. This effect has not great importance in patients with normal renal function. In patients with chronic renal insufficiency, cardiac insufficiency or hepatic insufficiency and also in situations with changes in plasma volume the reduction of the prostaglandin synthesis may lead to acute renal insufficiency, fluid retention and heart failure (see section 4.3 and 4.4). 10

11 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 h before or within 30 min after immediate release aspirin dosing (81 mg), a decreased effect of ASA 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. Codeine is a centrally acting weak analgesic. Codeine exerts its effect through μ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain. 5.2 Pharmacokinetic properties Absorption Ibuprofen is rapidly absorbed from the gastrointestinal tract with a bioavailability of 80-90%. Peak serum concentrations occur one to two hours after administration of immediate release formulations. Studies including a standard meal show that food does not markedly affect total bioavailability. Codeine is readily absorbed from the gastro-intestinal tract. Also rectal absorption has been reported. Maximum concentration in plasma reaches a peak within one hour after oral administration Distribution Ibuprofen is extensively bound to plasma proteins (99%). Ibuprofen has a small volume of distribution being about l/kg in adults. Codeine has low plasma protein binding with 7-25% of codeine bound to plasma proteins. Codeine has been reported to have an apparent volume of distribution of 3-6 l/kg, indicating extensive distribution of the drug into tissues. Biotransformation Ibuprofen is rapidly metabolized in the liver through cytochrome P450, preferentially CYP2C9, to two primary inactive metabolites, 2-hydroxyibuprofen and 3-carboxyibuprofen. Following oral ingestion of the drug, slightly less than 90% of an oral dose of ibuprofen can be accounted for in the urine as oxidative metabolites and their glucuronic conjugates. Very little ibuprofen is excreted unchanged in the urine. Codeine undergoes metabolism in the liver. Approximately 5% to 10% of an administered dose is converted to morphine via CYP2D6, about 10% is converted to norcodeine via CYP3A4, and about 70% to 80% is metabolized to codeine-6-glucuronide by UDP-glucuronosyltransferase 2B7 and 2B4. The glucuronide metabolites of morphine are morphine-3-glucuronide and morphine-6-glucuronide. Morphine and morphine- 6-glucuronide are known to have analgesic activity in humans. The analgesic activity of codeine-6- glucuronide in humans is unknown. Norcodeine and morphine-3-glucuronide are generally not considered to possess analgesic properties. Due to polymorphism of CYP2D6, some individuals may be ultra-rapid metabolisers of codeine. In these individuals, codeine is converted into its active metabolite, morphine, more rapidly and completely than in other people, resulting in an increased analgesic effect. The prevalence of ultra-rapid metabolisers varies, and is estimated to be 0.5 to 1% in Chinese, Japanese, and Hispanics; 1 to 10% in Caucasians; 3% in African Americans; and 16 to 28% in North Africans, Ethiopians and Arabs. Patients that lack functional CYP2D6 genes or are poor metabolisers of codeine may experience impaired analgesic effects. The prevalence of poor metabolisers is 5 to 10% of the Caucasian population. Elimination Excretion of ibuprofen by the kidney is both rapid and complete. The elimination half-life is approximately 2 hours. The excretion of ibuprofen is virtually complete 24 hours after the last dose. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. Approximately 10% of codeine is excreted unmetabolised. The elimination half-life of codeine and its 11

12 metabolites in plasma is 3 to 4 hours after oral or intramuscular administration, but prolonged in patients with renal impairment and in the elderly. Codeine crosses the placenta into the circulation of the fetus. After high codeine doses codeine is excreted in breast milk at pharmacologically significant concentrations.. Special populations Elderly Given that no renal impairment exists, there are only small, clinically insignificant differences in the pharmacokinetic profile and urinary excretion between young and elderly. Children The systemic exposure of ibuprofen following weight adjusted therapeutic dosage (5mg/kg to 10 mg/kg bodyweight) in children aged 1 year or over, appears similar to that in adults. Children 3 months to 2.5 years appeared to have a higher volume of distribution (L/kg) and clearance (L/kg/h) of ibuprofen than did children >2.5 to 12 years of age. Renal impairment For patients with mild renal impairment increased plasma concentration of unbound (S)-ibuprofen, higher AUC values for (S)-ibuprofen and increased enantiomeric AUC (S/R) ratios as compared with healthy controls have been reported. In end-stage renal disease patients receiving dialysis the mean free fraction of ibuprofen was about 3% compared with about 1% in healthy volunteers. Severe impairment of renal function may result in accumulation of ibuprofen metabolites. The significance of this effect is unknown. The metabolites can be removed by haemodialysis (see sections 4.2, 4.3 and 4.4). The renal clearance of codeine and its metabolites is significantly reduced in patients with end-stage renal disease on regular haemodialysis therapy. Hepatic impairment Alcoholic liver disease with mild to moderate hepatic impairment did not result in substantially altered pharmacokinetic parameters of ibuprofen. In cirrhotic patients with moderate hepatic impairment (Child Pugh s score 6-10) treated with racemic ibuprofen an average 2-fold prolongation of the half-life was observed and the enantiomeric AUC ratio (S/R) was significantly lower compared to healthy controls suggesting an impairment of metabolic inversion of (R)-ibuprofen to the active (S)-enantiomer (see sections 4.2, 4.3 and 4.4). No formal studies have been conducted with codeine in patients with hepatic impairment. Codeine, however, undergoes biotransformation to active metabolites in the liver, and therefore it is expected that the disposition of codeine is affected in the presence of hepatic impairment. 5.3 Preclinical safety data There are no preclinical data considered relevant to clinical safety beyond data included in other sections of this Summary of product characteristics. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Microcrystalline cellulose 12

13 Povidone (k90) Carmellose calcium Silica, colloidal anhydrous Stearic acid Film-coating: Hypromellose (E464) Titanium dioxide (E171) Talc Paraffin, hard 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store in the original package in order to protect from light. 6.5 Nature and contents of container PVC / aluminum blisters in cartons. Pack sizes: 10, 20, 30, 50 and 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER Orion Corporation Orionintie 1 FI Espoo Finland 8. MARKETING AUTHORISATION NUMBER(S) [to be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [to be completed nationally] 10. DATE OF REVISION OF THE TEXT