Mybulen 200 Mg/10 Mg/350 Mg Film-Coated Tablets

MYBULEN is indicated for the relief of mild to moderate pain of inflammatory origin with or without fever for a maximum period of 5 days.

Posology
DO NOT EXCEED THE RECOMMENDED DOSAGE.
Use the lowest effective dose for the shortest possible duration of treatment.
Adults (over the age of 12 years): Take one to two tablets six hourly if necessary. Do not take more than 6 tablets in a 24-hour period. Consult your healthcare provider if you require further treatment after 5 days.
Paediatric population
Not recommended for children 12 years of age and younger.
Method of administration
For oral administration.

MYBULEN is contraindicated in:
u2022 Patients with hypersensitivity to ibuprofen, paracetamol, codeine or to any excipients in MYBULEN (see section 6.1).
u2022 Patients with a history of gastrointestinal bleeding, ulceration or perforation (PUBs) related to previous NSAIDs, including MYBULEN.
u2022 Patients with an active or a history of recurrent gastrointestinal ulcer, haemorrhage or perforations.
u2022 Patients with impaired hepatic and renal function (see section 4.4).
u2022 Patients with heart failure or cardiovascular disease.
u2022 Patients who are sensitive to aspirin or other non-steroidal anti-inflammatory medicine (NSAIDs).
u2022 Patients during an attack of bronchial asthma, uncontrolled asthma, acute asthma, bronchospasm or in heart failure secondary to chronic lung disease.
u2022 Patients with nasal polyps associated with aspirin-induced bronchospasm.
u2022 Patients with respiratory depression, especially in the presence of cyanosis and excessive bronchial secretion, after operations on the biliary tract, acute alcoholism, head injuries and conditions in which intracranial pressure is raised.
u2022 Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping such treatment (see section 4.5).
u2022 Patients who are receiving coumarin anticoagulants (see section 4.5).
u2022 Safety in lactation has not been established.
u2022 Women around 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/foetal renal dysfunction and premature closure of the foetal ductus arteriosus (see section 4.4 and 4.6).

Ibuprofen as in MYBULEN
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2).
Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with MYBULEN therapy (see section 4.3).
MYBULEN should only be administered under strict consideration of the benefit-risk ratio in the following conditions: Systemic Lupus Erythematosus (SLE) or mixed connective tissue diseases; congenital disturbance of porphyrin metabolism (e.g. acute intermittent porphyria).
Special care has to be taken in the following cases:
u2022 Hypertension
u2022 Disturbed haematopoiesis
u2022 Blood coagulation defects
u2022 Allergies, hay fever, chronic swelling of nasal mucosa, adenoids, chronic obstructive airway disease
u2022 Immediately after major surgical interventions
Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs, including MYBULEN, especially gastrointestinal bleeding, perforation or ulceration (PUBs), which may be fatal. Elderly patients are more likely to develop adverse hepatic or renal effects, and if gastrointestinal ulceration or bleeding occurs it is more likely to cause serious consequences.
Gastrointestinal bleeding, ulceration and perforation
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs, such as ibuprofen, as in MYBULEN, at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. The risk of gastrointestinal bleeding, perforation or ulceration (PUBs) is higher with increasing doses of MYBULEN, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), and the elderly. Patients with a history of gastrointestinal toxicity, particularly if elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medicines which could increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors or anti-platelet medicines such as acetylsalicylic acid (see section 4.5).
The use of ibuprofen, as in MYBULEN, with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the increased risk of ulceration or bleeding (see section 4.5). When gastrointestinal bleeding or ulceration occurs in patients receiving MYBULEN, treatment with MYBULEN should be stopped.
MYBULEN should be given with caution to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohnu2019s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia) as the condition may be exacerbated (see section 4.8).

Ibuprofen as in MYBULEN
Concomitant use of ibuprofen and the following medicines should be avoided:
Acetylsalicylic acid
Concomitant administration of ibuprofen, as in MYBULEN, and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects. Data suggest that ibuprofen, as in MYBULEN, 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 MYBULEN may reduce the cardio protective effect of low-dose acetylsalicylic acid cannot be excluded.
Other NSAIDs including cyclooxygenase-2 selective inhibitors
As a result of synergistic effects, the concurrent use of several NSAIDs can increase the risk of gastrointestinal ulcers and haemorrhage. Co-administration of ibuprofen, as in MYBULEN, with other NSAIDs should therefore be avoided (see section 4.4). Use of two or more NSAIDs concomitantly may result in an increase in side effects.
Anti-coagulants
MYBULEN may enhance the effects of anti-coagulants such as warfarin or heparin (see section 4.3 and 4.4).
Methotrexate
Increased and prolonged methotrexate plasma concentration and an increased risk of methotrexate toxicity. NSAID, such as ibuprofen, as in MYBULEN, inhibits the tubular secretion of methotrexate and certain metabolic interactions can occur resulting in decreased clearance of methotrexate. The administration of Ibuprofen within 24 hours before or after the administration of methotrexate can lead to an elevated concentration of methotrexate and an increase in its toxic effects. Therefore, concomitant use of MYBULEN and high doses of methotrexate should be avoided. Also, the potential risk of interactions in low dose treatment with methotrexate should be considered, especially in patients with impaired renal function. In combined treatment, renal function should be monitored.
Ibuprofen should be taken only with caution in combination with the following medicines:
Corticosteroids
Increased risk of gastrointestinal perforation, ulceration or bleeding (PUBs) (see section 4.4).

MYBULEN is not recommended for use by pregnant or breastfeeding women (see section 4.3 and 4.4).
Pregnancy
Ibuprofen as in MYBULEN
First trimester
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about 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.
Second and third trimester
During the third trimester of pregnancy, prostaglandin synthesis inhibitors, such as MYBULEN, may expose the foetus to:
u2022 cardiopulmonary toxicity (with premature closure of the foetal ductus arteriosus) in utero, and in persistent pulmonary hypertension of the newborn;
u2022 renal dysfunction, which may progress to renal failure with oligo-hydramniosis (see section 4.4);
At the end of pregnancy, the mother and the neonate may be exposed to:
u2022 possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
u2022 inhibition of uterine contractions resulting in delayed or prolonged labour (see section 4.4).
Because of these risks, the use of MYBULEN, dose and duration, between 20 and 30 weeks of gestation should be limited and avoided at around 30 weeks of gestation and later in pregnancy (see sections 4.3 and 4.4).
Codeine phosphate as in MYBULEN
MYBULEN contains codeine phosphate, a narcotic analgesic. Use of narcotic analgesics during pregnancy is associated with foetal adverse effects, which include physical dependence and withdrawal, retardation of growth, and neonatal respiratory depression with high doses.
Breastfeeding
Ibuprofen as in MYBULEN
Ibuprofen, as in MYBULEN, is excreted in the breast milk in low concentrations. With therapeutic doses during short term treatment the risk for influence on infant seems unlikely. If, however, longer treatment is prescribed, early weaning should be considered. MYBULEN should not be used during breastfeeding.
Codeine phosphate as in MYBULEN
MYBULEN contains codeine phosphate. Breastfed infants of mothers taking codeine may be at an increased risk of toxicity from its metabolite morphine.
Fertility
Ibuprofen as in MYBULEN
There is some evidence that medicines which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

MYBULEN has a minor influence on the ability to drive or use machines. Since adverse reactions such as dizziness, drowsiness and visual disturbances have been reported in patients receiving MYBULEN, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that MYBULEN does not adversely affect their ability to do so (see section 4.8).

a) Summary of the safety profile
Ibuprofen as in MYBULEN
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following administration. Gastritis has been observed, less frequently. Clinical studies suggest that use of ibuprofen, as in MYBULEN, particularly at a high dose (2 400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment, such as ibuprofen, as in MYBULEN. In view of the MYBULENu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients (see section 4.3 and section 4.4).
b) Tabulated list of adverse reactions
Ibuprofen as in MYBULEN
System organ class
Frequent
Less frequent
Frequency unknown (cannot be estimated from the available data)
Infections and infestations
Rhinitis, aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, nausea, vomiting, fever or disorientation.
Blood and the lymphatic system disorders
Haematopoietic disorders (leucopenia, pancytopenia, agranulocytosis, thrombocytopenia with or without purpura, aplastic anaemia, haemolytic anaemia, anaemia, neutropenia). The first symptoms or signs may include: fever, sore throat, surface mouth ulcers, flu-like symptoms, severe fatigue, nasal and skin bleeding, unexplained bleeding and bruising.
Immune system disorders
Hypersensitivity reactions such as fever, angioedema, urticaria, pruritus, purpura and exanthema as well as asthma attacks (sometimes with hypotension), severe hypersensitivity reactions. The symptoms may include: facial oedema, swelling of the tongue, internal laryngeal swelling with constriction of the airways, dyspnoea, tachycardia, fall of blood pressure to the point of life-threatening shock
Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea.
Psychiatric disorders
Confusional state, nervousness, insomnia, depression, anxiety, hallucination.
Nervous system disorders
Dizziness. Drowsiness, headache, somnolence, fatigue, agitation, irritability. Paraesthesia, vertigo
Eye disorders
Blurred vision, other ocular reactions, toxic amblyopia. Visual impairment, toxic optic neuropathy.
Ear and labyrinth disorders
Tinnitus. Impaired hearing.
Cardiac disorders
Heart failure may be precipitated in compromised patients, angina pectoris, cardiac dysrhythmias, palpitations, myocardial infarction, acute pulmonary oedema. Oedema, hypertension.
Respiratory, thoracic and mediastinal disorders
Bronchospasm. Alveolitis, pulmonary eosinophilia.
Gastrointestinal disorders
Heartburn, dyspepsia, abdominal cramps and pain, nausea, vomiting, flatulence, diarrhoea, constipation. Peptic ulceration, perforation or gastrointestinal bleeding, sometimes fatal; gastrointestinal ulcers, sometimes with bleeding and perforation, occult blood loss which may lead to anaemia, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohnu2019s disease, inflammatory bowel disease, complications of colonic diverticula (perforation, fistula), gastritis, oesophagitis, pancreatitis, intestinal strictures, bloating, decreased appetite.
Hepatobiliary disorders
Abnormalities of liver function tests, hepatitis, jaundice, liver dysfunction, liver damage, especially in long-term use, hepatic failure. Hepatotoxicity.
Skin and subcutaneous tissue disorders
Skin rash, pruritus. Photosensitivity reaction, severe forms of skin reactions (erythema multiforme, exfoliative dermatitis, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, necrotising fasciitis
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)/ Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE), Acute generalised exanthematous pustulosis (AGEP)
Renal and urinary disorders
Impairment of renal function, acute reversible renal failure, haematuria, renal papillary necrosis in long-term use, development of oedema especially in patients with arterial hypertension or renal insufficiency, nephritic syndrome, interstitial nephritis which can be associated with renal failure. Renal tubular acidosis
General disorders and administrative site conditions
Malaise
Investigations
Increase of blood urea nitrogen, serum transaminases and alkaline phosphatase, decrease in haemoglobin and haematocrit values, inhibition of platelet aggregation, prolonged bleeding time, decrease of serum calcium, increase in serum uric acid.

Treatment is symptomatic and supportive (see section 4.4).
Ibuprofen as in MYBULEN
Most patients who have ingested significant amounts of ibuprofen, as in MYBULEN, will manifest symptoms within 4 to 6 hours.
Symptoms
The most frequently reported symptoms of overdose include nausea, vomiting, abdominal pain, lethargy, blurred vision and drowsiness. Central nervous system (CNS) effects include headache, tinnitus, dizziness, convulsion, and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea, diarrhoea and depression of the CNS and respiratory system have also been reported. Disorientation, excitation, fainting and cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported. In cases of significant overdose, renal failure and liver damage are possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as vertigo, dizziness, drowsiness, occasionally excitation and loss of consciousness or coma. Children may also develop myoclonic cramps. In serious poisoning metabolic acidosis may occur, hypothermia and hyperkalaemia may also occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors.
Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8). Respiratory depression and cyanosis may occur. Exacerbation of asthma is possible in asthmatics.
Treatment
Treatment should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Within one hour of ingestion of a potentially toxic amount, oral administration of activated charcoal should be considered.
Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam or lorazepam. Other measures may be indicated by the patientu2019s clinical condition. If ibuprofen has already been absorbed, alkaline substances should be administered to promote the excretion of the acid ibuprofen in the urine. Bronchodilators should be given for asthma. No specific antidote is available.
Paracetamol as in MYBULEN
Prompt treatment is essential. In the event of an overdosage, consult a doctor immediately, or take the person to a hospital directly. A delay in starting treatment may mean that the antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed.
Susceptibility to paracetamol toxicity is increased in patients who have taken repeated high doses (greater than 5 to 10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of medicines that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine.
Symptoms
Symptoms of paracetamol overdose in the first 24 hours, include pallor, nausea, vomiting, anorexia and possibly abdominal pain. Mild symptoms during the first two days of acute poisoning do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours, or later after ingestion, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and international normalised ratio (INR) (prolongation of the prothrombin time). Liver damage may lead to encephalopathy, coma and death.
Acute renal failure with acute tubular necrosis may develop, even in the absence of severe liver damage. Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac dysrhythmias have been reported.
Treatment
N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible preferably within eight hours of overdosage, although treatment up to 36 hours after ingestion may still be of benefit, especially if more than 150 mg/kg of paracetamol was taken. An initial dose of 150 mg/kg N-acetylcysteine in 200 ml dextrose injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 ml dextrose injection over the next four hours, and then 100 mg/kg in 1 000 ml dextrose injection over the next sixteen hours. The volume of intravenous fluid should be modified for children. Although the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. A plasma paracetamol level should be determined four hours after ingestion in all cases of suspected overdosage. Levels done before four hours, unless high, may be misleading. Patients at risk of liver damage, and hence requiring continued treatment with N-acetylcysteine, can be identified according to their plasma paracetamol level. The plasma paracetamol level can be plotted against time since ingestion in the treatment nomogram below. The nomogram should be used only in relation to a single acute ingestion.
Those whose plasma paracetamol levels are above the u201cnormal treatment lineu201d, should continue N-acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the u201chigh risk treatment lineu201d. Prothrombin index correlates best with survival. Monitor all patients with significant ingestions for at least ninety-six hours.
Codeine phosphate as in MYBULEN
Symptoms
Respiratory depression is the most important feature of overdosage and occurs with circulatory failure and deepening coma. Pinpoint pupils, hypotension and hypothermia, excitement and convulsions, especially in children, and non-cardiogenic pulmonary oedema occur.
Treatment
Treatment of overdosage is symptomatic and supportive. Immediate attention should be given to maintaining adequate respiration. Naloxone should be given intravenously in a dose of 0,4 mg every 2 to 3 minutes until improvement occurs or to a maximum of 10 mg. Children may be given 0,01 mg/kg initially followed by a dose of 0,1 mg/kg.