Mybulen Capsules 200 mg/ 10 mg/ 250 mg Capsules

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

Posology
DO NOT EXCEED THE RECOMMENDED DOSE. Use the lowest effective dose for the shortest possible duration of treatment.
Adults (over the age of 12 years)
Take one to two capsules 4 hourly. Do not take more than 6 capsules in a 24 hour period. Consult your healthcare provider if you require further treatment after 5 days. MYBULEN CAPSULES should not be administered continuously for longer than 5 days as safety has not been established.
Paediatric population
Not recommended for children 12 years of age and younger.
Method of administration
For oral administration.

MYBULEN CAPSULES are contraindicated in:
u2022 Patients with hypersensitivity to ibuprofen, paracetamol, codeine, or to any excipients in MYBULEN CAPSULES (see section 6.1).
u2022 Patients who are sensitive to aspirin or other NSAIDs.
u2022 Patients with a history of gastrointestinal ulceration, bleeding or perforation (PUBs) related to previous NSAIDs, including MYBULEN CAPSULES.
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 during an attack of bronchial asthma, uncontrolled 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 Diarrhoea associated with pseudomembranous colitis.
u2022 Safety in lactation has not been established (see section 4.6).
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
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 CAPSULES therapy (see section 4.3). MYBULEN CAPSULES 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 CAPSULES, especially gastrointestinal ulceration, bleeding and perforation (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 CAPSULES, at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.
The risk of gastrointestinal bleeding, ulceration or perforation (PUBs) is higher with increasing doses of MYBULEN CAPSULES, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. Patients with a history of gastrointestinal toxicity, particularly when 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 CAPSULES, 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 CAPSULES, treatment with MYBULEN CAPSULES should be stopped. MYBULEN CAPSULES 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 these conditions may be exacerbated (see section 4.8).

Ibuprofen
Concomitant use of ibuprofen and the following medicines should be avoided:
Acetylsalicylic acid
Concomitant administration of ibuprofen, as in MYBULEN CAPSULES, and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects. Data suggest that ibuprofen, as in MYBULEN CAPSULES, 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 CAPSULES 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 CAPSULES, 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 CAPSULES may enhance the effects of anti-coagulants such as warfarin or heparin (see section 4.3 and 4.4).

MYBULEN CAPSULES are not recommended for use by pregnant or breastfeeding women (see section 4.3 and 4.4).
Pregnancy
Ibuprofen
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 CAPSULES, 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 CAPSULES, 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
MYBULEN CAPSULES 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.
Paracetamol
Paracetamol as part of a combination medicine, as contained in MYBULEN CAPSULES, should not be taken. Frequent use of paracetamol in late pregnancy may be associated with an increased risk of persistent wheezing in the infant which may persist into childhood.
Breastfeeding
Ibuprofen
Ibuprofen, as in MYBULEN CAPSULES is excreted in the breast milk in very low concentrations. With therapeutic doses during short term treatment the risk for influence on the infant seems unlikely. If, however, longer treatment is prescribed, early weaning should be considered. MYBULEN CAPSULES should not be used during breastfeeding.
Codeine phosphate
MYBULEN CAPSULES contains codeine phosphate. Breastfed infants of mothers taking codeine may be at an increased risk of toxicity from its metabolite morphine.
Fertility
Ibuprofen
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 CAPSULES 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 CAPSULES, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that MYBULEN CAPSULES does not adversely affect their ability to do so (see section 4.8).

a) Summary of the safety profile
Ibuprofen: 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. Less frequently, gastritis has been observed. Clinical studies suggest that use of ibuprofen, as in MYBULEN CAPSULES, particularly at a high dose (2400 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 CAPSULES. In view of MYBULEN CAPSULESu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients (see section 4.4).
b) Tabulated list of adverse reactions
Ibuprofen
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 (leukopenia, 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 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
Eye disorders
Blurred vision, other ocular reactions, toxic amblyopia
Visual impairment, toxic optic neuropathy
Ear and labyrinth disorders
Tinnitus
Impaired hearing, vertigo
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
Gastrointestinal disorders
Heartburn, dyspepsia, abdominal cramps and pain, nausea, vomiting, flatulence, diarrhoea, constipation, gastric irritation
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, Crohnu2019s disease and inflammatory bowel disease, complications of colonic diverticula (perforation, fistula), gastritis, bloating, decreased appetite, oesophagitis, pancreatitis, intestinal strictures
Hepatobiliary disorders
Abnormalities of liver function tests, hepatitis, jaundice, liver dysfunction, liver damage, especially in long-term use, hepatic failure
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), Acute generalised exanthematous pustulosis (AGEP)
Renal and urinary disorders
Impairment of renal function, acute renal failure, renal papillary necrosis in long-term use; development of oedema especially in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis which can be associated with renal failure
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
Paracetamol
System organ class
Frequent
Less frequent
Frequency unknown (cannot be estimated from the available data)
Blood and the lymphatic system disorders
Haematological reaction (including agranulocytosis, thrombocytopenia, neutropenia, pancytopenia, leukopenia)
Hepatobiliary disorders
Hepatitis
Skin and subcutaneous tissue disorders
Hypersensitivity reactions resulting in reversible skin rash (which may be accompanied by fever and mucosal lesions) or blood disorders
Renal and urinary disorders
Renal colic, renal failure
Codeine phosphate
System organ class
Frequent
Less frequent
Frequency unknown (cannot be estimated from the available data)
Nervous system disorders
Confusion, drowsiness, restlessness, changes in mood, vertigo, raised intracranial pressure
Eye disorders
Miosis
Cardiac disorders
Bradycardia, palpitations, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Respiratory depression
Gastrointestinal disorders
Nausea, vomiting, constipation, dry mouth
Hepatobiliary disorders
Biliary spasm
Skin and subcutaneous tissue disorders
Sweating, facial flushing, urticaria, pruritus
Renal and urinary disorders
Micturition difficulties, ureteric spasm
General disorders and administrative site conditions
Hypothermia
c) Description of selected adverse reactions
Ibuprofen
Acute reversible renal failure has been reported. Hypersensitivity reactions have been reported following treatment with ibuprofen, as in MYBULEN CAPSULES. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or (c) assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme). The pathogenic mechanism of medicine-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 medicine intake, and disappearance of symptoms after medicine discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen, in patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

Symptoms
The most frequently reported symptoms of overdose for the ingredients as contained in MYBULEN CAPSULES are mentioned below.
Ibuprofen
Most patients who have ingested significant amounts of ibuprofen, as in MYBULEN CAPSULES, will manifest symptoms within 4 to 6 hours. Symptoms such as 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. Large overdoses are generally well tolerated when no other medicines are being taken. 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. Respiratory depression and cyanosis may occur. Exacerbation of asthma is possible in asthmatics.
Paracetamol
Symptoms of paracetamol overdosage 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 of paracetamol, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentrations 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. Cerebral oedema and non-specific myocardial depression have occurred.
Codeine phosphate
Symptoms of overdosage include excitement and, in children, convulsions may occur. Symptoms may result in central nervous system and respiratory depression with hypoxia, hypotension, shock, gastric hypomotility with ileus, and non-cardiogenic pulmonary oedema. The opiate intoxication syndrome is described as a triad of depressed level of consciousness, miotic pupils, and decreased frequency and depth of respirations.
Treatment
The following treatment is indicated for the ingredients as contained in MYBULEN CAPSULES
Prompt treatment is essential as MYBULEN CAPSULES contains paracetamol.
Ibuprofen
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. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. 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 patient's 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
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. Although evidence is limited it is recommended that an adult person who has ingested 5 to 10 grams or more of paracetamol (or a child who has had more than 140 mg/kg) within the preceding four hours, should have the stomach emptied by lavage (emesis may be adequate for children) and a single dose of 50 g activated charcoal given via the lavage tube. Ingestion of amounts of paracetamol smaller than this may require treatment in patients susceptible to paracetamol poisoning (see above). In patients who are stuperose or comatose, endotracheal intubation should precede gastric lavage in order to avoid aspiration. 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 1000 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 as a 5 % solution 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
Treatment of overdosage is symptomatic and supportive. Treatment is based on clinical presentation. Plasma codeine levels are not clinically useful. Support the respiratory and cardiovascular function. Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests and chest x-ray in patients with significant exposure. Consider pre-hospital administration of activated charcoal as aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Use a minimum of 240 millilitres of water per 30 grams charcoal. Optimum dose has not been established, but the usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight); and 1 gram/kilogram in infants up to 1 year old. Consider naloxone as an antidote in patients with a decreased level of consciousness. The most frequently recommended initial naloxone dose for codeine overdose is 0.4 to 2 milligrams given as an intravenous bolus in both children and adults. This dose can also be given subcutaneously in the absence of intravenous access, or intratracheally.