INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo MYBULEN CAPSULES

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

MYBULEN CAPSULES

COMPOSITION
Each capsule contains:

Ibuprofen 200,0 mg
Paracetamol 250,0 mg
Codeine Phosphate 10,0 mg

PHARMACOLOGICAL CLASSIFICATION:
A 2.8 Analgesic combinations.

PHARMACOLOGICAL ACTION:
Paracetamol has analgesic and antipyretic effects. Ibuprofen has analgesic, antipyretic and anti-inflammatory activities.
Ibuprofen exerts its anti-inflammatory action peripherally in inflamed tissue by reducing prostaglandin activity and by inhibiting synthesis and/or actions of other local mediators of the inflammatory response.
Codeine is metabolised to morphine, which in turn, exerts an analgesic effect.
Pharmacokinetics:
Paracetamol: Absorption following oral administration is rapid and almost complete.
Paracetamol is metabolised in the liver primarily by conjugation.
Paracetamol has a half-life of 1 to 4 hours, time to peak concentration of 0.5 to 2 hours, time to peak effect of 1 to 3 hours and a duration of action of 3 to 4 hours.
Paracetamol is renally excreted primarily as metabolites and 3% of a dose may be excreted unchanged.
Ibuprofen: Rapidly absorbed after oral administration. Onset of action for pain relief is 30 minutes and the time for peak effect for fever is 2 to 4 hours. The half-life of ibuprofen is about 2 hours and the duration of action for fever is 6 to 8 hours or more and is 4 to 6 hours for pain. More than 90% of an ingested dose is excreted in the urine as metabolites or their conjugates.
Codeine: Readily absorbed from the gastrointestinal tract. Half-life is 2.5 to 4 hours. Codeine is metabolised in the liver. The cytochrome P450 enzyme 2D6 converts codeine to morphine, one of its metabolites. About 10% of the dose is demethylated to morphine. Onset of action is 30 to 45 minutes. The time to peak effect is 1 to 2 hours. Duration of action is 4 hours. Codeine is eliminated via the kidneys.

INDICATIONS:
MYBULEN CAPSULES are indicated for the relief of mild to moderate pain of inflammatory origin with or without fever.

CONTRA-INDICATIONS
Allergy to any of the ingredients of MYBULEN CAPSULES.
Acute respiratory depression.
Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of stopping such treatment (SEE INTERACTIONS).
Diarrhoea associated with pseudomembranous colitis.
Severe liver impairment.
Peptic ulcer disease or gastrointestinal bleeding.
Patients sensitive to aspirin or other nonsteroidal anti-inflammatory medicines.
Uncontrolled asthma or bronchospasm.
Nasal polyps associated with aspirin-induced bronchospasm.
Patients with bleeding disorders.

WARNINGS
MYBULEN CAPSULES should be used with caution in the following:
Acute abdominal conditions - Diagnosis or clinical course may be obscured.
Acute asthma attack or respiratory impairment or disease - May decrease respiratory drive and increase airway resistance in these patients.
Cardiac arrhythmias - May be induced or exacerbated.
Convulsions or history thereof - May be induced or exacerbated.
Alcoholism, drug abuse or dependence - Patient is predisposed to drug abuse.
Gallbladder disease or gallstones - May cause biliary tract spasm.
Recent gastrointestinal tract surgery.
Head injury, increased intracranial pressure or intracranial lesions - Risk of respiratory depression and further increase in intracranial pressure. MYBULEN CAPSULES may also cause sedation and pupillary changes that may obscure the clinical course of head injury.
Hepatic function impairment - MYBULEN CAPSULES are metabolised in the liver.
Renal function impairment - MYBULEN CAPSULES may cause urinary retention. Also as the metabolites are excreted via the kidneys, renal impairment may lead to accumulation resulting in an increase in adverse effects.
Hypothyroidism - Increased risk of respiratory depression and prolonged central nervous system depression.
Adrenocortical insufficiency.
Inflammatory or obstructive bowel disorders 1,3 - Risk of toxic megacolon may be increased.
Prostatic hypertrophy, obstruction, urethral stricture or recent urinary tract surgery - as urinary retention may be precipitated by MYBULEN CAPSULES.
Elderly or debilitated patients - Dosage should be reduced.
Dosages of MYBULEN CAPSULES in excess of those recommended may cause severe liver damage.

In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately.

MYBULEN CAPSULES should be used with caution in the following conditions:
Alcoholism or impaired liver function - Increased risk of hepatotoxicity.
Renal function impairment - Increased risk of adverse effects with prolonged use of high doses, occasional use is acceptable.
The antipyretic, analgesic and anti-inflammatory action of MYBULEN CAPSULES may mask symptoms of the occurrence of worsening of infection.
MYBULEN CAPSULES should be used with caution in the following:
Conditions predisposing to and exacerbated by fluid retention such as compromised cardiac function, congestive heart disease, pre-existing oedema, hypertension and renal function impairment - MYBULEN CAPSULES may cause fluid retention and oedema.
Inflammatory or ulcerative disease of the upper or lower gastrointestinal tract.
Asthma - May be exacerbated.
Allergic conditions - Possibility of cross sensitivity.
Anaemia - May be exacerbated.
Bleeding disorders - Increased risk of bleeding.
Hepatic function impairment - Increased risk of hepatotoxicity.
Renal function impairment - Renal failure may be provoked, especially in patients with pre-existing renal impairment.

INTERACTIONS
MAOIs - Possible severe and sometimes fatal reactions may occur. (See CONTRA-INDICATIONS)
Alcohol or central nervous system depressants - Depressant effects are enhanced.
Anticholinergics - Increased risk of severe constipation.
Antidiarrhoeals - Increased risk of severe constipation and central nervous system depression.
Hypotension-producing medications - Hypotensive effects may be potentiated.
Hepatotoxic medicines - Increased risk of hepatoxicity.
Enzyme inducing medicines - Increased risk of hepatoxicity. Possible decrease in therapeutic effects of paracetamol.
Metoclopramide - Absorption of paracetamol may be accelerated.
Probenecid - Excretion of paracetamol may be affected and plasma concentrations altered.
Cholestyramine - Absorption of paracetamol is reduced if given within one hour of cholestyramine.
Anticoagulants - Enhancement of anticoagulant effect and the possibility of gastrointestinal ulceration or bleeding.
Alcohol, corticosteroids, clopidogrel, ticlopidine, bisphosphonates, oxpentifylline - Increased risk of gastrointestinal bleeding and ulceration.
Antidiabetic agents - Hypoglycaemic effects of these medicines may be increased.
Digoxin - Increase in serum digoxin concentrations.
Lithium - Increase in the steady-state concentration of lithium.
Methotrexate - Increased and prolonged methotrexate plasma concentration and an increased risk of methotrexate toxicity.
Nephrotoxic medicines e.g. ciclosporin - Increased risk of nephrotoxicity.
Antihypertensives or diuretics - Reduction or reversal of the antihypertensive effect may occur.
Bone marrow depressants - The leucopenic and/or thrombocytopenic effects of these medicines may be increased.
PREGNANCY AND LACTATION
Safety and efficacy in pregnancy and lactation has not been established.

DOSAGE AND DIRECTIONS FOR USE
DO NOT EXCEED THE RECOMMENDED DOSE.
Not recommended for children under twelve years of age.
Adults: 1 to 2 capsules 4 hourly. Do not take more than 12 capsules in 24 hours.
MYBULEN CAPSULES should not be administered continuously for longer than 4 days as safety has not been established.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects:
IBUPROFEN
Frequent:
Skin: Skin rash, pruritus.
Neurological: Dizziness.
Less frequent:
Haematological: Agranulocytosis, thrombocytopenia.
Cardiovascular: Heart failure may be precipitated in compromised patients, angina pectoris, cardiac arrhythmias.
Neurological: nervousness, depression, drowsiness, insomnia, headache.
Gastrointestinal: Peptic ulceration, gastro-intestinal bleeding, dyspepsia, nausea, abdominal cramps and pain, bloating, constipation, decreased appetite, diarrhoea.
Kidney/Genitourinary: Impairment of renal function, acute reversible renal failure, oedema.
Liver: Abnormalities of liver function tests.
Ocular: Blurred vision and other ocular reactions.
Other: Tinnitis, hypersensitivity reactions.
PARACETAMOL
Less frequent:
Haematological: Haematological reaction (including thrombocytopenia, leucopenia, pancytopenia, neutropenia and agranulocytosis). '5f
Kidney/Genitourinary: Renal colic, renal failure.
Liver: Hepatitis.
Other: Sensitivity reactions resulting in reversible skin rash (which may be accompanied by fever and mucosal lesions) or blood disorders.
CODEINE PHOSPHATE
Less frequent:
Cardiovascular: Bradycardia, palpitations, orthostatic hypotension.
Neurological: Confusion, vertigo, restlessness, changes in mood, hypothermia, raised intracranial pressure, drowsiness.
Gastrointestinal: Nausea, vomiting, constipation, dry mouth.
Kidney/Genitourinary: Micturition difficulties, ureteric or biliary spasm.
Ocular: Changes in myosis.
Respiratory: Respiratory depression.
Skin: Sweating, facial flushing, urticaria, pruritus.
SPECIAL PRECAUTIONS:
Avoid alcohol (See DRUG INTERACTIONS)
May cause drowsiness; ability to perform skilled tasks, drive or operate machinery may be impaired.
DEPENDENCE MAY DEVELOP WITH PROLONGED USE OF HIGH DOSES.
If taking for pain, including arthritic pain, and the pain persists for longer than 10 days, or if taking for fever and the fever persists for longer than 3 days or if the condition deteriorates or new symptoms develop, the doctor needs to be contacted as additional treatment may be necessary.
Avoid alcohol - Increased risk of liver toxicity, especially in alcoholics with high doses and prolonged use.
Diabetic patients may experience false results with blood glucose tests.
Elderly patients - These patients are more likely to develop adverse hepatic or renal effects and if gastrointestinal ulceration or bleeding occurs is more likely to cause serious consequences.
Surgery - Possible enhanced bleeding if surgery is required.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS AND SPECIAL PRECAUTIONS)
PARACETAMOL:
{for NORMOGRAM please see original Package Insert}
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 5-10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of drugs that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine.
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.
Symptoms of ibuprofen overdose: Gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting) central nervous system symptoms (e.g. lethargy, drowsiness), gastrointestinal haemorrhage, acute renal failure, convulsions and coma.
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 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 arrhythmias have been reported.
Cerebral oedema and non-specific myocardial depression have occurred.
Treatment of overdose:
Although evidence is limited it is recommended that an adult who has ingested 5-10 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, endotrachael 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. If activated charcoal is used then it should be removed by gastric lavage as it may interfere with absorption of orally administered acetylcysteine and decrease its efficacy.
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 normogram.
Those whose plasma paracetamol levels are above the “normal treatment line”, 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 “high risk treatment line”.
Prothrombin index correlates best with survival. Monitor all patients with significant ingestions for at least ninety-six hours.
CODEINE
Codeine overdose 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 respirations.
Treatment is based more on clinical presentation than on specific laboratory data, except when complications have occurred.
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.
Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
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.

IDENTIFICATION
A size “0”capsule shell with a blue cap and blue body containing a white to off-white, compacted powder.

PRESENTATION
Polypropylene securitainers containing a silica gel sachet, and foam insert, closed with a PE cap containing 30 and 100 capsules.

STORAGE
Store below 25°C in tightly closed containers. Protect from moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
A38/2.8/0527

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF PACKAGE INSERT
16 March 2005

        68459574985/050322
        UNIPRINT

New addition to this site: September 2005
Source: Pharmaceutical Industry

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