QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains

Active ingredient:  

Paracetamol  500mg, Codeine phosphate 30mg  

Inactive ingredient:  

Cellulose – microcrystalline, Gelatin, Magnesium stearate, Starch – Wheat, Talc – purified

PHARMACODYNAMIC PROPERTIES

Paracetamol has analgesic and antipyretic activity similar to aspirin. The analgesic effect of paracetamol is thought to be due to inhibition of prostaglandin synthesis in the central nervous system and in the periphery, and, to a lesser extent, by blocking pain impulse generation in the periphery.  The antipyretic effect is due to a central action on the hypothalamic heat-regulating centre to produce peripheral vasodilatation and subsequent heat loss.

Codeine phosphate is an opioid analgesic that binds with stereospecific receptors at many sites within the CNS to alter processes affecting both the perceptions of pain and the emotional response to pain.  There are multiple sub-types of opioid receptors, each mediating various therapeutic and/or side effects of drugs.  Its analgesic effect is thought to be due to its partial metabolic conversion to morphine.  Codeine has about one-sixth the analgesic activity of morphine.  Codeine can also cause other effects eg CNS depression, nausea and vomiting, orthostatic hypotension and constipation.

It has been shown that the analgesic effects of paracetamol and codeine are additive due to their different mechanisms of action.

PHARMACOKINETIC PROPERTIES

Absorption

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring some 30 minutes to 2 hours after ingestion.  The onset of therapeutic action is 30 minutes and the duration of effect is 4 hours.

Codeine is well absorbed from the gastrointestinal tract and peak plasma concentrations are reached one hour after oral administration.  Onset of action occurs in 15-30 minutes and analgesia is maintained for 4-6 hours.

Distribution

Paracetamol is rapidly and uniformly distributed into most body tissues.  It crosses the placenta and is present in breast milk.

Codeine is rapidly distributed to skeletal muscle, kidneys, liver, gastrointestinal tract, lungs, spleen and brain.  It crosses the placenta and is distributed in low levels in breast milk.

Metabolism

Approximately 90-95% of the paracetamol dose is metabolised in the liver, primarily by conjugation with glucuronic acid, sulphuric acid and cysteine. An intermediate metabolite which may accumulate in overdosage is hepatotoxic and possibly nephrotoxic.

Codeine is metabolised mainly in the liver. The major metabolic pathway involves glucuronidation of codeine to codeine-6-glucuronide. Codeine can also undergo O- and N-demethylation catalysed by CYP2D6 and CYP3A4 respectively. Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite. About 10% of an administered dose of codeine is converted by O-demethylation to morphine which subsequently undergoes glucuronidation to morphine-3 or morphine-6 glucuronide, or N-demethylation to normorphine. Approximately 5-10% of the Caucasian population cannot convert codeine to morphine as they are deficient in the CYP2D6 enzyme.  Codeine is also converted by N-demethylation to norcodeine which subsequently undergoes glucuronidation to norcodeine glucuronide or O-demethylation to normorphine.

Excretion

Approximately 85% of a dose of paracetamol is recovered from the urine within 24 hours after ingestion.  About 5% is unchanged, the balance consisting mainly of the glucuronide and sulfate conjugates.  The elimination half-life varies from 1 to 4 hours and may be prolonged in acute overdosage, in liver disease, the elderly and the neonate.

Codeine is excreted mainly by the kidneys as its metabolite codeine-6-glucuronide. 5-25% is excreted unchanged and approximately 10% is excreted as unchanged or conjugated morphine. The plasma half-life of codeine is 2-4 hours. Only traces of codeine and its metabolites are found in the faeces.

THERAPEUTIC INDICATIONS

Codalgin Forte is indicated for the relief of moderate to severe pain which does not respond to milder analgesics.

POSOLOGY AND METHOD OF ADMINISTRATION

Adults:  One to two tablets to be taken with water; repeat in four hours if necessary. Do not exceed 8 tablets per day.

Children:  For children, the dose of codeine is 0.5 mg/kg.  Codalgin Forte contains 500 mg of paracetamol and 30 mg of codeine phosphate per tablet. The usual dose for children 7-12 years is half a tablet to be taken with water; repeated in four hours if necessary. Do not exceed 3 tablets per day. Codalgin Forte is not suitable for use in children under 7 years of age.

CONTRAINDICATIONS

Paracetamol should not be used in patients with active alcoholism as chronic excessive alcohol ingestion predisposes patients to paracetamol hepatotoxicity.

Paracetamol should not be used in patients with a history of intolerance to the drug.

Codeine should not be used in cases of acute respiratory depression (eg acute asthma, acute exacerbations of chronic obstructive pulmonary disease) since codeine may exacerbate the condition.

Codalgin Forte should not be used in patients with a past history of allergic reactions to codeine.

Hypersensitivity to any of the tablet excipients.

Due to codeine’s structural similarity to morphine and oxycodone, patients experiencing systemic allergy (generalised rash, shortness of breath) to these drugs should not receive codeine.

Codeine is contraindicated in patients with diarrhoea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract, or diarrhoea associated with pseudomembranous colitis caused by antibiotic administration since codeine may slow the elimination of the toxic material or antibiotic.

Children under 18 years old has made ​​tonsillectomy and / or VA tricks

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Codalgin Forte should be given with care to patients with impaired renal or hepatic function, viral hepatitis, and to patients taking other drugs which affect the liver. In view of the increased risk of hepatotoxicity, the benefit should be weighed against the risk when administering Codalgin Forte to patients with viral hepatitis or pre existing hepatic disease.  In such patients, hepatic function determinations may be required at periodic intervals during high dose or long-term therapy.

Codeine should be used with caution in patients with a history of drug abuse or with recent gastrointestinal tract surgery.

Codalgin Forte may cause drowsiness and/or dizziness. Those affected should not drive or operate machinery.

Physical and/or psychological dependence may occur with the repeated administration of codeine.  Tolerance may also result following repeated administration.

Codeine should be administered with great caution in patients with head injury, brain tumour or increased intracranial pressure since codeine may increase the risk of respiratory depression and further elevate intracranial pressure.  In addition codeine can produce side effects such as confusion, miosis and vomiting which are important signs in following the clinical course of patients with head injuries.

Codeine should be administered with great caution in patients with decreased respiratory reserve (eg in emphysema, kyphoscoliosis, hypoxia, hypercapnia or even severe obesity) or cor pulmonale, or chronic obstructive pulmonary disease since codeine may exacerbate respiratory impairment.

Codeine should be administered with great caution if at all in patients with CNS depression, since codeine may exacerbate the condition. Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression. Codeine should be administered with caution in patients with acute abdominal conditions since codeine may obscure the diagnosis or the course of the disease. Codeine should be administered with caution in patients with severe inflammatory bowel disease (risk of toxic megacolon may be increased, especially with repeated dosing). Codeine should be administered with caution in patients with hypothyroidism, adrenocortical insufficiency (eg Addison’s disease), shock, myxedema, acute alcohol intoxication or delerium tremens since codeine may exacerbate the symptoms or increase the risk of respiratory and/or CNS depression. Codeine should be administered with caution in patients taking Monoamine Oxidase Inhibitors (MAOI’s). Codeine should be administered with caution in patients with a history of convulsive disorders (convulsions may be induced or exacerbated by codeine).

Codeine should be administered with caution in patients with prostatic hypertrophy, urethral stricture or recent urinary tract surgery since codeine may cause urinary retention.

Due to the risk of respiratory failure, only use the codeine-containing drugs for acute pain relief in moderate to children over 12 years while the other painkillers such as paracetamol and ibuprofen are not effective.

Codeine should be used at the lowest dose that effectively and in the shortest time.

Not recommended for use codeine for children with problems related to breathing (eg, shortness of breath or wheezing when sleeping, …)

Exercise caution when using codeine for children under 12 years (due to research information about the influence of the drug for this object is limited).

Exercise caution when using medicines for breastfeeding women (drug may be excreted into breast milk).

USE IN CHILDREN:

Codalgin Forte can be given in reduced doses to children over the age of 7 years.  This medication is not suitable for children under 7 years of age.

USE IN THE ELDERLY:

The elderly are more likely to have age-related renal impairment and may be more susceptible to the respiratory effects of opioid analgesics. Dose reduction may be required.

INTERACTIONS WITH OTHER DRUGS

Salicylates and NSAIDs:

Prolonged concurrent use of paracetamol and salicylates or non-steroidal anti-inflammatory drugs may increase the risk of adverse renal effects.

Diflusinal:

Diflunisal may increase the plasma concentrations of paracetamol by 50%.

General anaesthetics:

Codeine may potentiate the effects of general anaesthetics.

Tranquillisers, sedatives and hypnotics:

Codeine may potentiate the effects of these drugs.

CNS depressants:

Codeine may potentiate the effects of CNS depressants.

Alcohol:

Codeine may potentiate the effects of alcohol and the likelihood of toxicity may be increased by its concomitant use

Opioid analgesics:

Concurrent use of codeine and other opioid agonists is usually inappropriate as additive CNS depression, respiratory depressant and hypotensive effects may occur.

Anticholinergics:

Concomitant use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention.

Monoamine Oxidase Inhibitors:

Non-selective MAOI’s intensify the effects of opioid drugs which can cause anxiety, confusion and significant respiratory depression.  Severe and sometimes fatal reactions have occurred in patients concurrently administered MAO inhibitors and pethidine. Codeine should not be given to patients taking non-selective MAOI’s or within 10 days of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOI’s (Reversible Inhibitors of Monoamine Oxidase A) and codeine, caution is advised with this drug combination.

Barbiturates and antiepileptic medications:

The likelihood of toxicity may be increased by the concomitant use of enzyme inducing agents such as alcohol, barbiturates or anti epileptic drugs.

Coumarins:

Repeated high doses of paracetamol increase the anti coagulant response to coumarins

Chloramphenicol:

Paracetamol may also increase chloramphenicol concentrations.

Antihypertensives:

Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and lead to orthostatic hypotension.

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide):

Concurrent use of these agents with codeine may increase the risk of severe constipation.

Metoclopramide:

Codeine may antagonise the effects of metoclopramide on gastrointestinal motility.

Neuromuscular blocking agents:

Codeine may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.

Cholestyramine:

Cholestyramine reduces the absorption of paracetamol if given within one hour of paracetamol administration.

USES IN PREGNANCY AND LACTATION

Use in Pregnancy:

Paracetamol crosses the placenta, however problems in humans have not been documented.

Opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. Administration of codeine during labour may cause respiratory depression in the newborn infant.

Use in Lactation:

Paracetamol is excreted in breast milk but neither paracetamol nor its metabolites were detected in the urine of nursing infants after 650 mg maternal dose.

Codeine does pass into breast milk so it should be avoided in breastfeeding women.

Codalgin Forte  tablets should not be administered while breast-feeding.

EFFECTS ON ABILITY TO DRIVE AND OPERATE MACHINES

Codalgin Forte may cause drowsiness and/or dizziness. Those affected should not drive or operate machinery.

UNDESIRABLE EFFECTS

Adverse effects of Codalgin Forte are generally infrequent and include:

Haematologic

Less frequent to rare	Agranulocytosis
	Anaemia
	Thrombocytopenia

Genitourinary

Less frequent to rare	Renal failure
	Uraemia
	Urinary retention or hesitance

Hypersensitive

Less frequent to rare	Skin rashes and other allergic reactions
	Histamine release (hypotension, flushing of the face, tachycardia, breathlessness)

Gastrointestinal

Common	Constipation
	Nausea
	Vomiting

Neurological

Common	Drowsiness
	Dizziness
Less frequent to rare	Euphoria, dysphoria
	At higher doses codeine may cause respiratory depression

Inform doctors with side effects when using medicine.

OVERDOSAGE

Overdosage with Codalgin tablets involves treatment of both paracetamol and codeine poisoning.

Symptoms:

Paracetamol:

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may proceed to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop in the absence of severe liver damage. Cardiac arrhythmias have been reported.  Liver damage is likely in adults who have taken 10 g or more of paracetamol, due to excess quantities of a toxic metabolite becoming irreversibly bound to liver tissue.

Codeine:

Symptoms of codeine overdosage include vomiting, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis, miosis and coma.

STORAGE: Protect from sunlight and moisture, Store below 30ºC.

HOW SUPPLIED: Box of 2 blisters x 10 tablet.

EXPIRY: 4 years from the manufacturing date.

SPECIFICATION: Manufacturer

WARNING:

Read carefully the leaflet before use.

For further information, please contact your doctor.

Keep out of reach of children.

Manufactured by

ASPEN PHARMA PTY LTD