Active ingredients: Paracetamol Codeine phosphate. Chemical names: N-(4-Hydroxyphenyl)acetamide 4,5a-epoxy-3-methoxy-17-methyl-7,8-

Transcription

1 Codapane Paracetamol / Codeine phosphate PRODUCT INFORMATION NAME OF THE MEDICINE Active ingredients: Paracetamol Codeine phosphate Chemical names: N-(4-Hydroxyphenyl)acetamide 4,5a-epoxy-3-methoxy-17-methyl-7,8- Structural formulas: didehydromorphinan-6a-ol phosphate Molecular formulas: C 8 H 9 NO 2 C 18 H 21 NO 3,H 3 PO 4,½H 2 O Molecular weights: CAS Registry No: DESCRIPTION Paracetamol is a white, crystalline powder, sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. Codeine phosphate is a white, crystalline powder or small, colourless crystals, freely soluble in water, slightly soluble in alcohol, practically insoluble in ether. Each tablet contains the active ingredients paracetamol 500 mg and codeine phosphate 8 mg. The tablets also contain the following inactive ingredients; crospovidone, silica - colloidal anhydrous, stearic acid, magnesium stearate and sodium lauryl sulfate. The tablets are sugar-free, lactose-free and gluten-free. PHARMACOLOGY Paracetamol is a para-aminophenol derivative that exhibits analgesic and antipyretic activity. It does not possess anti-inflammatory activity. Codeine phosphate is an opioid analgesic which binds with stereo-specific receptors at many sites within the central nervous system. It alters processes affecting both the perception of pain and the emotional response to pain. Codeine has about one-sixth the analgesic activity of morphine.

2 Codapane Product Information 2 Pharmacokinetics Following oral administration, paracetamol is absorbed rapidly and completely from the gastrointestinal tract, with peak plasma concentrations occurring 10 to 60 minutes after administration. Paracetamol is uniformly distributed throughout most body fluids; the apparent volume of distribution is 1 to 1.2 L/kg. Paracetamol can cross the placenta and is excreted in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. Paracetamol is metabolised by the hepatic microsomal enzyme system. In adults, at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45 to 55%) or sulfate (20 to 30%). A minor proportion (less than 20%) is metabolised to catechol derivatives and mercapturic acid compounds via oxidation. Paracetamol is metabolised differently by infants and children compared to adults, the sulfate conjugate being predominant. Paracetamol is excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol with 85 to 90% of the administered dose eliminated in the urine within 24 hours of ingestion. The elimination half-life varies from 1 to 3 hours. Food intake delays paracetamol absorption. Codeine phosphate is absorbed from the gastrointestinal tract and peak plasma concentrations are reached 1 hour after oral administration. Codeine is metabolised in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney within 24 hours. The metabolites are mainly conjugates with glucuronic acid. Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite. The plasma half-life varies between 3 and 4 hours after oral administration. INDICATIONS For the temporary relief of moderate to severe pain and discomfort associated with headache, migraine headache, tension headache, earache, toothache, dental procedures, muscle pain, period pain, arthritis, rheumatics, osteoarthritis, back pain, neuralgia, sore throat and symptoms of cold and flu. Reduces fever and/or the discomfort associated with fever. CONTRAINDICATIONS Codapane is contraindicated in people with known hypersensitivity to paracetamol, codeine or excipients of Codapane. people with active alcoholism. people with acute respiratory depression.

3 Codapane Product Information 3 mothers who are breastfeeding, unless prescribed by a doctor (see PRECAUTIONS Use in Lactation). PRECAUTIONS Codapane is for the relief of minor and temporary ailment and should be used strictly as directed. Prolonged use without medical supervision could be harmful. Depending on the genetic variability of CYP2D6, the individual metabolising capacity for codeine may vary. Even therapeutic doses can lead to increased formation of the active metabolite morphine resulting in clinical signs of morphine intoxication (see OVERDOSAGE). Codeine should be administered with caution in patients with hypothyroidism, adrenocortical insufficiency (eg Addison s disease), shock, myxoedema, acute alcohol intoxication or delirium tremens since codeine may exacerbate the symptoms or increase the risk of respiratory and/or CNS depression. Hepatic/renal Dysfunction Codapane should be administered with caution to patients with hepatic or renal dysfunction. Opioid Dependence Prolonged use of high doses of codeine may produce dependence. Intracranial Pressure 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. Decreased Respiratory Reserve 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. CNS Depression Codeine should be administered with great caution if at all in patients with CNS depression, since codeine may exacerbate the condition. Gastrointestinal Disorders 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 acute abdominal conditions since codeine may obscure the diagnosis or the course of the disease.

4 Codapane Product Information 4 Monoamine Oxidase Inhibitors (MAOI s) Codeine should be administered with caution in patients taking Monoamine Oxidase Inhibitors (MAOI s) (see PRECAUTIONS - Interactions with Other Medicines). Seizures Codeine should be administered with caution in patients with a history of convulsive disorders (convulsions may be induced or exacerbated by codeine). Genitourinary Disorders. Codeine should be administered with caution in patients with prostatic hypertrophy, urethral stricture or recent urinary tract surgery since codeine may cause urinary retention. Use in Pregnancy (Category A) Codapane may be used during pregnancy on the advice of the doctor. However, it is recommended that nondrug therapies such as rest and massage are tried first. Australian categorisation definition of Category A. Drugs that have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed. Use in Lactation Paracetamol is excreted in breast milk. Peak concentrations of 10 to 15 micrograms/ml have been measured within 1 to 2 hours of a single 650 mg maternal dose. The half-life of paracetamol in breast milk is 1.35 to 3.5 hours. Neither paracetamol or its metabolites were detected in the urine of breastfed infants following the maternal 650 mg dose. In nursing mothers, who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. The lowest effective dose should be used, for the shortest possible time. Nursing mothers should be informed about carefully monitoring the infant during treatment for any sign and symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, and should seek immediate medical care if such symptoms or signs are noticed. Codeine-containing products must not be used while breastfeeding unless prescribed by a doctor (see CONTRAINDICATIONS). Paediatric Use Not recommended for children under 7 years of age. Use in the Elderly Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression.

5 Codapane Product Information 5 Interactions with Other Medicines Anticoagulants. Dose reduction of anticoagulants may be required if the treatment with Codapane is prolonged. Alcohol. Codeine may potentiate the effects of alcohol and the likelihood of toxicity may be increased by its concomitant use. The likelihood of paracetamol toxicity may also be increased by the concomitant use of alcohol with paracetamol. Opioid analgesics. Concurrent use of codeine and other opioid agonists is usually inappropriate as additive CNS depression, respiratory depressant and hypotensive effects may occur. Opioid agonists that decrease gastric emptying will decrease the absorption of paracetamol. Anticholinergics. Concomitant use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention. Anticholinergics that decrease the gastric emptying, such as propantheline, will decrease the absorption of paracetamol. Monoamine oxidase inhibitors. Nonselective MAOIs 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 nonselective MAOIs or within 14 days of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOIs (reversible inhibitors of monoamine oxidase A) and codeine, caution is advised with this drug combination. The absorption of paracetamol is decreased by MAO inhibitors that decrease gastric emptying. Metoclopramide. Drugs that increase gastric emptying, such as metoclopramide, may accelerate the absorption of paracetamol. Codeine may antagonise the effects of metoclopramide on gastrointestinal motility. Barbiturates and antiepileptic medications. The likelihood of toxicity may be increased by the concomitant use of enzyme inducing agents such as alcohol, barbiturates or antiepileptic drugs. Paracetamol Salicylates and NSAIDs. Prolonged concurrent use of paracetamol and salicylates or nonsteroidal antiinflammatory drugs may increase the risk of adverse renal effects. Diflunisal. Diflunisal may increase the plasma concentrations of paracetamol by 50%. Coumarins. Repeated high doses of paracetamol increase the anticoagulant response to coumarins. Chloramphenicol. Paracetamol may also increase chloramphenicol concentrations. Cholestyramine. Cholestyramine reduces the absorption of paracetamol if given within one hour of paracetamol administration.

6 Codapane Product Information 6 Codeine General anaesthetics. Codeine may potentiate the effects of general anaesthetics. Tranquillizers, sedatives and hypnotics. Concurrent use of codeine with these agents may enhance the potential respiratory depressant effects of codeine. CNS depressants. Codeine may potentiate the effects of CNS depressants. 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. Neuromuscular blocking agents. Codeine may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression. CYP2D6 enzyme inhibitors. Possible drug interactions between CYP2D6 inhibitors, such as quinidine, phenothiazines and antipsychotic agents, and codeine. Laboratory Tests Plasma amylase and lipase activity. Codeine may cause increased biliary tract pressure, thus increasing plasma amylase and/or lipase concentrations. Gastric emptying studies. Gastric emptying is delayed by codeine so gastric emptying studies will not be valid. Effect on Ability to Drive or Operate Machinery Codapane may cause drowsiness. Those affected should not drive or operate machinery. ADVERSE EFFECTS Adverse effects of Codapane tablets are generally infrequent and include the following. Haematological. Less frequent to rare. Agranulocytosis, anaemia, thrombocytopenia. Genitourinary. Less frequent to rare. Renal failure, uraemia, urinary retention or hesitancy. Hypersensitivity. Less frequent to rare. Skin rashes and other allergic reactions, histamine release (hypotension, flushing of the face, tachycardia, breathlessness). Gastrointestinal. Common. Constipation, dyspepsia, nausea, vomiting. Neurological. Common. Drowsiness, dizziness. Less frequent to rare. Euphoria, dysphoria. At higher doses codeine may cause respiratory depression.

7 Codapane Product Information 7 DOSAGE AND ADMINISTRATION Adults and Children over 12 years. One to two tablets, taken with water, every three to four hours if necessary (maximum eight tablets in 24 hours). Children (7 to 12 years). Half to one tablet, taken with water, every three to four hours if necessary (maximum four tablets in 24 hours). OVERDOSAGE Acute overdosage with Paracetamol, whether accidental or deliberate, is relatively common and can be extremely serious because of the narrow margin between therapeutic and toxic doses. Overdose can result in severe hepatic damage and sometimes acute renal tubular necrosis. Symptoms Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma. In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol of 10 to 15 g (20-30 tablets); a dose of 25 g (50 tablets) or more is potentially fatal. Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of hepatic failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop. Treatment Prompt treatment is essential even when there are no obvious symptoms. If an overdose is taken or suspected, the Poisons Information Centre should be contacted immediately for advice (call ), or the patient should go to a hospital straight away, even if they feel well, because of the risk of delayed, serious liver damage. In cases of overdosage, methods of reducing absorption of ingested drug are important. Prompt administration of activated charcoal 50 g in 150 ml of water and 150 ml sorbitol 50% solution by mouth may reduce absorption. It is recommended that intravenous fluids such as Normal Saline be given concurrently. Gastric lavage is indicated if the patient is unwilling or unable to drink an activated charcoal/sorbitol mixture. If the history suggests that paracetamol 15 g or more has been ingested, administer the following antidote: Intravenous acetylcysteine 20%. Administer acetylcysteine immediately without waiting for positive urine test or plasma level results if 8 hours or less since overdose ingestion. Initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in glucose 5% 500 ml over four hours and 100 mg/kg in glucose 5% 1 L over 16 hours. If more than 8 hours have elapsed since the overdosage was taken, the antidote may be less effective.

8 Codapane Product Information 8 PRESENTATION AND STORAGE CONDITIONS Codapane, round, white tablet, marked P breakline C on one side, α on the reverse; blister pack, 10s*, 12s*, 20s*, 24s, 30s*, 36s* and 40s*. * Not marketed in Australia. Store below 30 C. POISON SCHEDULE OF THE MEDICINE S3 (Pharmacist Only Medicine) NAME AND ADDRESS OF THE SPONSOR Alphapharm Pty Limited (ABN ) Chase Building 2 Wentworth Park Road Glebe NSW DATE OF APPROVAL Approved by the Therapeutic Goods Administration on 25 March Date of most recent amendment: 15 April 2010.