CODEINE PHOSPHATE PARACETAMOL AND CAFFEINE

Posology Adults 1 or 2 tablets each administration, depending on the extent of pain, taken 1 to 3 times daily, at intervals of at least 6 hours. The minimum interval time between doses shouldn’t be reduced. However, in case of more severe pain, this dosage can be increased up to 8 tablets per day (maximum dosage).

The maximum total daily dose of paracetamol should not exceed 4 g per day; the maximum total daily dose of codeine should not exceed 240 mg. Paediatric population Adolescents aged 16 to 18 years of age One to two tablets every 6 hours.

Do not exceed 4 doses, equivalent to 6 tablets. Adolescents aged 12 to 15 years of age 1 tablet every 6 hours. Do not exceed 4 doses, equivalent to 4 tablets. 4). Elderly patients Elderly patients, especially those who are frail or immobile, may require a reduced dose or frequency of dosing.

Renal Impairment Patients who have been diagnosed with kidney impairment must seek medical advice before taking this medication. It is recommended, when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours.

4). Hepatic Impairment Patients who have been diagnosed with hepatic impairment or Gilbert’s Syndrome must seek medical advice before taking this medication. 4). 9). Method of administration For oral administration only. Tablets should be dissolved in at least half a glass of water.

The resulting solution should be drunk immediately.

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post- marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system.

The following convention has been utilised for the classification of undesirable effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, 363 <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

Paracetamol Body System Undesirable effect Frequency Blood and lymphatic system disorders Thrombocytopenia Agranulocytosis Not known Anaphylaxis Not known Immune system disorders Allergies (not including angioedema) Rare Metabolism and nutrition disorders High anion gap metabolic acidosis Not known Respiratory, thoracic and mediastinal disorders Bronchospasm* Not known Hepatobiliary disorders Hepatic dysfunction Not known Cutaneous hypersensitivity reactions including skin rashes, pruritus, sweating, purpura, urticaria and angioedema Very rare Skin and subcutaneous tissue disorders Very rare cases of serious skin reactions have been reported.

4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients. * There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Caffeine Body System Undesirable effect Frequency Central nervous system Nervousness Dizziness Not known When the recommended paracetamol-caffeine-codeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.

Codeine Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class. The frequency of these reactions is not known. 4) Not known Gastrointestinal disorder Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis Not known Nervous system disorder Dizziness Hyperalgesia Drowsiness Not known General disorders and administration Drug withdrawal syndrome Uncommon Renal and urinary disorders Difficulty with micturition Not known Skin and subcutaneous tissue disorder Pruritus, sweating Not known Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with non- cirrhotic alcoholic liver disease. Paracetamol should be administered only with particular caution under the following circumstances: • Hepatocellular insufficiency • Chronic alcoholism • Renal failure (GFR ≤ 50 ml/min) • Gilbert’s Syndrome (familial non-haemolytic jaundice) • Concomitant treatment with medicinal products affecting hepatic function • Glucose-6-phosphatase dehydrogenase deficiency • Haemolytic anaemia • Glutathione deficiency • Dehydration • Chronic malnutrition • The elderly, adults and adolescents weighing less than 50 kg.

g. chronic alcoholism), who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended.

The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors. Care should be observed in administering the product to any patient, whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy, hypothyroidism and those with inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis.

Care should also be observed if prolonged therapy is contemplated. Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued.

The diagnosis of medication overuse headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications. Precaution should be observed in patients with asthma who are sensitive to acetylsalicylic acid since mild bronchospasms are reported in association with paracetamol (cross reaction).

Do not exceed the stated dose. Patients should be advised not to take other paracetamol or codeine-containing products concurrently. 9). If symptoms persist for more than 3 days or get worse, or if any other symptoms occur, treatment should be discontinued, and a physician consulted.

Patients with obstructive bowel disorders or acute abdominal conditions should consult a doctor before using this product. Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients.

g. 9). 5) should not take this product. Codeine, as with other opioids should be used with caution in patients with hypotension, hypothyroidism, head injury or raised intracranial pressure. Excipients with known effect This medicinal product contains 419 mg sodium per effervescent tablet, equivalent to 21% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicine is considered high in sodium. This should be particularly taken into account for those on a low salt diet. This medicinal product contains 100 mg sorbitol in each effervescent tablet. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal products.

CYP2D6 metabolism Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency.

However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher-than-expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive […]

Zipamol Extra 8 mg/500 mg/30 mg Effervescent Tablets are contraindicated in patients with hypersensitivity to paracetamol, caffeine, codeine, opioid analgesics or any of the other constituents. 4). 6). In respiratory depression, chronic constipation.

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.