Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Delorbis Pharmaceuticals Ltd, 17 Athinon Street, Ergates Industrial Area, 2643 Ergates, P.O. Box 28629, 2081 Lefkosia, Cyprus, European Union
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.
Do not exceed the stated dose.
Patients should be advised to consult their doctor if their headaches become persistent. Patients should be advised not to take other paracetamol or codeine-containing products concurrently.
If symptoms persist consult your doctor.
Keep out of the reach and sight of children.
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.
Not recommended for use in children in whom respiratory function might be compromised as this may worsen the symptoms of morphine toxicity.
The label will state:
Front of pack:
Back of pack:
The leaflet will state:
Headlines section (to be prominently displayed)
Section 1: What the medicine is for:
Section 2: Before you taking
Section 3: Dosage
This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.
Section 4: Side effects
Some people may have side effects when taking this medicine. If you have any unwanted side effects you should seek advice from your doctor, pharmacist or other healthcare professional.
If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:
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.
Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:
| Population | Prevalence % |
|---|---|
| African/Ethiopian | 29% |
| African American | 3.4% to 6.5% |
| Asian | 1.2% to 2% |
| Caucasian | 3.6% to 6.5% |
| Greek | 6.0% |
| Hungarian | 1.9% |
| Northern European | 1%-2% |
There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). 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 metabolisers in their ability to metabolise codeine to morphine.
Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.
Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
Opioid analgesics should be given with care to patients receiving monoamine oxidase inhibitors. The effect of CNS depressants (including alcohol) may be potentiated by codeine; these interactions are unlikely to be significant at the dosage involved.
Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors (see section 4.4).
Codeine may antagonize the effects of metoclopramide and domperidone on gastrointestinal motility.
Codeine potentiates the central depressive effects of central nervous system depressants including alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.
Opiate analgesics may interact with monoamine oxidase inhibitors (MAOIs) and result in serotonin syndrome.
Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use during labour because of the potential for respiratory depression in the neonate.
The safety of paracetamol-codeine during pregnancy has not been established relative to the possible adverse effects of foetal development.
Codeine should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.
Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. When taking this medicine, patients should be told:
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 frequency of these adverse events is not known (cannot be estimated from available data).
Paracetamol:
| Body System | Undesirable effect |
|---|---|
| Blood and lymphatic system disorders | Thrombocytopenia Agranulocytosis |
| Immune system disorders | Anaphylaxis Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens-Johnson syndrome/toxic epidermal necrolysis |
| Respiratory, thoracic and mediastinal disorders | Bronchospasm* |
| Hepatobiliary disorders | Hepatic dysfunction |
* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
Codeine:
Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class. The frequency of these reactions is not known.
| Body System | Undesirable effect |
|---|---|
| Psychiatric disorders | Drug dependency can occur after prolonged use of codeine at higher doses |
| Gastrointestinal disorder | Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy |
| Nervous system disorder | Dizziness, worsening of headache with prolonged use, drowsiness |
| Skin and subcutaneous tissue disorder | Pruritus, sweating |
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reactions toto Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, www.moh.gov.cy/phs, Tel: +357 22608607, Fax: +357 22608669.
Not applicable.
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