CYP2D6 metabolismCodeine 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:
||3.4% to 6.5%
||1.2% to 2%
||3.6% to 6.5%
||1% to 2%
Post-operative use in childrenThere 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 ultrarapid or extensive metabolisers in their ability to metabolise codeine to morphine.
Children with compromised respiratory functionSolpadol 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.This product should only be used with great care in any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to its central and gastro-intestinal effects, those who are on concurrent CNS drugs, those with prostatic hypertrophy or those with inflammatory or obstructive bowel disorders.Care should also be observed if prolonged therapy is contemplated.Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease. In patients with kidney failure (creatinine clearance lower than 10 ml/min): the interval between doses should be increased (minimum 8 hours). See section 4.2.Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction (See Section 4.8) Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).
Severe-cutaneous adverse reactions (SCARs): Very rare cases of serious skin reactions such as Stevens-Johnson syndrome (SJS), and Toxic epidermal necrolysis (TEN) have been reported with the use of paracetamol. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop immediately Solpadol treatment and seek medical advicePatients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently.Consumption of alcohol during treatment is not recommended since the drug contains codeine.Tolerance and dependence can occur, especially with prolonged high dosage of codeine.The risk-benefit of continued use should be assessed regularly by the prescriber. Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms such as restlessness and irritability, once the drug is stopped (see Section 4.8).In patients with intracranial hypertension, codeine may increase the severity of this hypertension. Solpadol is contraindicated for use in these patients. Section 4.3.In patients who have had a cholecystectomy, codeine may induce acute biliary or pancreatic abdominal pain, which usually occurs with abnormal laboratory results, suggesting a spasm of the sphincter of Oddi. Solpadol is contraindicated for use in these patients. Section 4.3.If the patient has a productive cough, codeine may impede expectoration.Elderly patients: the initial dosage should be reduced to half the recommended dosage; this may be later increased based on patient tolerance and needs. See section 4.2In ultra-rapid opiate/codeine metabolisers, there is an increased risk of developing opioid toxicity even at low doses. Symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression.