PRAC recommendation Sample Clauses

PRAC recommendation. Codeine-containing products are authorised nationally in Europe and are indicated for the management of pain in adults and children. They are commonly used in combination with other analgesics such as non-steroidal anti-inflammatory drugs and non-opioid analgesics. The analgesic properties of codeine stem from its conversion to morphine by the cytochrome P450 enzyme CYP2D6 and the toxicity of codeine is mainly due to its opioid effects. It has been established that CYP2D6 is subject to extensive polymorphism, and individuals are normally classified as poor (PM), extensive (EM) or ultra-rapid metabolisers (UM), depending on the activity of the enzyme. Whereas EMs or UMs are at risk of morphine toxicity, PMs may be at an increased risk of a lack of efficacy. A number of cases of opioid toxicity in children treated with codeine have been described in the literature, some with a fatal outcome. These children underwent tonsillectomy for obstructive sleep apnoea and experienced respiratory depression after using codeine as an analgesic at a therapeutic dose. In addition, a published case report described respiratory depression resulting in death in a breastfed newborn whose mother was a CYP2D6 ultra-rapid metaboliser. The Pharmacovigilance Risk Assessment Committee (PRAC) discussed this issue during its September 2012 meeting and raised concerns regarding the potential for serious opioid toxicity associated with the use of codeine as an analgesic in the paediatric population. A referral under Article 31 of Directive 2001/83/EC was therefore initiated, to review the benefit-risk balance of codeine in the management of pain in children. Having reviewed the totality of the available data on the efficacy and safety of codeine-containing medicinal products indicated in the management of pain in children, including responses submitted by the marketing authorisation holders (MAHs), the PRAC noted that there is more limited information on the pharmacokinetics of codeine metabolism in children than is available for adults. The available data suggests that the maturity of the renal system and the drug metabolising enzymes, body weight or composition and the ontogeny of enzymes involved in the metabolism and pharmacology of codeine may be determinant for its analgesic or toxic effect and therefore result in pharmacokinetic differences in children compared to adults and between different age groups of children (neonates, infants). Regarding efficacy, having reviewed the ava...