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CPIC® Guideline for Codeine and CYP2D6

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Cytochrome P450 2D6 (CYP2D6) Genotype and Codeine Therapy: 2014 Update (April 2014)

Updates since publication:

April 2017: On April 20, the FDA updated a drug safety advisory for codeine and tramadol (full report here):

  • The FDA has issued its strongest warning, called a Contraindication, to the drug labels of codeine and tramadol alerting that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 years.
  • A new Contraindication to the tramadol label warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.
  • A new Warning to the drug labels of codeine and tramadol to recommend against their use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems.
  • A strengthened Warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants. These can include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.

Tables and figure provided in the main manuscript of the guideline:

Table 1. Assignment of likely codeine metabolism phenotypes based on cytochrome P450 2D6 (CYP2D6) diplotypes
Table 2. Codeine therapy recommendations based on cytochrome P450 2D6 (CYP2D6) phenotype
Figure 3. Codeine metabolism pathway in an individual with cytochrome P450 2D6 (CYP2D6) extensive metabolism or see PharmGKB Codeine and Morphine Pathway, Pharmacokinetics

Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Cytochrome P450 2D6 (CYP2D6) Genotype and Codeine Therapy: 2014 Update (April 2014)

Tables and figures included in the supplementa or referenced in the guideline:

Supplemental Table S1. Frequencies of CYP2D6 alleles in major race/ethnic groups For an updated version of this table see the CYP2D6 frequency table .
Supplemental Table S2. Commonly tested polymorphisms defining CYP2D6 variant alleles and their effect on CYP2D6 protein For an updated version of this table see the CYP2D6 allele definition table .
Supplemental Table S3. Association between allelic variants and CYP2D6 enzyme activity For an updated version of this table see the CYP2D6 allele functionality table .
Supplemental Table S4. Examples of CYP2D6 genotypes with resulting activity scores and phenotype classification For an updated version of this table see the CYP2D6 diplotype-phenotype table .
Supplemental Table S5. Predicted metabolizer phenotypes based on CYP2D6 diplotypes (allele combinations) For an updated version of this table see the CYP2D6 diplotype-phenotype table .
Supplemental Table S6. Evidence linking CYP2D6 phenotype or genotype with codeine metabolism or response

aSome of the tables included in the guideline may have been updated on-line, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.

Additional resources applicable to this guideline:

Drug resource mapping

Gene resource mapping

Original publication (February 2012):

This guideline has been endorsed by the American Society of Health-System Pharmacists (ASHP).