This section contains excerpted ¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2019 Statement from the US Food and Drug Administration (FDA)

Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultrarapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect.

Some individuals may be ultrarapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultrarapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultrarapid metabolizers should not use codeine sulfate tablets.

Please review the complete therapeutic recommendations that are located here: (3)

2020 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)

For CYP2D6 normal metabolizers (i.e. CYP2D6 activity score 1.25 to 2.25), a label recommended age- or weight-specific starting dose of codeine or tramadol, as recommended in the product label, is warranted. A label recommended starting dosing is also recommended for intermediate metabolizers (i.e. activity score of 0.25 to 1); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if warranted. For CYP2D6 poor metabolizers (i.e. activity score of 0), current evidence supports the avoidance of codeine and tramadol and the use of an alternative analgesics due to the likelihood of suboptimal or lack of effect. There is insufficient evidence in the literature to recommend a higher dose of codeine or tramadol in poor metabolizers, especially considering the evidence that some adverse events do not differ between poor and normal metabolizers (19). For CYP2D6 ultrarapid metabolizers (i.e. activity score of >2.25), codeine or tramadol should not be used, in order to avoid the risk of severe toxicity with label-recommended dosing. Non-opioid analgesics and if needed, other opioids that are not affected by CYP2D6 phenotype, are potential alternatives for use in CYP2D6 poor and ultrarapid metabolizers based on the type, severity and chronicity of the pain being treated.

Please review the complete therapeutic recommendations that are located here: (4).

2017 Summary of Recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

CYP2D6 Intermediate Metabolizers

For COUGH:

1. no action required

For PAIN:

It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

1. be alert to a reduced effectiveness
2. in the case of inadequate effectiveness:
   1. try a dose increase
   2. if this does not work: choose an alternative
      • Do not select tramadol, as this is also metabolised by CYP2D6
      • Morphine is not metabolised by CYP2D6.
      • Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
   3. if no alternative is selected: advise the patient to report inadequate analgesia

Poor Metabolizers

For COUGH:

1. no action required

For PAIN:

It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype.

1. choose an alternative

Do not select tramadol, as this is also metabolised by CYP2D6

• Morphine is not metabolised by CYP2D6.
• Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
  1. if an alternative is not an option: advise the patient to report inadequate analgesia.

Ultrarapid Metabolizers

DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

Codeine is contra-indicated

• if possible, select an alternative
  • For PAIN: do not select tramadol, as this is also metabolised by CYP2D6.

Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.

• For COUGH: noscapine is not metabolised by CYP2D6.

DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function:

• no action required

Please review the complete therapeutic recommendations that are located here: (5)

2013 Clinical practice Guideline from the “Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Clinical Recommendations Group: CYP2D6 genotyping for safe and efficacious codeine therapy” are located here: https://www.ncbi.nlm.nih.gov/pubmed/24214521 ( 65 ).

¹ The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labelled all formulations containing the generic drug.