These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on nortriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other secondary amines as well.
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the list below.
Important Instructions: Please use CYP2D6 Activity Score to select the appropriate row in the list below.
Ultrarapid Metabolizer (Activity Score >2.25)
Clinical Implication
- Increased CYP2D6 enzyme activity.
- Increased risk of treatment failure.
Therapeutic Recommendation
- Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring.
Normal – Ultrarapid Metabolizer (Activity Score 1.5+ or 2+)*
Clinical Implication
- Normal to increased CYP2D6 enzyme activity.
- Possible increased risk of treatment failure.
Therapeutic Recommendation
- Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring.
Normal Metabolizer (Activity Score 1.25-2.25)*
Clinical Implication
- Normal CYP2D6 enzyme activity.
- Normal response expected.
Therapeutic Recommendation
- Use standard doses of secondary amines
Intermediate – Ultrarapid Metabolizer (Activity Score 0.25+, 0.5+, 0.75+, or 1+)*
Clinical Implication
- Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations.
- Possible increased risk of treatment failure OR increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac).
Therapeutic Recommendation
- Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments.
Intermediate Metabolizer (Activity Score 0.25-1)*
Clinical Implication
- Decreased CYP2D6 enzyme activity.
- Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac).
Therapeutic Recommendation
- Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments.
Poor Metabolizer (Activity Score 0)
Clinical Implication
- No CYP2D6 enzyme activity.
- Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac).
Therapeutic Recommendation
- Avoid use of secondary amines or if warranted, decrease dose by 50% and utilize therapeutic drug monitoring to guide dose adjustments.
Unable to Genotype or Assay Failure
- The analysis failed to yield an informative result and thus no genotype is reported.
Unknown Phenotype
- This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.
*Previously some labs have designated an Activity Score of 1 as Normal Metabolizers
Reference
- Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040.