Annotation of Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information
for nortriptyline and CYP2D6

last updated 03/15/2017

Summary

The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

Annotation

December 2016 Update

Advance online publication December 2016.

Table 1: Dosing recommendations for nortriptyline based on CYP2D6 phenotype:

Adapted from Tables 1 and 2 of the 2016 guideline update.

Likely phenotypeActivity scoreGenotypesExamples of diplotypesImplicationsTherapeutic RecommendationsbClassification of recommendation for amitriptyline and nortriptylinec
CYP2D6 Ultrarapid metabolizer (~1-20% of patients)d>2.0An individual carrying more than two copies of functional alleles*1/*1xN, *1/*2xNIncreased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure.Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6.
If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments.e
Strong
CYP2D6 Normal metabolizer (~72-88% of patients)d1.0-2.0fAn individual carrying two normal function alleles or two decreased function alleles or one normal and no function allele or one normal and decreased function allele or combinations of duplicated alleles that result in an activity score of 1.0-2.0*1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5Normal metabolism of TCAs.Initiate therapy with recommended starting dose.gStrong
CYP2D6 Intermediate metabolizer (~1-13% of patients)d0.5An individual carrying one decreased and one no function allele*4/*41, *5/*9, *4/*10Reduced metabolism of TCAs to less active compounds when compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.Consider 25% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.eModerate
CYP2D6 Poor metabolizer (~1-10% of patients)d0An individual carrying only no function alleles*4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6.
If a TCA is warranted, consider 50% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.e
Strong

b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

c The rating scheme for the recommendation of classification is described in the Supplement.

d CYP2D6 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

g Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

May 2013

Advance online publication January 2013.

CPIC TCAs guideline

Total publications: 2

Reference
1. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical pharmacology and therapeutics. 2016. Kevin Hicks J, Sangkuhl Katrin, Swen Jesse J, Ellingrod Vicki L, Müller Daniel J, Shimoda Kazutaka, Bishop Jeffrey R, Kharasch Evan D, Skaar Todd C, Gaedigk Andrea, Dunnenberger Henry M, Klein Teri E, Caudle Kelly E, Stingl Julia C. PubMed
2. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clinical pharmacology and therapeutics. 2013. Hicks J K, Swen J J, Thorn C F, Sangkuhl K, Kharasch E D, Ellingrod V L, Skaar T C, Müller D J, Gaedigk A, Stingl J C. PubMed

Guideline History