Annotation of DPWG Guideline for nortriptyline and CYP2D6

Annotation
Related Chemicals
Publications
Clinical Annotations
Links
History
Navigate to...
Show section selector dropdown
Testing InfoLearn more about the Testing Info tag(opens in new window)Dosing InfoLearn more about the Dosing Info tag(opens in new window)Alternate DrugLearn more about the Alternate Drug tag(opens in new window)

Summary

The Dutch Pharmacogenetics Working Group Guideline for nortriptyline recommends a dose reduction for CYP2D6 poor or intermediate metabolizer patients. For CYP2D6 ultrarapid metabolizers, select an alternative drug or use 1.7 times the standard dose. Monitoring of nortriptyline and 10-hydroxynortriptyline plasma concentrations is recommended.

Specify a genotype or phenotype for specific annotations

Pick genotype or phenotype for CYP2D6
or

Alleles not present in the above pull-down menus have no recommendation.

Important information about alleles in DPWG guidelines.

Annotation

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

November 2018 Update

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype. They recommend a dose increase or use of an alternative antidepressant in CYP2D6 ultrarapid metabolizers (UMs) and a dose reduction in CYP2D6 poor metabolizers (PMs). Monitoring of nortriptyline and Z-10-hydroxynortriptyline plasma concentrations is also recommended.

Wording in table taken from the Dutch guidelines November 2018 update.

Scroll for more
Allele/Genotype/PhenotypeDrugDescriptionRecommendation
CYP2D6 UMnortriptylineThe risk of ineffectiveness and cardiotoxic effects may be increased. The gene variation leads to a decrease in the plasma concentration of nortriptyline and an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline.Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline and be alert to an increase in the plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. Plasma concentrations of Z-hydroxynortriptyline exceeding 40 ng/mL are considered toxic.
If a dose increase is not wanted due to the cardiotoxic hydroxy metabolite: avoid nortriptyline. Antidepressants that are not metabolised via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
CYP2D6 IMnortriptylineThe risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline.Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose.
The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.
CYP2D6 PMnortriptylineThe risk of side effects may be increased, because the gene variation leads to an increased plasma concentration of nortriptyline.Use 40% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline in order to set the maintenance dose.
The therapeutic range of nortriptyline is 50-150 ng/mL. Values exceeding 250 ng/mL are considered toxic.

Read for more information about this recommendation, Read about gene information from DPWG

Preemptive genotyping

Excerpts from the DPWG risk analysis document for nortriptyline and CYP2D6:

The Dutch Pharmacogenetics Working Group considers genotyping before starting nortriptyline to be potentially beneficial for the prevention of side effects and for drug efficacy. Genotyping can be considered on an individual patient basis. If, however, the genotype is available, the Dutch Pharmacogenetics Working Group recommends adhering to the gene-drug guideline.

Read more about how DPWG assigns their recommendations for preemptive genotyping.

2011 Guideline

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype [Article:21412232]. They recommend reducing the dose for poor and intermediate metabolizer patients and selecting an alternative drug or increasing the dose for ultra metabolizers.

Scroll for more
Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (2 inactive alleles)Reduce dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele)Reduce dose by 40% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
UM (gene duplication in absence of inactive or decreased activity alleles)Select alternative drug (e.g., citalopram, sertraline) or increase dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
Scroll for more
Allele TypeAlleles
active*1, *2, *33, *35
decreased activity*9, *10, *17, *29, *36, *41
inactive*3-*8, *11-*16, *19-*21, *38, *40, *42
  • *See Methods or [Article:18253145] for definition of "good" and "moderate" quality.
  • S: statistically significant difference.
  • Please see attached PDF for detailed information about the evaluated studies: Nortriptyline CYP2D6

PharmGKB ID

PA166104961