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.

2016 Statement from the US Food and Drug Administration (FDA): The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

Please review the complete therapeutic recommendations that are located here: (1).

2016 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC):

CYP2D6 dosing recommendations.

[…]. The recommended starting dose of amitriptyline or nortriptyline does not need adjustment for those with genotypes predictive of CYP2D6 normal metabolism. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers. The strength of this recommendation is classified as “moderate” because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or normal metabolizers in the literature, making these studies difficult to evaluate.

CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations. However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended. Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations; therefore, alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended.

CYP2C19 dosing recommendations.

[…]. The usual starting dose of amitriptyline may be used in CYP2C19 normal and intermediate metabolizers. Although CYP2C19 intermediate metabolizers would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 intermediate metabolizers should receive an alternate dose.

Patients taking amitriptyline who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations and an imbalance between parent drug and metabolites causing treatment failure and/or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events. For patients taking amitriptyline, extrapolated pharmacokinetic data suggest that CYP2C19 rapid or ultrarapid metabolizers may need a dose increase. Due to the need for further studies investigating the clinical importance of CYP2C19*17 regarding tricyclic metabolism and the possibility of altered concentrations, we recommend to consider an alternative tricyclic or other drug not affected by CYP2C19. This recommendation is classified as optional due to limited available data. If amitriptyline is administered to a CYP2C19 rapid or ultrarapid metabolizer, therapeutic drug monitoring is recommended.

CYP2C19 poor metabolizers are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations. The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Use an alternative agent not metabolized by CYP2C19 (e.g., nortriptyline and desipramine) or consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.

Please review the complete therapeutic recommendations that are located here: (2).

2011 Summary of recommendations from the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

For CYP2D6 ultrarapid metabolizers:

The genetic polymorphism leads to increased metabolic capacity of CYP2D6, which may cause a decrease in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and increased plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH- nortriptyline.

Recommendation:

1. Choose an alternative if possible. Antidepressants that are not metabolized via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: increase the dose to 1.25 times the standard dose, monitor the plasma concentrations and be alert to potential therapy failure due to decreased amitriptyline plus nortriptyline plasma concentrations and to increased plasma concentrations of the potentially cardiotoxic, active hydroxy metabolites.

For CYP2D6 intermediate metabolizers:

The genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause an increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and decreased plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH- nortriptyline.

Recommendation:

1. Choose an alternative if possible. Antidepressants that are not metabolized via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: use 60% of the standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline

As side effects are related to nortriptyline plasma concentrations and the efficacy to amitriptyline plus nortriptyline plasma concentrations, which are influenced to a lesser extent by CYP2D6, it is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, but the efficacy is maintained.

For CYP2D6 poor metabolizers:

The genetic polymorphism leads to decreased metabolic capacity of CYP2D6, which may cause an increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline and decreased plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH- nortriptyline.

Recommendation:

1. Choose an alternative if possible. Antidepressants that are not metabolized via CYP2D6 - or to a lesser extent - include, for example, citalopram and sertraline.
2. If an alternative is not an option: use 50% of the standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline

As side effects are related to nortriptyline plasma concentrations and the efficacy to amitriptyline plus nortriptyline plasma concentrations, which are influenced to a lesser extent by CYP2D6, it is not known whether it is possible to reduce the dose to such an extent that the side effects disappear, but the efficacy is maintained.

Please review the complete therapeutic recommendations that are located here: (32).

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 labeled all formulations containing the generic drug.