Table 5.

2016 CPIC Dosing recommendations for amitriptyline based on both CYP2D6 and CYP2C19 phenotypes a,b

PhenotypeCYP2D6 Ultrarapid metabolizerCYP2D6 Normal metabolizerCYP2D6 Intermediate metabolizerCYP2D6 Poor metabolizer
CYP2C19 ultrarapid or rapid metabolizerAvoid amitriptyline usec
Classification of recommendationd: Optional		Consider alternative drug not metabolized by CYP2C19c,e
Classification of recommendationd: Optional		Consider alternative drug not metabolized by CYP2C19 c,e
Classification of recommendationd: Optional		Avoid amitriptyline usec
Classification of recommendationd: Optional
CYP2C19 normal metabolizerAvoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers)f,g
Classification of recommendationd: Strong		Initiate therapy with recommended starting doseh
Classification of recommendationd: Strong		Consider a 25% reduction of recommended starting dosef,h
Classification of recommendationd: Moderate		Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h
Classification of recommendationd: Strong
CYP2C19 intermediate metabolizerAvoid amitriptyline usec
Classification of recommendationd: Optional		Initiate therapy with recommended starting doseh
Classification of recommendationd: Strong		Consider a 25% reduction of recommended starting dosef,h
Classification of recommendationd: Optional		Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h
Classification of recommendationd: Optional
CYP2C19 poor metabolizerAvoid amitriptyline usec
Classification of recommendationd: Optional		Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef,h
Classification of recommendationd: Moderate		Avoid amitriptyline usec
Classification of recommendationd: Optional		Avoid amitriptyline usec
Classification of recommendationd: Optional
a

Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

b

The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine (the classification of this recommendation is optional).

c

If amitriptyline is warranted, utilize therapeutic drug monitoring to guide dose adjustment.

d

The rating scheme for the recommendation classification is described in Supplementary Data (2). See CYP2D6 and CYP2C19 combined dosing recommendations for explanation of classification of recommendations for this table.

e

TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine.

f

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended.

g

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

h

Patients may receive an initial low dose of TCAs, 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.

Table has been adapted from Hicks J.K., Sangkuhl K., Swen J.J., Ellingrod V.L., Müller D.J., Shimoda K., Bishop J.R., Kharasch E.D., Skaar T.C., Gaedigk A., Dunnenberger H.M., Klein T.E., Caudle K.E. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical pharmacology and therapeutics. 2016 Dec 20 [Epub ahead of print] (2).

From: Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype

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