Chemical: Drug
venlafaxine

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Prescribing Info (1) Drug Labels (1) Clinical Annotations (35)

last updated 08/10/2011

1. Annotation of DPWG Guideline for venlafaxine and CYP2D6

Summary

For CYP2D6 poor (PM) and intermediate metabolizers (IM), select an alternative to venlafaxine or adjust dose to clinical response and monitor patient's plasma metabolite level. For CYP2D6 ultrarapid metabolizers(UM), titrate dose to a maximum of 150% of the normal dose or select an alternative to venlafaxine.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotypes [Article:21412232]. For PM and IM genotypes, they state that there are not sufficient data to allow calculation of dose adjustment, and they recommend selecting an alternative drug or adjusting dose to clinical response and monitoring (O-desmethyl)venlafaxine plasma concentration. For UM genotypes, they recommend titrating dose to a maximum of 150% of the normal dose(based on venlafaxine and (O-desmethyl)venlafaxine plasma concentration) or selecting an alternative drug.

Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
PM (two inactive (3-8, 11-16, 19-21, 38, 40, *42) alleles)	Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration.	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.
IM (two decreased-activity (9, 10, 17, 29, 36, 41) alleles or carrying one active (1, 2, 33, 35) and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele, or carrying one decreased-activity (9, 10, 17, 29, 36, 41) allele and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele)	Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration.	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 (a gene duplication in absence of inactive (3-8, 11-16, 19-21, 38, 40, 42) or decreased-activity (9, 10, 17, 29, 36, *41) alleles)	Be alert to decreased venlafaxine and increased (O-desmethyl)venlafaxine plasma concentration. Titrate dose to a maximum of 150% of the normal dose or select alternative drug (e.g., citalopram, sertraline).	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S).

*See Methods or [Article:18253145] for definition of "good quality."
S: statistically significant difference.
Please see attached PDF for detailed information about the evaluated studies: Venlafaxine CYP2D6

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last updated 10/25/2013

1. Annotation of FDA Label for venlafaxine and CYP2D6

On FDA Biomarker List

Informative PGx

Summary

Venlafaxine (Effexor) is an inhibitor of neuronal serotonin and norepinephrine reuptake and weak inhibitor of dopamine reuptake used in the treatment of depression. It is metabolized by CYP2D6, and to a lesser extent, CYP3A4 (shown in vitro).

Annotation

Excerpt from the Venlafaxine (Effexor) drug label:

CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Venlafaxine (Effexor) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

Anxiety Disorders
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Death
- Warnings section, Precautions section
- source: PHONT
Depression
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depression, Postpartum
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depressive Disorder
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depressive Disorder, Major
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Obsessive-Compulsive Disorder
- Warnings section
- source: PHONT
CYP1A2
- Drug interactions section
- source: U.S. Food and Drug Administration
CYP2C19
- Drug interactions section
- source: U.S. Food and Drug Administration
CYP2C9
- Drug interactions section
- source: U.S. Food and Drug Administration
CYP2D6
- metabolism/PK, Drug interactions section
- source: U.S. Food and Drug Administration
CYP3A4
- metabolism/PK, Drug interactions section
- source: U.S. Food and Drug Administration

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