MyDrugGenome

Rationale

This drug gene interaction (DGI) pertains to the interaction between the CYP2D6 gene and fluvoxamine. Fluvoxamine (Luvox®) belongs to a class of drugs known as selective serotonin re-uptake inhibitors (SSRIs). SSRIs work by blocking the re-uptake of serotonin. The increase in serotonin levels has been linked to the management of depression, social anxiety disorder, obsessive-compulsive disorder, panic disorder, premenstrual dysphoric disorder, and post-traumatic stress disorder among other conditions. Extensive literature and FDA warning labels indicate patients with genetically reduced CYP2D6 function experience lower systemic exposure to the active metabolite of fluvoxamine and have an increased risk of side effects than patients with normal CYP2D6 protein function. Specific genetic differences in the CYP2D6 gene may require dose adjustments of fluvoxamine or an alternative medication in order to achieve therapeutic benefits or to avoid side effects.

Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).

Genetic Variant Information

The CYP2D6 (sounds like “sip-2-dee-6”) gene encodes an enzyme that is involved in the metabolism of fluvoxamine. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well fluvoxamine is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2D6 protein while other variants result in a normal-functioning CYP2D6 protein. A duplication of variants can lead to a hyper-active CYP2D6 protein. Different ‘metabolizer statuses’ are assigned to patients depending on their genetic information (genotype).

See chart below for a description of each metabolizer status and any implications for treatment.

CYP2D6 metabolizer status	Variants (genotype)	Implication for fluvoxamine
Poor metabolizer	ONLY no-function alleles	Greatly reduced metabolism of fluvoxamine when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects.
Intermediate metabolizer	ONE decreased function allele AND ONE no-function allele OR TWO decreased function alleles OR ONE normal function AND ONE no-function allele	Reduced metabolism of fluvoxamine when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects.
Normal metabolizer	TWO normal function alleles OR ONE normal function AND ONE decreased function allele	Normal metabolism of fluvoxamine.
Ultrarapid metabolizer	MORE THAN TWO copies of function alleles	No data available for fluvoxamine ultrarapid metabolizers.

The patient’s reported genotype corresponds to a phenotype (i.e., metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP2D6_Diplotype_Phenotype_Table”.

Results Interpretation

Quality of Results

Genotyping for CYP2D6 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.

Supporting Evidence

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors

This link will take you to the main page on the CPIC website relating to CYP2D6, CYP2C19 and SSRIs. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status). Additionally, examples of point of care clinical decision support can be found at the bottom of the page.

Please note that additional drugs may have CYP2D6 interactions. For more information on drug-gene interactions, please use the search feature on the CPIC website.