Chemical: Drug

escitalopram

Annotation

This annotation is based on the CPIC® guideline for selective serotonin reuptake inhibitors and CYP2D6 and CYP2C19.

August 2015

Advanced online publication May 2015

• Guidelines regarding the use of pharmacogenomic tests in dosing of selective serotonin reuptake inhibitors have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
• Excerpts from the 2015 selective serotonin reuptake inhibitors dosing guidelines (for citalopram/escitalopram and CYP2C19):
  • "CYP2C19 ultrarapid metabolizers have significantly lower exposure to these drugs when compared to extensive metabolizers, and therefore may have an increased probability of failing therapy. Because there are insufficient data to calculate an initial citalopram or escitalopram dose for CYP2C19 ultrarapid metabolizers, an alternative SSRI not extensively metabolized by CYP2C19 may be an option if deemed appropriate given other medications and clinical considerations."
  • "Elevated concentrations of these drugs have been observed in poor metabolizers, which may increase the risk of adverse drug reactions. To potentially prevent an adverse effect, an alternative SSRI not extensively metabolized by CYP2C19 should be considered. If citalopram or escitalopram is warranted an initial dosage decrease of 50% should be considered. For citalopram, the FDA recommends a 50% dose reduction (or a maximum dose of 20 mg/day in adults) for CYP2C19 poor metabolizers due to risk of QT prolongation (the FDA recommendation does not apply to escitalopram)."
  • "The recommendations in the guideline and below apply primarily to actions based on genetic tests only; drug interactions and other clinical factors can have a major influence for prescribing decisions for SSRIs and should be taken into consideration before initiating drug therapy."
  • "Data describing the relationship between CYP2D6 or CYP2C19 genotype and SSRI systemic exposure or steady state plasma concentrations in pediatric patients are scarce...CYP2C19 activity may be increased in children relative to adults; therefore, these recommendations should be used with caution in children and accompanied by close monitoring."
• Download and read:
  • Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors
  • 2015 Supplement
  • 2015 CYP2C19 SSRI translation table
  • CYP2C19 frequency table legend
  • CYP2C19 frequency table

Table 1: Dosing recommendations for citalopram and escitalopram based on CYP2C19 phenotype:

Adapted from Tables 1 and 3a of the 2015 guideline manuscript.

^a Rating scheme described in Supplement.

^b CYP2C19 metabolizer status frequencies are based on average multi-ethnic frequency.

^c Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

^d The predicted metabolizer phenotype for the*2/*17 genotypes is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2. See Supplemental Materials for a more comprehensive list of predicted metabolizer phenotypes.

^e Per the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

^f Percent dose adjustments corresponding to percent difference in oral clearances have been calculated/estimated by Stingl et al. [Article:22565785].

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for escitalopram based on the CYP2C19 genotype [Article:21412232]. They conclude to monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine) for the CYP2C19 UM phenotype.

• *See Methods or [Article:18253145] for definition of "good quality."
• Please see attached PDF for detailed information about the evaluated studies: Escitalopram CYP2C19

Annotation

Escitalopram (Lexapro) is indicated for the treatment of acute and maintenance treatment of major depressive disorder in adults and adolescents aged 12-17 years and for acute treatment of generalized anxiety disorder. Excerpts from the escitalopram drug label:

The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.

In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram.

...steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the escitalopram drug label.

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

Annotation

Please note that the information contained within this drug label annotation is available through a collaboration with the Japanese Society of Pharmacogenomics, who provided a translation of the pharmacogenetic information contained in the PMDA package insert.

Excerpts from the package insert for escitalopram:

The recommended dose is 10 mg maximum in patients with hepatic impairment, elderly patients and those with genetically absent CYP2C19 activity (poor metabolizers) as these patients are at increased risk of developing QT prolongation and other side effects due to increased plasma concentrations of this product.

After 21 days of dosing, Cmax, AUC and T1/2 were about 2-fold higher in the CYP2C19 PM group compared to the CYP2C19 EM group...

After repeated oral dosing of 10 mg once daily for 21 days in healthy patients (5 CYP2C19 PMs and 5 EMs), the amount of escitalopram excreted in urine by 24 hours after final dosing was 17.4% of administered dosage in the CYP2C19 EM group and 30.7% in the CYP2C19 PM group...

CYP2D6 (Data from non-Japanese subjects). Oral or intravenous administration of the product in healthy adults resulted in a 1.2-fold increase in Cmax and a 1.3-fold increase in AUC compared to CYP2D6 EMs in 1 of 8 CYP2D6 PMs, but Cmax and AUC in the other 7 subjects were similar to those of CYP2D6 EMs.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the escitalopram package insert (in Japanese).

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