Chemical: Drug

citalopram

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 citalopram based on 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: Citalopram CYP2C19

Annotation

Citalopram (Celexa) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class. The FDA-approved drug label for citalopram highlights information regarding CYP2C19 poor metabolizers, as well as information about usage of drugs that inhibit CYP2D6. Both enzymes are responsible for citalopram metabolism.

Excerpts from the citalopram drug label:

In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively. Celexa 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation.

In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of Celexa (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with Celexa.

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

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

Annotation

Citalopram is indicated for treatment of depressive illness. Excerpts from the citalopram product monograph:

CYP2C19 Poor Metabolisers: An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers of CYP2C19. The dose may be increased to a maximum of 20 mg daily depending on individual patient response.

In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. An initial dose of 10 mg is recommended for known poor metabolisers of CYP2C19.

For the complete product monograph text with sections containing pharmacogenetic information highlighted, see the citalopram product monograph.

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